Tropical Medicine publications 2017

Toda M, Njeru I, Zurovac D, Kareko D, O-Tipo S, Mwau M, Morita K. 2017. Understanding mSOS: A qualitative study examining the implementation of a text-messaging outbreak alert system in rural Kenya. PLoS One, 12 (6), pp. e0179408. | Citations: 1 (Scopus) | Show Abstract | Read more

Outbreaks of epidemic diseases pose serious public health risks. To overcome the hurdles of sub-optimal disease surveillance reporting from the health facilities to relevant authorities, the Ministry of Health in Kenya piloted mSOS (mobile SMS-based disease outbreak alert system) in 2013-2014. In this paper, we report the results of the qualitative study, which examined factors that influence the performances of mSOS implementation. In-depth interviews were conducted with 11 disease surveillance coordinators and 32 in-charges of rural health facilities that took part in the mSOS intervention. Drawing from the framework analysis, dominant themes that emerged from the interviews are presented. All participants voiced their excitement in using mSOS. The results showed that the technology was well accepted, easy to use, and both health workers and managers unanimously recommended the scale-up of the system despite challenges encountered in the implementation processes. The most challenging components were the context in which mSOS was implemented, including the lack of strong existing structure for continuous support supervision, feedback and response action related to disease surveillance. The study revealed broader health systems issues that should be addressed prior to and during the intervention scale-up.

Juel HB, Thomaides-Brears HB, Darton TC, Jones C, Jones E, Shrestha S, Sie R, Eustace A, Galal U, Kurupati P et al. 2017. Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model. Front Immunol, 8 (JAN), pp. 1916. | Show Abstract | Read more

Effective vaccines againstSalmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of twoSalmonellaTyphi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge withS. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-typeS. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-typeS. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid.

Le Thi Phuong T, Rattanavong S, Vongsouvath M, Davong V, Phu Huong Lan N, Campbell JI, Darton TC, Thwaites GE, Newton PN, Dance DAB, Baker S. 2017. Non-typhoidal Salmonella serovars associated with invasive and non-invasive disease in the Lao People's Democratic Republic. Trans R Soc Trop Med Hyg, 111 (9), pp. 418-424. | Show Abstract | Read more

Background: Invasive non-typhoidal Salmonella (iNTS) disease is a well-described cause of mortality in children and human immunodeficiency virus (HIV)-infected adults in sub-Saharan Africa. Additionally, there is an ill-defined burden of iNTS disease in Southeast Asia. Methods: Aiming to investigate the causative serovars of non-invasive and iNTS disease and their associated antimicrobial susceptibility profiles in the Lao People's Democratic Republic, we performed multilocus sequence typing and antimicrobial susceptibility profiling on 168 NTS (63 blood and 105 faecal) organisms isolated in Lao between 2000 and 2012. Results: Six different serovars were isolated from blood; Salmonella enterica serovar Enteritidis (n=28), S. enterica serovar Typhimurium (n=19) and S. enterica serovar Choleraesuis (n=11) accounted for >90% (58/63) of the iNTS disease cases. In contrast, the isolates from diarrhoeal faeces were comprised of 18 different serovars, the mostly commonly identified being S. enterica Typhimurium (n=28), S. enterica Weltevreden (n=14) and S. enterica Stanley (n=15). S. enterica Enteritidis and S. enterica Choleraesuis were significantly more associated with systemic disease than diarrhoeal disease in this patient group (p<0.001). Conclusions: We find a differing distribution of Salmonella sequence types/serovars between those causing iNTS disease and non-invasive disease in Lao. We conclude that there is a small but not insignificant burden of iNTS disease in Lao. Further clinical and epidemiological investigations are required to assess mortality and the role of comorbidities such as HIV.

Vijay S, Hai HT, Thu DDA, Johnson E, Pielach A, Phu NH, Thwaites GE, Thuong NTT. 2017. Ultrastructural Analysis of Cell Envelope and Accumulation of Lipid Inclusions in Clinical Mycobacterium tuberculosis Isolates from Sputum, Oxidative Stress, and Iron Deficiency. Front Microbiol, 8 (JAN), pp. 2681. | Show Abstract | Read more

Introduction: Mycobacteria have several unique cellular characteristics, such as multiple cell envelope layers, elongation at cell poles, asymmetric cell division, and accumulation of intracytoplasmic lipid inclusions, which contributes to their survival under stress conditions. However, the understanding of these characteristics in clinical Mycobacterium tuberculosis (M. tuberculosis) isolates and under host stress is limited. We previously reported the influence of host stress on the cell length distribution in a large set of clinical M. tuberculosis isolates (n = 158). Here, we investigate the influence of host stress on the cellular ultrastructure of few clinical M. tuberculosis isolates (n = 8) from that study. The purpose of this study is to further understand the influence of host stress on the cellular adaptations of clinical M. tuberculosis isolates. Methods: We selected few M. tuberculosis isolates (n = 8) for analyzing the cellular ultrastructure ex vivo in sputum and under in vitro stress conditions by transmission electron microscopy. The cellular adaptations of M. tuberculosis in sputum were correlated with the ultrastructure of antibiotic sensitive and resistant isolates in liquid culture, under oxidative stress, iron deficiency, and exposure to isoniazid. Results: In sputum, M. tuberculosis accumulated intracytoplasmic lipid inclusions. In liquid culture, clinical M. tuberculosis revealed isolate to isolate variation in the extent of intracytoplasmic lipid inclusions, which were absent in the laboratory strain H37Rv. Oxidative stress, iron deficiency, and exposure to isoniazid increased the accumulation of lipid inclusions and decreased the thickness of the cell envelope electron transparent layer in M. tuberculosis cells. Furthermore, intracytoplasmic compartments were observed in iron deficient cells. Conclusion: Our ultrastructural analysis has revealed significant influence of host stress on the cellular adaptations in clinical M. tuberculosis isolates. These adaptations may contribute to the survival of M. tuberculosis under host and antibiotic stress conditions. Variation in the cellular adaptations among clinical M. tuberculosis isolates may correlate with their ability to persist in tuberculosis patients during antibiotic treatment. These observations indicate the need for further analyzing these cellular adaptations in a large set of clinical M. tuberculosis isolates. This will help to determine the significance of these cellular adaptations in the tuberculosis treatment.

Phu VD, Nadjm B, Duy NHA, Co DX, Mai NTH, Trinh DT, Campbell J, Khiem DP, Quang TN, Loan HT et al. 2017. Ventilator-associated respiratory infection in a resource-restricted setting: impact and etiology. J Intensive Care, 5 pp. 69. | Show Abstract | Read more

Background: Ventilator-associated respiratory infection (VARI) is a significant problem in resource-restricted intensive care units (ICUs), but differences in casemix and etiology means VARI in resource-restricted ICUs may be different from that found in resource-rich units. Data from these settings are vital to plan preventative interventions and assess their cost-effectiveness, but few are available. Methods: We conducted a prospective observational study in four Vietnamese ICUs to assess the incidence and impact of VARI. Patients ≥ 16 years old and expected to be mechanically ventilated > 48 h were enrolled in the study and followed daily for 28 days following ICU admission. Results: Four hundred fifty eligible patients were enrolled over 24 months, and after exclusions, 374 patients' data were analyzed. A total of 92/374 cases of VARI (21.7/1000 ventilator days) were diagnosed; 37 (9.9%) of these met ventilator-associated pneumonia (VAP) criteria (8.7/1000 ventilator days). Patients with any VARI, VAP, or VARI without VAP experienced increased hospital and ICU stay, ICU cost, and antibiotic use (p < 0.01 for all). This was also true for all VARI (p < 0.01 for all) with/without tetanus. There was no increased risk of in-hospital death in patients with VARI compared to those without (VAP HR 1.58, 95% CI 0.75-3.33, p = 0.23; VARI without VAP HR 0.40, 95% CI 0.14-1.17, p = 0.09). In patients with positive endotracheal aspirate cultures, most VARI was caused by Gram-negative organisms; the most frequent were Acinetobacter baumannii (32/73, 43.8%) Klebsiella pneumoniae (26/73, 35.6%), and Pseudomonas aeruginosa (24/73, 32.9%). 40/68 (58.8%) patients with positive cultures for these had carbapenem-resistant isolates. Patients with carbapenem-resistant VARI had significantly greater ICU costs than patients with carbapenem-susceptible isolates (6053 USD (IQR 3806-7824) vs 3131 USD (IQR 2108-7551), p = 0.04) and after correction for adequacy of initial antibiotics and APACHE II score, showed a trend towards increased risk of in-hospital death (HR 2.82, 95% CI 0.75-6.75, p = 0.15). Conclusions: VARI in a resource-restricted setting has limited impact on mortality, but shows significant association with increased patient costs, length of stay, and antibiotic use, particularly when caused by carbapenem-resistant bacteria. Evidence-based interventions to reduce VARI in these settings are urgently needed.

Turner P, Suy K, Tan LV, Sar P, Miliya T, Hong NTT, Hang VTT, Ny NTH, Soeng S, Day NPJ et al. 2017. The aetiologies of central nervous system infections in hospitalised Cambodian children. BMC Infect Dis, 17 (1), pp. 806. | Show Abstract | Read more

BACKGROUND: Central nervous system (CNS) infections are an important cause of childhood morbidity and mortality. The aetiologies of these potentially vaccine-preventable infections have not been well established in Cambodia. METHODS: We did a one year prospective study of children hospitalised with suspected CNS infection at Angkor Hospital for Children, Siem Reap. Cerebrospinal fluid specimens (CSF) samples underwent culture, multiplex PCR and serological analysis to identify a range of bacterial and viral pathogens. Viral metagenomics was performed on a subset of pathogen negative specimens. RESULTS: Between 1st October 2014 and 30th September 2015, 284 analysable patients were enrolled. The median patient age was 2.6 years; 62.0% were aged <5 years. CSF white blood cell count was ≥10 cells/μL in 116/272 (42.6%) cases. CNS infection was microbiologically confirmed in 55 children (19.3%). Enteroviruses (21/55), Japanese encephalitis virus (17/55), and Streptococcus pneumoniae (7/55) accounted for 45 (81.8%) of all pathogens identified. Of the pathogens detected, 74.5% (41/55) were viruses and 23.6% (13/55) were bacteria. The majority of patients were treated with ceftriaxone empirically. The case fatality rate was 2.5%. CONCLUSIONS: Enteroviruses, JEV and S. pneumoniae are the most frequently detected causes of CNS infection in hospitalised Cambodian children.

Chernet A, Hensch N-P, Kling K, Sydow V, Hatz C, Paris DH, Rentsch K, Nickel B, Neumayr A, Labhardt ND. 2017. Serum 25-hydroxyvitamin D levels and intramuscular vitamin D3 supplementation among Eritrean migrants recently arrived in Switzerland. Swiss Med Wkly, 147 pp. w14568. | Show Abstract | Read more

In a cross-sectional screening programme, we assessed serum vitamin D levels in adult Eritrean refugees recently arrived in Switzerland. Median vitamin D level among 107 participants (95 males and 12 females) was 27 nmol/l (interquartile range 23-42 nmol/l), 86% had insufficient vitamin D levels (≤50 nmol/l) and 36% severe deficiency (<25 nmol/l). In 29 participants who received single-dose intramuscular vitamin D substitution (300 000 IU), median vitamin D levels increased from 25 to 35 nmol/l after 3 months (p = 0.005); only 11 (38%) reached sufficient vitamin D levels. Eritrean migrants should be routinely screened for vitamin D deficiency. Single-dose intramuscular supplementation appeared to be insufficient to achieve optimal levels in the majority of participants.

Roberts DJ, Cafferkey J, Plugge E. 2017. Cochrane systematic reviews of interventions for risk factors correlate weakly with global risk factor burden: a cross-sectional study. J Clin Epidemiol, | Show Abstract | Read more

BACKGROUND AND OBJECTIVES: Systematic reviews (SRs) are important for health-care decision-makers requiring evidence for interventions that target modifiable risk factors to prevent disease. We investigated whether Cochrane SR output correlated with risk factor burden as assessed by the Global Burden of Disease Study 2015. METHODS: We screened and extracted data from Cochrane reviews and protocols published since January 2011 investigating modifiable risk factors as outcomes. We calculated Spearman's rank correlation between number of occasions a risk factor was an SR outcome and that risk factor's global disease burden in disability-adjusted life years (DALYs). We also calculated standardized Pearson residuals (SPRs) of the variance between the observed and expected frequency of a risk factor featuring as an outcome. RESULTS: We obtained 400 unique SRs and 174 unique protocols from 6,392 Cochrane publications. Risk factors were an outcome a total of 965 times. The number of SR outcomes and DALYs per risk factor shared a weak-positive correlation (r = 0.45) for all risk factors, but was high (r = 0.83) for metabolic risks, similar for behavioral risks (r = 0.46), and weak negative for occupational and environmental risks (r = -0.40). SPRs for "high total cholesterol", "low bone mineral density", "alcohol and drug use" , and "child and maternal malnutrition" inferred a higher than expected frequency of outcomes, and for "air pollution", "dietary risk", and "unsafe water, sanitation, and hand-washing", fewer than expected. CONCLUSION: Our study investigated whether Cochrane risk factor SRs align with global risk factor burden, demonstrating a weak-positive correlation. Interventions modifying air pollution and dietary risks were sparsely studied, given disease burden.

Khan AM, Hu Y, Miotto O, Thevasagayam NM, Sukumaran R, Abd Raman HS, Brusic V, Tan TW, Thomas August J. 2017. Analysis of viral diversity for vaccine target discovery. BMC Med Genomics, 10 (Suppl 4), pp. 78. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Viral vaccine target discovery requires understanding the diversity of both the virus and the human immune system. The readily available and rapidly growing pool of viral sequence data in the public domain enable the identification and characterization of immune targets relevant to adaptive immunity. A systematic bioinformatics approach is necessary to facilitate the analysis of such large datasets for selection of potential candidate vaccine targets. RESULTS: This work describes a computational methodology to achieve this analysis, with data of dengue, West Nile, hepatitis A, HIV-1, and influenza A viruses as examples. Our methodology has been implemented as an analytical pipeline that brings significant advancement to the field of reverse vaccinology, enabling systematic screening of known sequence data in nature for identification of vaccine targets. This includes key steps (i) comprehensive and extensive collection of sequence data of viral proteomes (the virome), (ii) data cleaning, (iii) large-scale sequence alignments, (iv) peptide entropy analysis, (v) intra- and inter-species variation analysis of conserved sequences, including human homology analysis, and (vi) functional and immunological relevance analysis. CONCLUSION: These steps are combined into the pipeline ensuring that a more refined process, as compared to a simple evolutionary conservation analysis, will facilitate a better selection of vaccine targets and their prioritization for subsequent experimental validation.

Maina JK, Macharia PM, Ouma PO, Snow RW, Okiro EA. 2017. Coverage of routine reporting on malaria parasitological testing in Kenya, 2015-2016. Glob Health Action, 10 (1), pp. 1413266. | Show Abstract | Read more

BACKGROUND: Following the launch of District Health Information System 2 across facilities in Kenya, more health facilities are now capable of carrying out malaria parasitological testing and reporting data as part of routine health information systems, improving the potential value of routine data for accurate and timely tracking of rapidly changing disease epidemiology at fine spatial resolutions. OBJECTIVES: This study evaluates the current coverage and completeness of reported malaria parasitological testing data in DHIS2 specifically looking at patterns in geographic coverage of public health facilities in Kenya. METHODS: Monthly facility level data on malaria parasitological testing were extracted from Kenya DHIS2 between November 2015 and October 2016. DHIS2 public facilities were matched to a geo-coded master facility list to obtain coordinates. Coverage was defined as the geographic distribution of facilities reporting any data by region. Completeness of reporting was defined as the percentage of facilities reporting any data for the whole 12-month period or for 3, 6 and 9 months. RESULTS: Public health facilities were 5,933 (59%) of 10,090 extracted. Fifty-nine per Cent of the public facilities did not report any data while 36, 29 and 22% facilities had data reported at least 3, 6 and 9 months, respectively. Only 8% of public facilities had data reported for every month. There were proportionately more hospitals (86%) than health centres (76%) and dispensaries/clinics (30%) reporting. There were significant geographic variations in reporting rates. Counties along the malaria endemic coast had the lowest reporting rate with only 1% of facilities reporting consistently for 12 months. CONCLUSION: Current coverage and completeness of reporting of malaria parasitological diagnosis across Kenya's public health system remains poor. The usefulness of routine data to improve our understanding of sub-national heterogeneity across Kenya would require significant improvements to the consistency and coverage of data captured by DHIS2.

Kingston HW, Ghose A, Plewes K, Ishioka H, Leopold SJ, Maude RJ, Paul S, Intharabut B, Silamut K, Woodrow C et al. 2017. Disease Severity and Effective Parasite Multiplication Rate in Falciparum Malaria. Open Forum Infect Dis, 4 (4), pp. ofx169. | Show Abstract | Read more

Patients presenting with severe falciparum malaria in a Bangladeshi tertiary hospital had higher total parasite burden, estimated by parasitemia and plasma PfHRP2, than uncomplicated malaria patients despite shorter fever duration. This suggests that higher parasite multiplication rates (PMR) contribute to causing the higher biomass found in severe disease. Compared with patients without a history of previous malaria, patients with previous malaria carried a lower parasite biomass with similar fever duration at presentation, suggesting that host immunity reduces the PMR.

Hancock G, Morón-López S, Kopycinski J, Puertas MC, Giannoulatou E, Rose A, Salgado M, Hayton E-J, Crook A, Morgan C et al. 2017. Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects. J Int AIDS Soc, 20 (1), pp. 21171. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). METHODS: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination. RESULTS: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos inex vivoElispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group. CONCLUSIONS: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent. CLINICAL TRIALS REGISTRATION: NCT01024842.

Muraya KW, Jones C, Berkley JA, Molyneux S. 2017. "If it's issues to do with nutrition…I can decide…": gendered decision-making in joining community-based child nutrition interventions within rural coastal Kenya. Health Policy Plan, 32 (suppl_5), pp. v31-v39. | Show Abstract | Read more

Gender roles and relations play an important role in child health and nutritional status. While there is increasing recognition of the need to incorporate gender analysis in health planning and programme development, there has been relatively little attention paid to the gendered nature of child nutrition interventions. This qualitative study undertaken in rural Coastal Kenya aimed to explore the interaction between household gender relations and a community-based child nutrition programme, with a focus on household decision-making dynamics related to joining the intervention. Fifteen households whose children were enrolled in the programme were followed up over a period of 12 months. Over a total of 60 household visits, group and individual in-depth interviews were conducted with a range of respondents, supplemented by non-participant observations. Data were analysed using a framework analysis approach. Engagement with the intervention was highly gendered with women being the primary decision-makers and engagers. Women were responsible for managing child feeding and minor child illnesses in households. As such, involvement in community-based nutrition interventions and particularly one that targeted a condition perceived as non-serious, fell within women's domain. Despite this, the nutrition programme of interest could be categorized as gender-blind. Gender was not explicitly considered in the design and implementation of the intervention, and the gender roles and norms in the community with regards to child nutrition were not critically examined or challenged. In fact, the intervention might have inadvertently reinforced existing gender divisions and practices in relation to child nutrition, by (unintentionally) excluding men from the nutrition discussions and activities, and thereby supporting the notion of child feeding and nutrition as "women's business". To improve outcomes, community-based nutrition interventions need to understand and take into account gendered household dynamics, and incorporate strategies that promote behaviour change and attitude shifts in relation to gendered norms and child nutrition.

Saito M, Gilder ME, Nosten F, Guérin PJ, McGready R. 2017. Methodology of assessment and reporting of safety in anti-malarial treatment efficacy studies of uncomplicated falciparum malaria in pregnancy: a systematic literature review. Malar J, 16 (1), pp. 491. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. METHODS: Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). RESULTS: Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/48) followed participants through to pregnancy outcome. Fetal loss was assessed in 34 studies (89%, 34/38), but the definition of miscarriage and stillbirth were defined only in 11 (32%, 11/34) and 7 (21%, 7/34) studies, respectively. Preterm birth was assessed in 26 studies (68%, 26/38) but was defined in 16 studies (62%, 16/26). Newborn weight was assessed in 30 studies (79%, 30/38) and length in 10 studies (26%, 10/38). Assessment of birth weight took gestational age into account in four studies (13%, 4/30). Congenital abnormalities were reported in 32 studies (84%, 32/38). Other common risk factors for adverse pregnancy outcomes were not well-reported. CONCLUSION: Incomplete reporting and varied methodological assessment of pregnancy outcomes in anti-malarial drug efficacy studies limits comparison across studies. A standard list of minimal necessary parameters to assess and report the safety component of efficacy studies of anti-malarials in pregnancy is proposed.

ACTwatch Group, Ujuju C, Anyanti J, Newton PN, Ntadom G. 2017. When it just won't go away: oral artemisinin monotherapy in Nigeria, threatening lives, threatening progress. Malar J, 16 (1), pp. 489. | Show Abstract | Read more

BACKGROUND: Oral artemisinin monotherapy (AMT), an important contributor to multi-drug resistant malaria, has been banned in Nigeria. While oral AMT has scarcely been found for several years now in other malaria-endemic countries, availability has persisted in Nigeria's private sector. In 2015, the ACTwatch project conducted a nationally representative outlet survey. Results from the outlet survey show the extent to which oral AMT prevails in Nigeria's anti-malarial market, and provide key product information to guide strategies for removal. RESULTS: Between August 10th and October 3rd, 2015 a total of 13,480 outlets were screened for availability of anti-malarials and/or malaria blood testing services. Among the 3624 anti-malarial outlets, 33,539 anti-malarial products were audited, of which 1740 were oral AMT products, primarily artesunate (n = 1731). Oral AMT was imported from three different countries (Vietnam, China and India), representing six different manufacturers and 11 different brands. Availability of oral AMT was highest among pharmacies (84.0%) and Patent Propriety Medicine Vendors (drug stores, PPMVs) (38.7%), and rarely found in the public sector (2.0%). Oral AMT consisted of 2.5% of the national anti-malarial market share. Of all oral AMT sold or distributed, 52.3% of the market share comprised of a Vietnamese product, Artesunat®, manufactured by Mekophar Chemical Pharmaceutical Joint Stock Company. A further 35.1% of the market share were products from China, produced by three different manufacturers and 12.5% were from India by one manufacturer, Medrel Pharmaceuticals. Most of the oral AMT was distributed by PPMVs accounting for 82.2% of the oral AMT market share. The median price for a package of artesunate ($1.78) was slightly more expensive than the price of quality-assured (QA) artemether lumefantrine (AL) for an adult ($1.52). The median price for a package of artesunate suspension ($2.54) was three times more expensive than the price of a package of QA AL for a child ($0.76). CONCLUSION: Oral AMT is commonly available in Nigeria's private sector. Cessation of oral AMT registration and enforcement of the oral AMT ban for removal from the private sector are needed in Nigeria. Strategies to effectively halt production and export are needed in Vietnam, China and India.

Kalnoky M, Bancone G, Kahn M, Chu CS, Chowwiwat N, Wilaisrisak P, Pal S, LaRue N, Leader B, Nosten F, Domingo GJ. 2017. Cytochemical flow analysis of intracellular G6PD and aggregate analysis of mosaic G6PD expression. Eur J Haematol, | Show Abstract | Read more

BACKGROUND: Medicines that exert oxidative pressure on red blood cells (RBC) can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Due to X-chromosome inactivation, females heterozygous for G6PD with 1 allele encoding a G6PD-deficient protein and the other a normal protein produce 2 RBC populations each expressing exclusively 1 allele. The G6PD mosaic is not captured with routine G6PD tests. METHODS: An open-source software tool for G6PD cytofluorometric data interpretation is described. The tool interprets data in terms of % bright RBC, or cells with normal G6PD activity in specimens collected from 2 geographically and ethnically distinct populations, an African American cohort (USA) and a Karen and Burman ethnic cohort (Thailand) comprising 242 specimens including 89 heterozygous females. RESULTS: The tool allowed comparison of data across 2 laboratories and both populations. Hemizygous normal or deficient males and homozygous normal or deficient females cluster at narrow % bright cells with mean values of 96%, or 6% (males) and 97%, or 2% (females), respectively. Heterozygous females show a distribution of 10-85% bright cells and a mean of 50%. The distributions are associated with the severity of the G6PD mutation. CONCLUSIONS: Consistent cytofluorometric G6PD analysis facilitates interlaboratory comparison of cellular G6PD profiles and contributes to understanding primaquine-associated hemolytic risk.

Haniffa R, Pubudu De Silva A, de Azevedo L, Baranage D, Rashan A, Baelani I, Schultz MJ, Dondorp AM, Dünser MW. 2017. Improving ICU services in resource-limited settings: Perceptions of ICU workers from low-middle-, and high-income countries. J Crit Care, 44 pp. 352-356. | Show Abstract | Read more

PURPOSE: To evaluate perceptions of intensive care unit (ICU) workers from low-and-middle income countries (LMICs) and high income countries (HICs). MATERIALS AND METHODS: A cross sectional design. Data collected from doctors using an anonymous online, questionnaire. RESULTS: Hundred seventy-five from LMICs and 43 from HICs participated. Barriers in LMICs were lack of formal training (Likert score median 3 [inter quartile range 3]), lack of nurses (3[3]) and low wages (3[4]). Strategies for LMICs improvement were formal training of ICU staff (4[3]), an increase in number of ICU nurses (4[2]), collection of outcome data (3[4]), as well as maintenance of available equipment [3(3)]. The most useful role of HIC ICU staff was training of LMIC staff (4[2]). Donation of equipment [2(4)], drugs [2(4)], and supplies (2[4]) perceived to be of limited usefulness. The most striking difference between HIC and LMIC staff was the perception on the lack of physician leadership as an obstacle to ICU functioning (4[3] vs. 0[2], p<0.005). CONCLUSION: LMICs ICU workers perceived lack of training, lack of nurses, and low wages as major barriers to functioning. Training, increase of nurse workforce, and collection of outcome data were proposed as useful strategies to improve LMIC ICU services.

Wilder-Smith A, Preet R, Renhorn KE, Ximenes RA, Rodrigues LC, Solomon T, Neyts J, Lambrechts L, Willison H, Peeling R et al. 2017. ZikaPLAN: Zika Preparedness Latin American Network. Glob Health Action, 10 (1), pp. 1398485. | Show Abstract | Read more

The ongoing Zika virus (ZIKV) outbreak in Latin America, the Caribbean, and the Pacific Islands has underlined the need for a coordinated research network across the whole region that can respond rapidly to address the current knowledge gaps in Zika and enhance research preparedness beyond Zika. The European Union under its Horizon 2020 Research and Innovation Programme awarded three research consortia to respond to this need. Here we present the ZikaPLAN (Zika Preparedness Latin American Network) consortium. ZikaPLAN combines the strengths of 25 partners in Latin America, North America, Africa, Asia, and various centers in Europe. We will conduct clinical studies to estimate the risk and further define the full spectrum and risk factors of congenital Zika virus syndrome (including neurodevelopmental milestones in the first 3 years of life), delineate neurological complications associated with ZIKV due to direct neuroinvasion and immune-mediated responses in older children and adults, and strengthen surveillance for birth defects and Guillain-Barré Syndrome. Laboratory-based research to unravel neurotropism and investigate the role of sexual transmission, determinants of severe disease, and viral fitness will underpin the clinical studies. Social messaging and engagement with affected communities, as well as development of wearable repellent technologies against Aedes mosquitoes will enhance the impact. Burden of disease studies, data-driven vector control, and vaccine modeling as well as risk assessments on geographic spread of ZIKV will form the foundation for evidence-informed policies. While addressing the research gaps around ZIKV, we will engage in capacity building in laboratory and clinical research, collaborate with existing and new networks to share knowledge, and work with international organizations to tackle regulatory and other bottlenecks and refine research priorities. In this way, we can leverage the ZIKV response toward building a long-term emerging infectious diseases response capacity in the region to address future challenges.

Sengvilaipaseuth O, Castonguay-Vanier J, Chanthongthip A, Phonemixay O, Thongpaseuth S, Vongsouvath M, Newton PN, Bharucha T, Dubot-Pérès A. 2017. Poor performance of two rapid immunochromatographic assays for anti-Japanese encephalitis virus immunoglobulin M detection in cerebrospinal fluid and serum from patients with suspected Japanese encephalitis virus infection in Laos. Trans R Soc Trop Med Hyg, 111 (8), pp. 373-377. | Show Abstract | Read more

Background: Japanese encephalitis virus (JEV) is a leading identified cause of encephalitis in Asia, often occurring in rural areas with poor access to laboratory diagnostics. We evaluated two rapid diagnostic tests (RDTs) for anti-JEV immunoglobulin M (IgM) detection. Methods: Consecutive cerebrospinal fluid and serum from 388 patients (704 samples) with suspected JEV infections admitted to six hospitals in Laos were tested with one of two SD-Bioline anti-JEV IgM RDTs and the World Health Organization standard anti-JEV IgM enzyme-linked immunosorbent assay (ELISA; Panbio Japanese Encephalitis-Dengue IgM Combo ELISA. Results and Conclusions: The performance of both RDTs showed strikingly low sensitivity in comparison to anti-JEV IgM antibody capture ELISA (2.1-51.4%), suggesting low sensitivity of the RDTs. We highlight the fundamental prerequisite to validate RDTs prior to use to ensure that they meet standards for testing.

Saito M, Gilder ME, Nosten F, McGready R, Guérin PJ. 2017. Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges. Malar J, 16 (1), pp. 488. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: There is no agreed standard method to assess the efficacy of anti-malarials for uncomplicated falciparum in pregnancy despite an increased risk of adverse outcomes for the mother and the fetus. The aim of this review is to present the currently available evidence from both observational and interventional cohort studies on anti-malarial efficacy in pregnancy and summarize the variability of assessment and reporting found in the review process. METHODS: Efficacy methodology and assessment of artemisinin-based treatments (ABT) and quinine-based treatments (QBT) were reviewed systematically using seven databases and two clinical trial registries (protocol registration-PROSPERO: CRD42017054808). Pregnant women in all trimesters with parasitologically confirmed uncomplicated falciparum malaria were included irrespective of symptoms. This review attempted to re-calculate proportions of treatment success applying the same definition as the standard WHO methodology for non-pregnant populations. Aggregated data meta-analyses using data from randomized control trials (RCTs) comparing different treatments were performed by random effects model. RESULTS: A total of 48 eligible efficacy studies were identified including 7279 treated Plasmodium falciparum episodes. While polymerase chain reaction (PCR) was used in 24 studies for differentiating recurrence, the assessment and reporting of treatment efficacy was heterogeneous. When the same definition could be applied, PCR-corrected treatment failure of ≥ 10% at any time points was observed in 3/30 ABT and 3/7 QBT arms. Ten RCTs compared different combinations of ABT but there was a maximum of two published RCTs with PCR-corrected outcomes for each comparison. Five RCTs compared ABT and QBT. Overall, the risk of treatment failure was significantly lower in ABT than in QBT (risk ratio 0.22, 95% confidence interval 0.07-0.63), although the actual drug combinations and outcome endpoints were different. First trimester women were included in 12 studies none of which were RCTs of ABT. CONCLUSIONS: Efficacy studies in pregnancy are not only limited in number but use varied methodological assessments. In five RCTs with comparable methodology, ABT resulted in higher efficacy than QBT in the second and third trimester of pregnancy. Individual patient data meta-analysis can include data from observational cohort studies and could overcome some of the limitations of the current assessment given the paucity of data in this vulnerable group.

Beane A, De Silva AP, Munasinghe S, De Silva N, Arachchige SJ, Athapattu P, Sigera PC, Miskin MF, Liyanagama PM, Rathnayake RMD et al. 2017. Comparison of quick sequential organ failure assessment and modified systemic inflammatory response syndrome criteria in a lower middle income setting Journal of Acute Medicine, 7 (4), pp. 141-148. | Show Abstract | Read more

Introduction: Quick Sequential Organ Failure Assessment (qSOFA) is potentially feasible tool to identify risk of deteriorating in the context of infection for to use in resource limited settings. Purpose: To compare the discriminative ability of qSOFA and a simplified systemic inflammatory response syndrome (SIRS) score to detect deterioration in patients admitted with infection. Methods: Observational study conducted at District General Hospital Monaragala, Sri Lanka, utilising bedside available observations extracted from healthcare records. Discrimination was evaluated using area under the receiver operating curve (AUROC). 15,577 consecutive adult ( ≥ 18 years) admissions were considered. Patients classified as having infection per ICD-10 diagnostic coding were included. Results: Both scores were evaluated for their ability to discriminate patients at risk of death or a composite adverse outcome (death, cardiac arrest, intensive care unit [ICU], admission or critical care transfer). 1844 admissions (11.8%) were due to infections with 20 deaths (1.1%), 29 ICU admissions (1.6%), 30 cardiac arrests and 9 clinical transfers to a tertiary hospital (0.5%). Sixty-seven (3.6%) patients experienced at least one event. Complete datasets were available for qSOFA in 1238 (67.14%) and for simplified SIRS (mSIRS) in 1628 (88.29%) admissions. Mean (SD) qSOFA score and mSIRS score at admission were 0.58 (0.69) and 0.66 (0.79) respectively. Both demonstrated poor discrimination for predicting adverse outcome AUROC = 0.625; 95% CI, 0.56-0.69 and AUROC = 0.615; 95% CI, 0.55- 0.69 respectively) with no significant difference (p value = 0.74). Similarly, both systems had poor discrimination for predicting deaths (AUROC = 0.685; 95% CI, 0.55-0.82 and AUROC = 0.629; 95% CI, 0.50-0.76 respectively) with no statistically significant difference (p value = 0.31). Conclusions: qSOFA at admission had poor discrimination and was not superior to the bedside observations featured in SIRS. Availability of observations, especially for mentation, is poor in these settings and requires strategies to improve reporting.

Aluvaala J, Collins GS, Maina M, Berkley JA, English M. 2017. A systematic review of neonatal treatment intensity scores and their potential application in low-resource setting hospitals for predicting mortality, morbidity and estimating resource use. Syst Rev, 6 (1), pp. 248. | Show Abstract | Read more

BACKGROUND: Treatment intensity scores can predict mortality and estimate resource use. They may therefore be of interest for essential neonatal care in low resource settings where neonatal mortality remains high. We sought to systematically review neonatal treatment intensity scores to (1) assess the level of evidence on predictive performance in predicting clinical outcomes and estimating resource utilisation and (2) assess the applicability of the identified models to decision making for neonatal care in low resource settings. METHODS: We conducted a systematic search of PubMed, EMBASE (OVID), CINAHL, Global Health Library (Global index, WHO) and Google Scholar to identify studies published up until 21 December 2016. Included were all articles that used treatments as predictors in neonatal models. Individual studies were appraised using the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS). In addition, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used as a guiding framework to assess certainty in the evidence for predicting outcomes across studies. RESULTS: Three thousand two hundred forty-nine articles were screened, of which ten articles were included in the review. All of the studies were conducted in neonatal intensive care units with sample sizes ranging from 22 to 9978, with a median of 163. Two articles reported model development, while eight reported external application of existing models to new populations. Meta-analysis was not possible due heterogeneity in the conduct and reporting of the identified studies. Discrimination as assessed by area under receiver operating characteristic curve was reported for in-hospital mortality, median 0.84 (range 0.75-0.96, three studies), early adverse outcome and late adverse outcome (0.78 and 0.59, respectively, one study). CONCLUSION: Existing neonatal treatment intensity models show promise in predicting mortality and morbidity. There is however low certainty in the evidence on their performance in essential neonatal care in low resource settings as all studies had methodological limitations and were conducted in intensive care. The approach may however be developed further for low resource settings like Kenya because treatment data may be easier to obtain compared to measures of physiological status. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016034205.

Trevino SG, Nkhoma SC, Nair S, Daniel BJ, Moncada K, Khoswe S, Banda RL, Nosten F, Cheeseman IH. 2017. High-Resolution Single-Cell Sequencing of Malaria Parasites. Genome Biol Evol, 9 (12), pp. 3373-3383. | Show Abstract | Read more

Single-cell genomics is a powerful tool for determining the genetic architecture of complex communities of unicellular organisms. In areas of high transmission, malaria patients are often challenged by the activities of multiple Plasmodium falciparum lineages, which can potentiate pathology, spread drug resistance loci, and also complicate most genetic analysis. Single-cell sequencing of P. falciparum would be key to understanding infection complexity, though efforts are hampered by the extreme nucleotide composition of its genome (∼80% AT-rich). To counter the low coverage achieved in previous studies, we targeted DNA-rich late-stage parasites by Fluorescence-Activated Cell Sorting and whole genome sequencing. Our method routinely generates accurate, near-complete capture of the 23 Mb P. falciparum genome (mean breadth of coverage 90.7%) at high efficiency. Data from 48 single-cell genomes derived from a polyclonal infection sampled in Chikhwawa, Malawi allowed for unambiguous determination of haplotype diversity and recent meiotic events, information that will aid public health efforts.

Watson CH, Coriakula J, Ngoc DTT, Flasche S, Kucharski AJ, Lau CL, Thieu NTV, le Polain de Waroux O, Rawalai K, Van TT et al. 2017. Social mixing in Fiji: Who-eats-with-whom contact patterns and the implications of age and ethnic heterogeneity for disease dynamics in the Pacific Islands. PLoS One, 12 (12), pp. e0186911. | Show Abstract | Read more

Empirical data on contact patterns can inform dynamic models of infectious disease transmission. Such information has not been widely reported from Pacific islands, nor strongly multi-ethnic settings, and few attempts have been made to quantify contact patterns relevant for the spread of gastrointestinal infections. As part of enteric fever investigations, we conducted a cross-sectional survey of the general public in Fiji, finding that within the 9,650 mealtime contacts reported by 1,814 participants, there was strong like-with-like mixing by age and ethnicity, with higher contact rates amongst iTaukei than non-iTaukei Fijians. Extra-domiciliary lunchtime contacts follow these mixing patterns, indicating the overall data do not simply reflect household structures. Inter-ethnic mixing was most common amongst school-age children. Serological responses indicative of recent Salmonella Typhi infection were found to be associated, after adjusting for age, with increased contact rates between meal-sharing iTaukei, with no association observed for other contact groups. Animal ownership and travel within the geographical division were common. These are novel data that identify ethnicity as an important social mixing variable, and use retrospective mealtime contacts as a socially acceptable metric of relevance to enteric, contact and respiratory diseases that can be collected in a single visit to participants. Application of these data to other island settings will enable communicable disease models to incorporate locally relevant mixing patterns in parameterisation.

Haenssgen MJ, Ariana P. 2017. Healthcare access: A sequence-sensitive approach. SSM Popul Health, 3 pp. 37-47. | Citations: 1 (Scopus) | Show Abstract | Read more

It is widely accepted that healthcare-seeking behaviour is neither limited to nor terminated by access to one single healthcare provider. Yet the sequential conceptualisation of healthcare-seeking processes has not diffused into quantitative research, which continues to analyse healthcare access as a "one-off" event. The ensuing lack of understanding healthcare behaviour is problematic in light of the immense burden of premature death especially in low- and middle-income countries. This paper presents an alternative approach. Based on a novel survey instrument, we analyse original survey data from rural India and China that contain 119 unique healthcare pathways among 637 respondents. We offer three applications of how such sequential data can be analysed to enhance our understanding of people's health behaviour. First, descriptive analysis of sequential data enables more a comprehensive representation of people's health behaviours, for example the time spent in various healthcare activities, common healthcare pathways across different groups, or shifts in healthcare provider access during a typical illness. Second, by analysing the effect of mobile technology on healthcare-seeking process characteristics, we demonstrate that conventional, sequence-insensitive indicators are potentially inconsistent and misleading approximations when compared to a more precise, sequence-sensitive measure. Third, we describe how sequential data enable transparent and flexible evaluations of people's healthcare behaviour. The example of a sequence-insensitive evaluation suggests that household wealth has no statistical link to an illustrative "ideal" form of public healthcare utilisation. In contrast, sequence-sensitive evaluations demonstrate that household wealth is associated with an increased likelihood of bypassing referral processes and approaching unregulated and costly informal and private practitioners before accessing a public clinic. Sequential data therefore do not only reveal otherwise neglected locational idiosyncrasies, but they also yield deeper insights into the drivers of people's health behaviours compared to a conventional approach to "access to healthcare."

Reisman J, Deonarain D, Basnyat B. 2017. Impact of a Newly Constructed Motor Vehicle Road on Altitude Illness in the Nepal Himalayas. Wilderness Environ Med, 28 (4), pp. 332-338. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: This study investigated the impact that motor vehicle travel along a newly constructed road has on altitude illness (including acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema). The new road from Besisahar (760 m) to Manang (3540 m) in Nepal was completed in December 2014. METHODS: We enrolled all patients diagnosed with altitude illness at the Himalayan Rescue Association Manang clinic in fall 2016. Phi coefficients were calculated to test for an association between Nepali ethnicity and rapid ascent by motor vehicle. A retrospective review looked at all patients with altitude illness from fall (September-November) 2010 to spring (February-May) 2016. RESULTS: In fall 2016, more than half (54%) of patients with altitude illness traveled to Manang by motor vehicle, and one-third (33%) reached Manang from low altitude (Besisahar) in less than 48 hours. Nepali nationality had a significant association with motor vehicle travel (phi +0.69, P < .0001) as well as with rapid ascent to Manang (phi +0.72, P < .0001). Compared to previous seasons, fall 2016 saw the most patients diagnosed with altitude illness. The proportion of people with altitude illness who traveled by vehicle and reached Manang in less than 48 hours was significantly greater than the proportion prior to completion of the road (P < .0001 for both). CONCLUSIONS: Rapid ascent by the newly constructed road from Besisahar to Manang appears to be related to a significant increase in the number of patients with all forms of altitude illness, especially among Nepalis. The authors believe that educational interventions emphasizing prevention are urgently needed.

Ong CEL, Wongsuvan G, Chew JSW, Kim TY, Teng LH, Amornchai P, Wuthiekanun V, Day NPJ, Peacock SJ, Cheng TY et al. 2017. Presence of Burkholderia pseudomallei in Soil and Paddy Rice Water in a Rice Field in Northeast Thailand, but Not in Air and Rainwater. Am J Trop Med Hyg, 97 (6), pp. 1702-1705. | Show Abstract | Read more

Environmental Burkholderia pseudomallei has been postulated to be aerosolized during ploughing and heavy rain, and could result in inhalational melioidosis. Here, we determined the presence of B. pseudomallei in soil, paddy field water (PFW), air, and rainwater samples in a single rice paddy field in Ubon Ratchathani, northeast Thailand. In 2012, we collected 100 soil samples during the dry season, 10 PFW samples during the monsoon season, 77 air samples during ploughing (N = 31) and heavy rains (N = 46), and 60 rainwater samples during 12 rain events. We found that 32 soil samples (32%), six PFW samples (60%), and none of the air and rainwater samples were culture positive for B. pseudomallei. Other soil bacteria were isolated from air and rainwater samples. Mean quantitative count of B. pseudomallei estimated from two culture-positive PFW samples was 200 colony forming units/mL. Our findings suggest that the risk of melioidosis acquisition by inhalation in Thailand might be low.

Pava Z, Handayuni I, Trianty L, Utami RAS, Tirta YK, Puspitasari AM, Burdam F, Kenangalem E, Wirjanata G, Kho S et al. 2017. Passively versus Actively Detected Malaria: Similar Genetic Diversity but Different Complexity of Infection. Am J Trop Med Hyg, 97 (6), pp. 1788-1796. | Show Abstract | Read more

The surveillance of malaria is generally undertaken on the assumption that samples passively collected at health facilities are comparable to or representative of the broader Plasmodium reservoir circulating in the community. Further characterization and comparability of the hidden asymptomatic parasite reservoir are needed to inform on the potential impact of sampling bias. This study explores the impact of sampling strategy on molecular surveillance by comparing the genetic make-up of Plasmodium falciparum and Plasmodium vivax isolates collected by passive versus active case detection. Sympatric isolates of P. falciparum and P. vivax were collected from a large community survey and ongoing clinical surveillance studies undertaken in the hypomesoendemic setting of Mimika District (Papua, Indonesia). Plasmodium falciparum isolates were genotyped at nine microsatellite loci and P. vivax at eight loci. Measures of diversity and differentiation were used to compare different patient and parasitological sample groups. The results demonstrated that passively detected cases (symptomatic) had comparable population diversity to those circulating in the community (asymptomatic) in both species. In addition, asymptomatic patent infections were as diverse as subpatent infections. However, a significant difference in multiplicity of infection (MOI) and percentage of polyclonal infections was observed between actively and passively detected P. vivax cases (mean MOI: 1.7 ± 0.7 versus 1.4 ± 1.4, respectively; P = 0.001). The study findings infer that, in hypomesoendemic settings, passive sampling is appropriate for molecular parasite surveillance strategies using the predominant clone in any given infection; however, the findings suggest caution when analyzing complexity of infection. Further evaluation is required in other endemic settings.

Robinson MT, Jatupornpimol N, Sachaphimukh S, Lonnkvist M, Ruecker A, Cheah PY. 2017. The First Pint of Science Festival in Asia SCIENCE COMMUNICATION, 39 (6), pp. 810-820. | Show Abstract | Read more

© 2017, © The Author(s) 2017. The Pint of Science Festival is the largest annual international science festival. So far the event has been held simultaneously in Europe, North America, South America, Africa, and Australia but not in Asia. Pint of Science Thailand was held for the first time this year, in Thailand’s capital, Bangkok. This article briefly discusses some of the successes, challenges, and lessons learnt associated with running the first Pint of Science event in Asia, a culture very different to the Western Hemisphere cities that have currently hosted Pint of Science events.

Kinh NV, Wertheim HFL, Thwaites GE, Khue LN, Thai CH, Khoa NT, Thi Bich Ha N, Trung NV, Crook D, van Doorn HR. 2017. Developing an antimicrobial resistance reference laboratory and surveillance programme in Vietnam. Lancet Glob Health, 5 (12), pp. e1186-e1187. | Citations: 1 (Web of Science Lite) | Read more

Ming DKY, Rattanavong S, Bharucha T, Sengvilaipaseuth O, Dubot-Pérès A, Newton PN, Robinson MT. 2017. Angiostrongylus cantonensis DNA in Cerebrospinal Fluid of Persons with Eosinophilic Meningitis, Laos. Emerg Infect Dis, 23 (12), pp. 2112-2113. | Show Abstract | Read more

Definitive identification of Angiostrongylus cantonensis parasites from clinical specimens is difficult. As a result, regional epidemiology and burden are poorly characterized. To ascertain presence of this parasite in patients in Laos with eosinophilic meningitis, we performed quantitative PCRs on 36 cerebrospinal fluid samples; 4 positive samples confirmed the parasite's presence.

van Doorn HR. 2017. Emerging infectious diseases Medicine, 45 (12), pp. 798-801. | Show Abstract | Read more

© 2017 The spectrum of human pathogens and the infectious diseases they cause is continuously changing through evolution, selection and changes in the way human populations interact with their environment and each other. New human pathogens often emerge or re-emerge from an animal reservoir, emphasizing the central role that non-human reservoirs play in human infectious diseases. Pathogens can also re-emerge with new characteristics, such as multidrug resistance, or in different places, such as Ebola virus in West Africa in 2013 and Zika virus in Brazil in 2015, to cause new epidemics. Most human pathogens have a history of evolution in which they first emerge and cause epidemics, become unstably adapted, re-emerge periodically and then – without intervention – eventually become endemic, with the potential for future outbreaks.

McGivern G, Nzinga J, English M. 2017. 'Pastoral practices' for quality improvement in a Kenyan clinical network. Soc Sci Med, 195 pp. 115-122. | Show Abstract | Read more

We explain social and organisational processes influencing health professionals in a Kenyan clinical network to implement a form of quality improvement (QI) into clinical practice, using the concept of 'pastoral practices'. Our qualitative empirical case study, conducted in 2015-16, shows the way practices constructing and linking local evidence-based guidelines and data collection processes provided a foundation for QI. Participation in these constructive practices gave network leaders pastoral status to then inscribe use of evidence and data into routine care, through championing, demonstrating, supporting and mentoring, with the support of a constellation of local champions. By arranging network meetings, in which the professional community discussed evidence, data, QI and professionalism, network leaders also facilitated the reconstruction of network members' collective professional identity. This consequently strengthened top-down and lateral accountability and inspection practices, disciplining evidence and audit-based QI in local hospitals. By explaining pastoral practices in this way and setting, we contribute to theory about governmentality in health care and extend Foucauldian analysis of QI, clinical networks and governance into low and middle income health care contexts.

Rojek AM, Dunning J, Leliogdowicz A, Castle L, Van Lieshout M, Carson G, Sahr F, Olliaro P, Horby PW. 2017. Regulatory and operational complexities of conducting a clinical treatment trial during an Ebola Virus Disease epidemic. Clin Infect Dis, | Show Abstract | Read more

The first Phase II and III clinical trials for treatments for Ebola Virus Disease were conducted during the west Africa (2013-16) outbreak. We report the operational practicalities of conducting a phase II clinical trial of TKM-130803 to international standards during this outbreak.

Basnyat B, Hofmeyr R, Tölken G, De Decker R. 2017. Acute high-altitude illness. S Afr Med J, 107 (12), pp. 1047-1048. | Show Abstract | Read more

Letter by Basnyat on article by Hofmeyr et al. (Hofmeyr R, Tölken G, De Decker R. Acute high-altitude illness. S Afr J Med 2017;107(7):556-561.; and response by Hofmeyr et al.

Basilico N, Parapini S, Sparatore A, Romeo S, Misiano P, Vivas L, Yardley V, Croft SL, Habluetzel A, Lucantoni L et al. 2017. In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial. Molecules, 22 (12), | Show Abstract | Read more

Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16-53 nM), matched with a high potency against P. vivax field isolates (Mean IC50 29 nM). Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P.berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.

Salje J. 2017. Orientia tsutsugamushi: A neglected but fascinating obligate intracellular bacterial pathogen. PLoS Pathog, 13 (12), pp. e1006657. | Read more

Stirrup OT, Copas AJ, Phillips AN, Gill MJ, Geskus RB, Touloumi G, Young J, Bucher HC, Babiker AG, CASCADE Collaboration in EuroCoord. 2017. Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion. HIV Med, | Show Abstract | Read more

OBJECTIVES: To investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. We make use of all pre-treatment CD4 counts, because analyses using only a single observation at initiation may be subject to biases. METHODS: We used data from the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) multinational cohort collaboration of HIV-1 seroconverters. We analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003-March 2014 (n = 7600 for primary analysis) using a statistical model in which the characteristics of recovery in CD4 counts are determined by multiple predictive factors. Secondary analyses were performed incorporating uncertainty in the exact timing of seroconversion to allow more precise estimation of the benefit of very early treatment initiation. RESULTS: 'True' CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. Allowing for lack of complete certainty in the date of seroconversion, CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post-treatment CD4 recovery. For other patient and drug characteristics, associations with recovery were statistically significant but small in magnitude. CONCLUSIONS: CD4 count at cART initiation is the most important factor in predicting post-treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid.

Theobald S, Morgan R, Hawkins K, Ssali S, George A, Molyneux S. 2017. The importance of gender analysis in research for health systems strengthening. Health Policy Plan, 32 (suppl_5), pp. v1-v3. | Show Abstract | Read more

This editorial discusses a collection of papers examining gender across a range of health policy and systems contexts, from access to services, governance, health financing, and human resources for health. The papers interrogate differing health issues and core health systems functions using a gender lens. Together they produce new knowledge on the multiple impacts of gender on health experiences and demonstrate the importance of gender analyses and gender sensitive interventions for promoting well-being and health systems strengthening. The findings from these papers collectively show how gender intersects with other axes of inequity within specific contexts to shape experiences of health and health seeking within households, communities and health systems; illustrate how gender power relations affect access to important resources; and demonstrate that gender norms, poverty and patriarchy interplay to limit women's choices and chances both within household interactions and within the health sector. Health systems researchers have a responsibility to promote the incorporation of gender analyses into their studies in order to inform more strategic, effective and equitable health systems interventions, programmes, and policies. Responding to gender inequitable systems, institutions, and services in this sector requires an 'all hands-on deck' approach. We cannot claim to take a 'people-centred approach' to health systems if the status quo continues.

Anopheles gambiae 1000 Genomes Consortium, Data analysis group, Partner working group, Sample collections—Angola:, Burkina Faso:, Cameroon:, Gabon:, Guinea:, Guinea-Bissau:, Kenya: et al. 2017. Genetic diversity of the African malaria vector Anopheles gambiae. Nature, 552 (7683), pp. 96-100. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes, which transmit the disease. To gain a deeper understanding of how mosquito populations are evolving, here we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, and identified over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control using gene-drive systems will need to take account of high levels of genetic diversity in natural mosquito populations.

Beane A, Ambepitiyawaduge PDS, Thilakasiri K, Stephens T, Padeniya A, Athapattu P, Mahipala PG, Sigera PC, Dondorp AM, Haniffa R. 2017. Practices and Perspectives in Cardiopulmonary Resuscitation Attempts and the Use of Do Not Attempt Resuscitation Orders: A Cross-sectional Survey in Sri Lanka. Indian J Crit Care Med, 21 (12), pp. 865-868. | Show Abstract | Read more

Objective: The objective of this study is to describe the characteristics of in-hospital cardiopulmonary resuscitation (CPR) attempts, the perspectives of junior doctors involved in those attempts and the use of do not attempt resuscitation (DNAR) orders. Methods: A cross-sectional telephone survey aimed at intern doctors working in all medical/surgical wards in government hospitals. Interns were interviewed based on the above objective. Results: A total of 42 CPR attempts from 82 hospitals (338 wards) were reported, 3 of which were excluded as the participating doctor was unavailable for interview. 16 (4.7%) wards had at least 1 patient with an informal DNAR order. 42 deaths were reported. 8 deaths occurred without a known resuscitation attempt, of which 6 occurred on wards with an informal DNAR order in place. 39 resuscitations were attempted. Survival at 24 h was 2 (5.1%). In 5 (13%) attempts, CPR was the only intervention reported. On 25 (64%) occasions, doctors were "not at all" or "only a little bit surprised" by the arrest. Conclusions: CPR attempts before death in hospitals across Sri Lanka is prevalent. DNAR use remains uncommon.

Kanaan NC, Peterson AL, Pun M, Thapa GB, Tiwari A, Basyal B, Holck PS, Starling J, Freeman TF, Gehner JR et al. 2017. In Response to Ibuprofen vs Acetaminophen in AMS Prevention by Kanaan et al Reply WILDERNESS & ENVIRONMENTAL MEDICINE, 28 (4), pp. 385-387.

Cheah PY, Day NPJ, Parker M, Bull S. 2017. Sharing Individual-Level Health Research Data: Experiences, Challenges and a Research Agenda. Asian Bioeth Rev, 9 (4), pp. 393-400. | Show Abstract | Read more

Since January 2016, the Mahidol Oxford Tropical Medicine Research Unit (MORU) has trialled a data-sharing policy where requests to access research datasets are processed through a Data Access Committee. In this paper, we share our experiences establishing data management systems and data-sharing infrastructure including a data-sharing policy, data access committee and related procedures. We identified a number of practical and ethical challenges including requests for datasets collected without specific or broad consent to data sharing and requests from pharmaceutical companies for data to support drug registration applications. We also encountered significant resource constraints which required the development of appropriate human resources and infrastructure. We suggest a research agenda to promote responsible and equitable data sharing while safeguarding the rights and interests of research participants and researchers.

Gupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, Kaleebu P, Watera C, Aghokeng A, Mutenda N et al. 2017. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis, | Show Abstract | Read more

BACKGROUND: Pretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs. METHODS: This study was a systematic review and meta-regression analysis. We assessed regional prevalence of pretreatment drug resistance and risk of pretreatment drug resistance in people initiating ART who reported previous ART exposure. We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs. We searched for studies in PubMed and Embase and conference abstracts and presentations from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference, and the International Drug Resistance Workshop for the period Jan 1, 2001, to Dec 31, 2016. To assess the prevalence of drug resistance within a specified region at any specific timepoint, we extracted study level data and pooled prevalence estimates within the region using an empty logistic regression model with a random effect at the study level. We used random effects meta-regression to relate sampling year to prevalence of pretreatment drug resistance within geographical regions. FINDINGS: We identified 358 datasets that contributed data to our analyses, representing 56 044 adults in 63 countries. Prevalence estimates of pretreatment NNRTI resistance in 2016 were 11·0% (7·5-15·9) in southern Africa, 10·1% (5·1-19·4) in eastern Africa, 7·2% (2·9-16·5) in western and central Africa, and 9·4% (6·6-13·2) in Latin America and the Caribbean. There were substantial increases in pretreatment NNRTI resistance per year in all regions. The yearly increases in the odds of pretreatment drug resistance were 23% (95% CI 16-29) in southern Africa, 17% (5-30) in eastern Africa, 17% (6-29) in western and central Africa, 11% (5-18) in Latin America and the Caribbean, and 11% (2-20) in Asia. Estimated increases in the absolute prevalence of pretreatment drug resistance between 2015 and 2016 ranged from 0·3% in Asia to 1·8% in southern Africa. INTERPRETATION: Pretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHO's 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition. FUNDING: Bill & Melinda Gates Foundation and World Health Organization.

Coldiron ME, Von Seidlein L, Grais RF. 2017. Seasonal malaria chemoprevention: successes and missed opportunities. Malar J, 16 (1), pp. 481. | Show Abstract | Read more

Seasonal malaria chemoprevention (SMC) was recommended in 2012 for young children in the Sahel during the peak malaria transmission season. Children are given a single dose of sulfadoxine/pyrimethamine combined with a 3-day course of amodiaquine, once a month for up to 4 months. Roll-out and scale-up of SMC has been impressive, with 12 million children receiving the intervention in 2016. There is evidence of its overall benefit in routine implementation settings, and a meta-analysis of clinical trial data showed a 75% decrease in clinical malaria compared to placebo. SMC is not free of shortcomings. Its target zone includes many hard-to-reach areas, both because of poor infrastructure and because of political instability. Treatment adherence to a 3-day course of preventive treatment has not been fully documented, and could prove challenging. As SMC is scaled up, integration into a broader, community-based paradigm which includes other preventive and curative activities may prove beneficial, both for health systems and for recipients.

Tun STT, von Seidlein L, Pongvongsa T, Mayxay M, Saralamba S, Kyaw SS, Chanthavilay P, Celhay O, Nguyen TD, Tran TN-A et al. 2017. Towards malaria elimination in Savannakhet, Lao PDR: mathematical modelling driven strategy design. Malar J, 16 (1), pp. 483. | Show Abstract | Read more

BACKGROUND: The number of Plasmodium falciparum malaria cases around the world has decreased substantially over the last 15 years, but with the spread of resistance against anti-malarial drugs and insecticides, this decline may not continue. There is an urgent need to consider alternative, accelerated strategies to eliminate malaria in countries like Lao PDR, where there are a few remaining endemic areas. A deterministic compartmental modelling tool was used to develop an integrated strategy for P. falciparum elimination in the Savannakhet province of Lao PDR. The model was designed to include key aspects of malaria transmission and integrated control measures, along with a user-friendly interface. RESULTS: Universal coverage was the foundation of the integrated strategy, which took the form of the deployment of community health workers who provided universal access to early diagnosis, treatment and long-lasting insecticidal nets. Acceleration was included as the deployment of three monthly rounds of mass drug administration targeted towards high prevalence villages, with the addition of three monthly doses of the RTS,S vaccine delivered en masse to the same high prevalence sub-population. A booster dose of vaccine was added 1 year later. The surveillance-as-intervention component of the package involved the screening and treatment of individuals entering the simulated population. CONCLUSIONS: In this modelling approach, the sequential introduction of a series of five available interventions in an integrated strategy was predicted to be sufficient to stop malaria transmission within a 3-year period. These interventions comprised universal access to early diagnosis and adequate treatment, improved access to long-lasting insecticidal nets, three monthly rounds of mass drug administration together with RTS,S vaccination followed by a booster dose of vaccine, and screening and treatment of imported cases.

Bonnington CA, Phyo AP, Ashley EA, Imwong M, Sriprawat K, Parker DM, Proux S, White NJ, Nosten F. 2017. Plasmodium falciparum Kelch 13 mutations and treatment response in patients in Hpa-Pun District, Northern Kayin State, Myanmar. Malar J, 16 (1), pp. 480. | Show Abstract | Read more

BACKGROUND: Artemisinin resistance, linked to polymorphisms in the Kelch gene on chromosome 13 of Plasmodium falciparum (k13), has outpaced containment efforts in South East Asia. For national malaria control programmes in the region, it is important to establish a surveillance system which includes monitoring for k13 polymorphisms associated with the clinical phenotype. METHODS: Between February and December 2013, parasite clearance was assessed in 35 patients with uncomplicated P. falciparum treated with artesunate monotherapy followed by 3-day ACT in an isolated area on the Myanmar-Thai border with relatively low artemisinin drug pressure. Molecular testing for k13 mutations was performed on dry blood spots collected on admission. RESULTS: The proportion of k13 mutations in these patients was 41.7%, and only 5 alleles were detected: C580Y, I205T, M476I, R561H, and F446I. Of these, F446I was the most common, and was associated with a longer parasite clearance half-life (median) 4.1 (min-max 2.3-6.7) hours compared to 2.5 (min-max 1.6-8.7) in wildtype (p = 0·01). The prevalence of k13 mutant parasites was much lower than the proportion of k13 mutants detected 200 km south in a much less remote setting where the prevalence of k13 mutants was 84% with 15 distinct alleles in 2013 of which C580Y predominated. CONCLUSIONS: This study provides evidence of artemisinin resistance in a remote part of eastern Myanmar. The prevalence of k13 mutations as well as allele diversity varies considerably across short distances, presumably because of historical patterns of artemisinin use and population movements.

Muthumbi E, Lowe BS, Muyodi C, Getambu E, Gleeson F, Scott JAG. 2017. Risk factors for community-acquired pneumonia among adults in Kenya: a case-control study. Pneumonia (Nathan), 9 (1), pp. 17. | Show Abstract | Read more

Background: Pneumonia is a leading cause of morbidity and mortality among adults worldwide; however, the risk factors for community-acquired pneumonia in Africa are not well characterized. Methods: The authors recruited 281 cases of community-acquired pneumonia and 1202 hospital controls among patients aged ≥15 years who attended Kilifi District Hospital/Coast Provincial General Hospital in Kenya between 1994 and 6. Cases were admissions with an acute illness with ≥2 respiratory signs and evidence of consolidation on a chest radiograph. Controls were patients without signs of pneumonia, frequency matched by age, sex and hospital. Risk factors related to socio-demographic factors, drug use, clinical history, contact patterns and exposures to indoor air pollution were investigated by questionnaire, anthropometric measurements and laboratory assays. Associations were evaluated using a hierarchical logistic regression model. Results: Pneumonia was associated with human immunodeficiency virus (HIV) infection (Odds Ratio [OR] 2.06, 95% CI 1.44-3.08), anemia (OR 1.91, 1.31-2.74), splenomegaly (OR 2.04, 95% CI 1.14-3.41), recent history of pneumonia (OR 4.65, 95% CI 1.66-12.5), history of pneumonia >2 years previously (OR 17.13, 95% CI 5.01-60.26), coryza in the 2 weeks preceding hospitalization (OR 2.09, 95% CI 1.44-3.03), current smoking (2.19, 95% CI 1.39-3.70), use of khat (OR 3.44, 95% CI 1.72-7.15), use of snuff (OR 2.67, 95% CI 1.35-5.49) and contact with several animal species. Presence of a Bacillus Calmette-Guerin (BCG) scar was associated with protection (OR 0.51, 95% CI 0.32-0.82). The risk factors varied significantly by sex. Conclusion: Pneumonia in Kenyan adults was associated with global risk factors, such as HIV and smoking, but also with specific local factors like drug use and contact with animals. Intervention strategies should account for sex-specific differences in risk factors.

Alegana VA, Wright J, Bosco C, Okiro EA, Atkinson PM, Snow RW, Tatem AJ, Noor AM. 2017. Malaria prevalence metrics in low- and middle-income countries: an assessment of precision in nationally-representative surveys. Malar J, 16 (1), pp. 475. | Show Abstract | Read more

BACKGROUND: One pillar to monitoring progress towards the Sustainable Development Goals is the investment in high quality data to strengthen the scientific basis for decision-making. At present, nationally-representative surveys are the main source of data for establishing a scientific evidence base, monitoring, and evaluation of health metrics. However, little is known about the optimal precisions of various population-level health and development indicators that remains unquantified in nationally-representative household surveys. Here, a retrospective analysis of the precision of prevalence from these surveys was conducted. METHODS: Using malaria indicators, data were assembled in nine sub-Saharan African countries with at least two nationally-representative surveys. A Bayesian statistical model was used to estimate between- and within-cluster variability for fever and malaria prevalence, and insecticide-treated bed nets (ITNs) use in children under the age of 5 years. The intra-class correlation coefficient was estimated along with the optimal sample size for each indicator with associated uncertainty. FINDINGS: Results suggest that the estimated sample sizes for the current nationally-representative surveys increases with declining malaria prevalence. Comparison between the actual sample size and the modelled estimate showed a requirement to increase the sample size for parasite prevalence by up to 77.7% (95% Bayesian credible intervals 74.7-79.4) for the 2015 Kenya MIS (estimated sample size of children 0-4 years 7218 [7099-7288]), and 54.1% [50.1-56.5] for the 2014-2015 Rwanda DHS (12,220 [11,950-12,410]). CONCLUSION: This study highlights the importance of defining indicator-relevant sample sizes to achieve the required precision in the current national surveys. While expanding the current surveys would need additional investment, the study highlights the need for improved approaches to cost effective sampling.

Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Al Mekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A et al. 2017. Corticosteroid Therapy for Critically Ill Patients with the Middle East Respiratory Syndrome. Am J Respir Crit Care Med, | Show Abstract | Read more

RATIONALE: Corticosteroid therapy is commonly used among critically ill patients with the Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients' clinical condition at the time of corticosteroid therapy initiation. OBJECTIVES: To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. METHODS: MERS ICU patients were included from 14 Saudi Arabian centers between September 2012 and October 2015. We carried out marginal structural modeling to account for baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS: Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (Quartile Q1, 3: 1.0, 7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141/151 [93.4%] vs. 121/158 [76.6%], p≤0.0001) and had higher 90-day crude mortality (112/151 [74.2%] vs. 91/158 [57.6%], p=0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio 0.75, 95% CI 0.52, 1.07, p=0.12), but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio 0.35, 95% CI: 0.17, 0.72, p=0.005). CONCLUSIONS: Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders, but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies.

Lopez AL, Deen J, Azman AS, Luquero FJ, Kanungo S, Dutta S, von Seidlein L, Sack DA. 2017. Immunogenicity and protection from a single dose of internationally available killed oral cholera vaccine: a systematic review and meta-analysis. Clin Infect Dis, | Show Abstract | Read more

In addition to improved water supply and sanitation, the two-dose killed oral cholera vaccine (OCV) is an important tool for the prevention and control of cholera. We aimed to document the immunogenicity and protection (efficacy and effectiveness) conferred by a single OCV dose against cholera. The meta-analysis showed an estimated 73% and 77% of individuals seroconverted to the Ogawa and Inaba serotypes, respectively, after an OCV first dose. The estimates of single-dose vaccine protection from available studies are 87% at 2 months decreasing to 33% at 2 years. Current immunologic and clinical data suggest that protection conferred by a single dose of killed OCV may be sufficient to reduce short-term risk in outbreaks or other high-risk settings, which may be especially useful when vaccine supply is limited. However, until more data suggests otherwise, a second dose should be given as soon as circumstances allow to ensure robust protection.

Vijay S, Vinh DN, Hai HT, Ha VTN, Dung VTM, Dinh TD, Nhung HN, Tram TTB, Aldridge BB, Hanh NT et al. 2017. Influence of Stress and Antibiotic Resistance on Cell-Length Distribution in Mycobacterium tuberculosis Clinical Isolates. Front Microbiol, 8 (NOV), pp. 2296. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Mycobacterial cellular variations in growth and division increase heterogeneity in cell length, possibly contributing to cell-to-cell variation in host and antibiotic stress tolerance. This may be one of the factors influencing Mycobacterium tuberculosis persistence to antibiotics. Tuberculosis (TB) is a major public health problem in developing countries, antibiotic persistence, and emergence of antibiotic resistance further complicates this problem. We wanted to investigate the factors influencing cell-length distribution in clinical M. tuberculosis strains. In parallel we examined M. tuberculosis cell-length distribution in a large set of clinical strains (n = 158) from ex vivo sputum samples, in vitro macrophage models, and in vitro cultures. Our aim was to understand the influence of clinically relevant factors such as host stresses, M. tuberculosis lineages, antibiotic resistance, antibiotic concentrations, and disease severity on the cell size distribution in clinical M. tuberculosis strains. Increased cell size and cell-to-cell variation in cell length were associated with bacteria in sputum and infected macrophages rather than liquid culture. Multidrug-resistant (MDR) strains displayed increased cell length heterogeneity compared to sensitive strains in infected macrophages and also during growth under rifampicin (RIF) treatment. Importantly, increased cell length was also associated with pulmonary TB disease severity. Supporting these findings, individual host stresses, such as oxidative stress and iron deficiency, increased cell-length heterogeneity of M. tuberculosis strains. In addition we also observed synergism between host stress and RIF treatment in increasing cell length in MDR-TB strains. This study has identified some clinical factors contributing to cell-length heterogeneity in clinical M. tuberculosis strains. The role of these cellular adaptations to host and antibiotic tolerance needs further investigation.

Parker DM, Tripura R, Peto TJ, Maude RJ, Nguon C, Chalk J, Sirithiranont P, Imwong M, von Seidlein L, White NJ, Dondorp AM. 2017. A multi-level spatial analysis of clinical malaria and subclinical Plasmodium infections in Pailin Province, Cambodia. Heliyon, 3 (11), pp. e00447. | Show Abstract | Read more

Background: The malaria burden is decreasing throughout the Greater Mekong Subregion, however transmission persists in some areas. Human movement, subclinical infections and complicated transmission patterns contribute to the persistence of malaria. This research describes the micro-geographical epidemiology of both clinical malaria and subclinical Plasmodium infections in three villages in Western Cambodia. Methods: Three villages in Western Cambodia were selected for the study based on high reported Plasmodium falciparum incidence. A census was conducted at the beginning of the study, including demographic information and travel history. The total population was 1766. Cross-sectional surveys were conducted every three months from June 2013 to June 2014. Plasmodium infections were detected using an ultra-sensitive, high-volume, quantitative polymerase chain reaction (uPCR) technique. Clinical episodes were recorded by village health workers. The geographic coordinates (latitude and longitude) were collected for all houses and all participants were linked to their respective houses using a demographic surveillance system. Written informed consent was obtained from all participants. Results: Most clinical episodes and subclinical infections occurred within a single study village. Clinical Plasmodium vivax episodes clustered spatially in each village but only lasted for a month. In one study village subclinical infections clustered in geographic proximity to clusters of clinical episodes. The largest risk factor for clinical P. falciparum episodes was living in a house where another clinical P. falciparum episode occurred (model adjusted odds ratio (AOR): 6.9; CI: 2.3-19. 8). Subclinical infections of both P. vivax and P. falciparum were associated with clinical episodes of the same species (AOR: 5.8; CI: 1.5-19.7 for P. falciparum and AOR: 14.6; CI: 8.6-25.2 for P. vivax) and self-reported overnight visits to forested areas (AOR = 3.8; CI: 1.8-7. 7 for P. falciparum and AOR = 2.9; CI: 1.7-4.8 for P. vivax). Discussion: Spatial clustering within the villages was transient, making the prediction of spatial clusters difficult. Interventions that are dependent on predicting spatial clusters (such as reactive case detection) would only have detected a small proportion of cases unless the entire village was screened within a limited time frame and with a highly sensitive diagnostic test. Subclinical infections may be acquired outside of the village (particularly in forested areas) and may play an important role in transmission.

Pang S-C, Andolina C, Malleret B, Christensen PR, Lam-Phua S-G, Razak MABA, Chong C-S, Li D, Chu CS, Russell B et al. 2017. Singapore's Anopheles sinensis Form A is susceptible to Plasmodium vivax isolates from the western Thailand-Myanmar border. Malar J, 16 (1), pp. 465. | Show Abstract | Read more

BACKGROUND: Singapore has been certified malaria-free by the World Health Organization since November 1982. However, sporadic autochthonous malaria outbreaks do occur. In one of the most recent outbreaks of vivax malaria, an entomological investigation identified Anopheles sinensis as the most probable vector. As metaphase karyotype studies divided An. sinensis into two forms, A and B, with different vector competence: the investigation of vector competence of An. sinensis found in Singapore was thus pursued using Plasmodium vivax field isolates from the Thailand-Myanmar border. METHODS: Adults and larvae An. sinensis were collected from Singapore from 14 different locations, using various trapping and collection methods between September 2013 and January 2016. Molecular identification of An. sinensis species were conducted by amplifying the ITS2 and CO1 region using PCR. Experimental infections of An. sinensis using blood from seven patients infected with P. vivax from the Thailand-Myanmar border were conducted with Anopheles cracens (An. dirus B) as control. RESULTS: Phylogenetic analysis showed that An. sinensis (F22, F2and collected from outbreak areas) found in Singapore was entirely Form A, and closely related to An. sinensis Form A from Thailand. Artificial infection of these Singapore strain An. sinensis Form A resulted in the development of oocysts in four experiments, with the number of sporozoites produced by one An. sinensis ranging from 4301 to 14,538. CONCLUSIONS: Infection experiments showed that An. sinensis Form A from Singapore was susceptible to Thai-Myanmar P. vivax strain, suggesting a potential role as a malaria vector in Singapore.

Kamau A, Nyaga V, Bauni E, Tsofa B, Noor AM, Bejon P, Scott JAG, Hammitt LL. 2017. Trends in bednet ownership and usage, and the effect of bednets on malaria hospitalization in the Kilifi Health and Demographic Surveillance System (KHDSS): 2008-2015. BMC Infect Dis, 17 (1), pp. 720. | Show Abstract | Read more

BACKGROUND: Use of bednets reduces malaria morbidity and mortality. In Kilifi, Kenya, there was a mass distribution of free nets to children < 5 years in 2006. In 2009, a new policy was implemented to offer bednets to pregnant women and children < 5 years free of charge. Nets were again distributed to children and adults through national mass campaigns in 2012 and 2015. We aimed to evaluate trends in bednet ownership and usage, and the effect of bednets on the incidence of malaria hospitalization in children < 5 years within the Kilifi Health and Demographic Surveillance System (KHDSS). METHODS: Bednet ownership and usage were assessed during eight routine enumeration rounds of the KHDSS between 2008 and 2015. Malaria admissions (i.e. admissions to hospital with P. falciparum > 2500 parasitemia per μl) among children < 5 years were captured using a system of continuous vital registration that links admissions at Kilifi County Hospital to the KHDSS population register. Survival analysis was used to assess relative risk of hospitalization with malaria among children that reported using a bednet compared to those who did not. RESULTS: We observed 63% and 62% mean bednet ownership and usage, respectively, over the eight-survey period. Among children < 5 years, reported bednet ownership in October-December 2008 was 69% and in March-August 2009 was 73% (p < 0.001). An increase was also observed following the mass distribution campaigns in 2012 (62% in May-July 2012 vs 90% in May-October 2013, p < 0.001) and 2015 (68% in June-September 2015 vs 93% in October-November 2015, p < 0.001). Among children <5 years who reported using a net the night prior to the survey, the incidence of malaria hospitalization per 1000 child-years was 2.91 compared to 4.37 among those who did not (HR = 0.67, 95% CI: 0.52, 0.85 [p = 0.001]). CONCLUSION: On longitudinal surveillance, increasing bednet ownership and usage corresponded to mass distribution campaigns; however, this method of delivering bednets did not result in sustained improvements in coverage. Among children < 5 years old bednet use was associated with a 33% decreased incidence of malaria hospitalization.

Malla L, Perera-Salazar R, McFadden E, English M. 2017. Comparative effectiveness of injectable penicillin versus a combination of penicillin and gentamicin in children with pneumonia characterised by indrawing in Kenya: a retrospective observational study. BMJ Open, 7 (11), pp. e019478. | Show Abstract | Read more

OBJECTIVES: Kenyan guidelines for antibiotic treatment of pneumonia recommended treatment of pneumonia characterised by indrawing with injectable penicillin alone in inpatient settings until early 2016. At this point, they were revised becoming consistent with WHO guidance after results of a Kenyan trial provided further evidence of equivalence of oral amoxicillin and injectable penicillin. This change also made possible use of oral amoxicillin for outpatient treatment in this patient group. However, given non-trivial mortality in Kenyan children with indrawing pneumonia, it remained possible they would benefit from a broader spectrum antibiotic regimen. Therefore, we compared the effectiveness of injectable penicillin monotherapy with a regimen combining penicillin with gentamicin. SETTING: We used a large routine observational dataset that captures data on all admissions to 13 Kenyan county hospitals. PARTICIPANTS AND MEASURES: The analyses included children aged 2-59 months. Selection of study population was based on inclusion criteria typical of a prospective trial, primary analysis (experiment 1, n=4002), but we also explored more pragmatic inclusion criteria (experiment 2, n=6420) as part of a secondary analysis. To overcome the challenges associated with the non-random allocation of treatments and missing data, we used propensity score (PS) methods and multiple imputation to minimise bias. Further, we estimated mortality risk ratios using log binomial regression and conducted sensitivity analyses using an instrumental variable and PS trimming. RESULTS: The estimated risk of dying, in experiment 1, in those receiving penicillin plus gentamicin was 1.46 (0.85 to 2.43) compared with the penicillin monotherapy group. In experiment 2, the estimated risk was 1.04(0.76 to 1.40). CONCLUSION: There is no statistical difference in the treatment of indrawing pneumonia with either penicillin or penicillin plus gentamicin. By extension, it is unlikely that treatment with penicillin plus gentamicin would offer an advantage to treatment with oral amoxicillin.

Murphy GAV, Waters D, Ouma PO, Gathara D, Shepperd S, Snow RW, English M. 2017. Estimating the need for inpatient neonatal services: an iterative approach employing evidence and expert consensus to guide local policy in Kenya. BMJ Glob Health, 2 (4), pp. e000472. | Show Abstract | Read more

Universal access to quality newborn health services will be essential to meeting specific Sustainable Development Goals to reduce neonatal and overall child mortality. Data for decision making are crucial for planning services and monitoring progress in these endeavours. However, gaps in local population-level and facility-based data hinder estimation of health service requirements for effective planning in many low-income and middle-income settings. We worked with local policy makers and experts in Nairobi City County, an area with a population of four million and the highest neonatal mortality rate amongst counties in Kenya, to address this gap, and developed a systematic approach to use available data to support policy and planning. We developed a framework to identify major neonatal conditions likely to require inpatient neonatal care and identified estimates of incidence through literature review and expert consultation, to give an overall estimate for the year 2017 of the need for inpatient neonatal care, taking account of potential comorbidities. Our estimates suggest that almost 1 in 5 newborns (183/1000 live births) in Nairobi City County may need inpatient care, resulting in an estimated 24 161 newborns expected to require care in 2017. Our approach has been well received by local experts, who showed a willingness to work together and engage in the use of evidence in healthcare planning. The process highlighted the need for co-ordinated thinking on admission policy and referral care especially in a pluralistic provider environment helping build further appetite for data-informed decision making.

Tuti T, Agweyu A, Mwaniki P, Peek N, English M, Clinical Information Network Author Group. 2017. An exploration of mortality risk factors in non-severe pneumonia in children using clinical data from Kenya. BMC Med, 15 (1), pp. 201. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Childhood pneumonia is the leading infectious cause of mortality in children younger than 5 years old. Recent updates to World Health Organization pneumonia guidelines recommend outpatient care for a population of children previously classified as high risk. This revision has been challenged by policymakers in Africa, where mortality related to pneumonia is higher than in other regions and often complicated by comorbidities. This study aimed to identify factors that best discriminate inpatient mortality risk in non-severe pneumonia and explore whether these factors offer any added benefit over the current criteria used to identify children with pneumonia requiring inpatient care. METHODS: We undertook a retrospective cohort study of children aged 2-59 months admitted with a clinical diagnosis of pneumonia at 14 public hospitals in Kenya between February 2014 and February 2016. Using machine learning techniques, we analysed whether clinical characteristics and common comorbidities increased the risk of inpatient mortality for non-severe pneumonia. The topmost risk factors were subjected to decision curve analysis to explore if using them as admission criteria had any net benefit above the current criteria. RESULTS: Out of 16,162 children admitted with pneumonia during the study period, 10,687 were eligible for subsequent analysis. Inpatient mortality within this non-severe group was 252/10,687 (2.36%). Models demonstrated moderately good performance; the partial least squares discriminant analysis model had higher sensitivity for predicting mortality in comparison to logistic regression. Elevated respiratory rate (≥70 bpm), age 2-11 months and weight-for-age Z-score (WAZ) < -3SD were highly discriminative of mortality. These factors ranked consistently across the different models. For a risk threshold probability of 7-14%, there is a net benefit to admitting the patient sub-populations with these features as additional criteria alongside those currently used to classify severe pneumonia. Of the population studied, 70.54% met at least one of these criteria. Sensitivity analyses indicated that the overall results were not significantly affected by variations in pneumonia severity classification criteria. CONCLUSIONS: Children with non-severe pneumonia aged 2-11 months or with respiratory rate ≥ 70 bpm or very low WAZ experience risks of inpatient mortality comparable to severe pneumonia. Inpatient care is warranted in these high-risk groups of children.

Matamoros S, van Hattem JM, Arcilla MS, Willemse N, Melles DC, Penders J, Vinh TN, Thi Hoa N, COMBAT consortium, de Jong MD, Schultsz C. 2017. Global phylogenetic analysis of Escherichia coli and plasmids carrying the mcr-1 gene indicates bacterial diversity but plasmid restriction. Sci Rep, 7 (1), pp. 15364. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

To understand the dynamics behind the worldwide spread of the mcr-1 gene, we determined the population structure of Escherichia coli and of mobile genetic elements (MGEs) carrying the mcr-1 gene. After a systematic review of the literature we included 65 E. coli whole genome sequences (WGS), adding 6 recently sequenced travel related isolates, and 312 MLST profiles. We included 219 MGEs described in 7 Enterobacteriaceae species isolated from human, animal and environmental samples. Despite a high overall diversity, 2 lineages were observed in the E. coli population that may function as reservoirs of the mcr-1 gene, the largest of which was linked to ST10, a sequence type known for its ubiquity in human faecal samples and in food samples. No genotypic clustering by geographical origin or isolation source was observed. Amongst a total of 13 plasmid incompatibility types, the IncI2, IncX4 and IncHI2 plasmids accounted for more than 90% of MGEs carrying the mcr-1 gene. We observed significant geographical clustering with regional spread of IncHI2 plasmids in Europe and IncI2 in Asia. These findings point towards promiscuous spread of the mcr-1 gene by efficient horizontal gene transfer dominated by a limited number of plasmid incompatibility types.

Son DH, Thuy-Nhien N, von Seidlein L, Le Phuc-Nhi T, Phu NT, Tuyen NTK, Tran NH, Van Dung N, Van Quan B, Day NPJ et al. 2017. The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study. Malar J, 16 (1), pp. 444. | Show Abstract | Read more

BACKGROUND: Prophylaxis for high-risk populations, such as forest workers, could be one component for malaria elimination in the Greater Mekong Sub-region. A study was conducted to assess the malaria incidence in forest rangers and the feasibility of malaria prophylaxis for rangers sleeping in forest camps. METHODS: Forest rangers deployed in the Bu Gia Map National Park, Vietnam were invited to participate in the study. Plasmodium infections were cleared using presumptive treatment, irrespective of malaria status, with a 3-day course dihydroartemisinin/piperaquine (DP) and a 14-day course of primaquine. Before returning to the forest, study participants were randomly allocated to a 3-day course of DP or placebo. Fifteen days after returning from their forest deployment the participants were tested for Plasmodium infections using uPCR. RESULTS: Prior to treatment, 30 of 150 study participants (20%) were found to be infected with Plasmodium. Seventeen days (median) after enrolment the rangers were randomized to DP or placebo 2 days before returning to forest camps where they stayed between 2 and 20 days (median 9.5 days). One ranger in the DP-prophylaxis arm and one in the placebo arm were found to be infected with Plasmodium falciparum 15 days (median) after returning from the forest. The evaluable P. falciparum isolates had molecular markers indicating resistance to artemisinins (K13-C580Y) and piperaquine (plasmepsin), but none had multiple copies of pfmdr1 associated with mefloquine resistance. CONCLUSION: Anti-malarial prophylaxis in forest rangers is feasible. The findings of the study highlight the threat of multidrug-resistant malaria. Trial registration NCT02788864.

Bancone G, Gilder ME, Chowwiwat N, Gornsawun G, Win E, Cho WW, Moo E, Min AM, Charunwatthana P, Carrara VI et al. 2017. Prevalences of inherited red blood cell disorders in pregnant women of different ethnicities living along the Thailand-Myanmar border. Wellcome Open Res, 2 pp. 72. | Show Abstract | Read more

Background: Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas; G6PD deficiency is associated with oxidant-induced haemolysis and abnormal haemoglobin variants may cause chronic anaemia. In pregnant women, microcytic anaemia caused by haemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anaemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterise the prevalence of G6PD deficiency and haemoglobinopathies  among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups. Methods: Data were available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analysed in a subsample of women. Haemoglobin variants were diagnosed by HPLC or capillary electrophoresis and molecular methods. The prevalence and distribution of inherited red blood cell disorders was analysed with respect to ethnicity. Results: G6PD deficiency was common, especially in the Sgaw Karen ethnic group, in whom the G6PD Mahidol variant allele frequency was 20.7%. Quantitative G6PD phenotyping showed that 60.5% of heterozygous women had an intermediate enzymatic activity between 30% and 70% of the population median. HbE, beta-thalassaemia trait and Hb Constant Spring were found overall in 15.6% of women. Only 45.2% of women with low percentage of HbA 2 were carriers of mutations on the alpha globin genes. Conclusions: Distribution of G6PD and haemoglobin variants varied among the different ethnic groups, but the prevalence was generally high throughout the cohort. These findings encourage the implementation of an extended program of information and genetic counselling to women of reproductive age and will help inform future studies and current clinical management of anaemia in the pregnant population in this region.

Bancone G, Gilder ME, Chowwiwat N, Gornsawun G, Win E, Cho WW, Moo E, Min AM, Charunwatthana P, Carrara VI et al. 2017. Prevalences of inherited red blood cell disorders in pregnant women of different ethnicities living along the Thailand-Myanmar border Wellcome Open Research, 2 pp. 72-72. | Show Abstract | Read more

© 2017 Bancone G et al. Background: Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas; G6PD deficiency is associated with oxidant-induced hemolysis and abnormal hemoglobin variants may cause chronic anemia. In pregnant women, microcytic anemia caused by hemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterize the prevalence of G6PD deficiency, hemoglobinopathies, ABO and Rhesus blood groups among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups. Methods: Data was available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analyzed in a subsample of women. Hemoglobin variants were diagnosed by HPLC or capillary electrophoresis and molecular methods. Blood groups were diagnosed by agglutination test. The prevalence and distribution of inherited red blood cell disorders and blood groups was analyzed with respect to ethnicity. Results: G6PD deficiency was common, especially in the Sgaw Karen ethnic group, in whom the G6PD Mahidol variant allele frequency was 20.7%. Quantitative G6PD phenotyping showed that 60.5% of heterozygote women have an intermediate enzymatic activity between 30% and 70% of the population median. HbE, beta-thalassemia trait and alpha-thalassemia trait were found in 31.2% of women. Only 0.15% of women were Rhesus negative. Conclusions: Distribution of G6PD and hemoglobin variants varied among the different ethnic groups, but the prevalence was generally high throughout the cohort. These findings encourage the implementation of an extended program of information and genetic counseling to women of reproductive age and will help inform future studies and current clinical management of anemia in the pregnant population in this region.

Mogeni P, Williams TN, Omedo I, Kimani D, Ngoi JM, Mwacharo J, Morter R, Nyundo C, Wambua J, Nyangweso G et al. 2017. Detecting Malaria Hotspots: A Comparison of Rapid Diagnostic Test, Microscopy, and Polymerase Chain Reaction. J Infect Dis, 216 (9), pp. 1091-1098. | Show Abstract | Read more

Background: Malaria control strategies need to respond to geographical hotspots of transmission. Detection of hotspots depends on the sensitivity of the diagnostic tool used. Methods: We conducted cross-sectional surveys in 3 sites within Kilifi County, Kenya, that had variable transmission intensities. Rapid diagnostic test (RDT), microscopy, and polymerase chain reaction (PCR) were used to detect asymptomatic parasitemia, and hotspots were detected using the spatial scan statistic. Results: Eight thousand five hundred eighty-one study participants were surveyed in 3 sites. There were statistically significant malaria hotspots by RDT, microscopy, and PCR for all sites except by microscopy in 1 low transmission site. Pooled data analysis of hotspots by PCR overlapped with hotspots by microscopy at a moderate setting but not at 2 lower transmission settings. However, variations in degree of overlap were noted when data were analyzed by year. Hotspots by RDT were predictive of PCR/microscopy at the moderate setting, but not at the 2 low transmission settings. We observed long-term stability of hotspots by PCR and microscopy but not RDT. Conclusion: Malaria control programs may consider PCR testing to guide asymptomatic malaria hotspot detection once the prevalence of infection falls.

Janocha AJ, Comhair SAA, Basnyat B, Neupane M, Gebremedhin A, Khan A, Ricci KS, Zhang R, Erzurum SC, Beall CM. 2017. Antioxidant defense and oxidative damage vary widely among high-altitude residents. Am J Hum Biol, 29 (6), pp. e23039-e23039. | Citations: 1 (Scopus) | Show Abstract | Read more

OBJECTIVES: People living at high altitude experience unavoidable low oxygen levels (hypoxia). While acute hypoxia causes an increase in oxidative stress and damage despite higher antioxidant activity, the consequences of chronic hypoxia are poorly understood. The aim of the present study is to assess antioxidant activity and oxidative damage in high-altitude natives and upward migrants. METHODS: Individuals from two indigenous high-altitude populations (Amhara, n = 39), (Sherpa, n = 34), one multigenerational high-altitude population (Oromo, n = 42), one upward migrant population (Nepali, n = 12), and two low-altitude reference populations (Amhara, n = 29; Oromo, n = 18) provided plasma for measurement of superoxide dismutase (SOD) activity as a marker of antioxidant capacity, and urine for measurement of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of DNA oxidative damage. RESULTS: High-altitude Amhara and Sherpa had the highest SOD activity, while highland Oromo and Nepalis had the lowest among high-altitude populations. High-altitude Amhara had the lowest DNA damage, Sherpa intermediate levels, and high-altitude Oromo had the highest. CONCLUSIONS: High-altitude residence alone does not associate with high antioxidant defenses; residence length appears to be influential. The single-generation upward migrant sample had the lowest defense and nearly the highest DNA damage. The two high-altitude resident samples with millennia of residence had higher defenses than the two with multiple or single generations of residence.

Apinjoh TO, Mugri RN, Miotto O, Chi HF, Tata RB, Anchang-Kimbi JK, Fon EM, Tangoh DA, Nyingchu RV, Jacob C et al. 2017. Molecular markers for artemisinin and partner drug resistance in natural Plasmodium falciparum populations following increased insecticide treated net coverage along the slope of mount Cameroon: cross-sectional study. Infect Dis Poverty, 6 (1), pp. 136. | Show Abstract | Read more

BACKGROUND: Drug resistance is one of the greatest challenges of malaria control programmes, with the monitoring of parasite resistance to artemisinins or to Artemisinin Combination Therapy (ACT) partner drugs critical to elimination efforts. Markers of resistance to a wide panel of antimalarials were assessed in natural parasite populations from southwestern Cameroon. METHODS: Individuals with asymptomatic parasitaemia or uncomplicated malaria were enrolled through cross-sectional surveys from May 2013 to March 2014 along the slope of mount Cameroon. Plasmodium falciparum malaria parasitaemic blood, screened by light microscopy, was depleted of leucocytes using CF11 cellulose columns and the parasite genotype ascertained by sequencing on the Illumina HiSeq platform. RESULTS: A total of 259 participants were enrolled in this study from three different altitudes. While some alleles associated with drug resistance in pfdhfr, pfmdr1 and pfcrt were highly prevalent, less than 3% of all samples carried mutations in the pfkelch13 gene, none of which were amongst those associated with slow artemisinin parasite clearance rates in Southeast Asia. The most prevalent haplotypes were triple mutants Pfdhfr I51R59N108I164(99%), pfcrt- C72V73I74E75T76(47.3%), and single mutants PfdhpsS436G437K540A581A613(69%) and Pfmdr1 N86F184D1246(53.2%). CONCLUSIONS: The predominance of the Pf pfcrt CVIET and Pf dhfr IRN triple mutant parasites and absence of pfkelch13 resistance alleles suggest that the amodiaquine and pyrimethamine components of AS-AQ and SP may no longer be effective in their role while chloroquine resistance still persists in southwestern Cameroon.

Das S, Jang IK, Barney B, Peck R, Rek JC, Arinaitwe E, Adrama H, Murphy M, Imwong M, Ling CL et al. 2017. Performance of a High-Sensitivity Rapid Diagnostic Test for Plasmodium falciparum Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections. Am J Trop Med Hyg, 97 (5), pp. 1540-1550. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination. The performance of a new Alere™ Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four Plasmodium falciparum-induced blood-stage malaria (IBSM) studies. A quantitative reverse transcription PCR (qRT-PCR) and a highly sensitive enzyme-linked immunosorbent assay (ELISA) test for histidine-rich protein II (HRP2) were used as reference assays. The uRDT showed a greater than 10-fold lower limit of detection for HRP2 compared with the RDT. The sensitivity of the uRDT was 84% and 44% against qRT-PCR in Uganda and Myanmar, respectively, and that of the RDT was 62% and 0% for the same two sites. The specificities of the uRDT were 92% and 99.8% against qRT-PCR for Uganda and Myanmar, respectively, and 99% and 99.8% against the HRP2 reference ELISA. The RDT had specificities of 95% and 100% against qRT-PCR for Uganda and Myanmar, respectively, and 96% and 100% against the HRP2 reference ELISA. The uRDT detected new infections in IBSM study participants 1.5 days sooner than the RDT. The uRDT has the same workflow as currently available RDTs, but improved performance characteristics to identify asymptomatic malaria infections. The uRDT may be a useful tool for malaria elimination strategies.

Blessborn D, Kaewkhao K, Song L, White NJ, Day NPJ, Tarning J. 2017. Quantification of the antimalarial drug pyronaridine in whole blood using LC-MS/MS - Increased sensitivity resulting from reduced non-specific binding. J Pharm Biomed Anal, 146 pp. 214-219. | Show Abstract | Read more

Malaria is one of the most important parasitic diseases of man. The development of drug resistance in malaria parasites is an inevitable consequence of their widespread and often unregulated use. There is an urgent need for new and effective drugs. Pyronaridine is a known antimalarial drug that has received renewed interest as a partner drug in artemisinin-based combination therapy. To study its pharmacokinetic properties, particularly in field settings, it is necessary to develop and validate a robust, highly sensitive and accurate bioanalytical method for drug measurements in biological samples. We have developed a sensitive quantification method that covers a wide range of clinically relevant concentrations (1.5ng/mL to 882ng/mL) using a relatively low volume sample of 100μL of whole blood. Total run time is 5min and precision is within ±15% at all concentration levels. Pyronaridine was extracted on a weak cation exchange solid-phase column (SPE) and separated on a HALO RP amide fused-core column using a gradient mobile phase of acetonitrile-ammonium formate and acetonitrile-methanol. Detection was performed using electrospray ionization and tandem mass spectrometry (positive ion mode with selected reaction monitoring). The developed method is suitable for implementation in high-throughput routine drug analysis, and was used to quantify pyronaridine accurately for up to 42days after a single oral dose in a drug-drug interaction study in healthy volunteers.

Zellweger RM, Carrique-Mas J, Limmathurotsakul D, Day NPJ, Thwaites GE, Baker S, Southeast Asia Antimicrobial Resistance Network. 2017. A current perspective on antimicrobial resistance in Southeast Asia. J Antimicrob Chemother, 72 (11), pp. 2963-2972. | Show Abstract | Read more

Southeast Asia, a vibrant region that has recently undergone unprecedented economic development, is regarded as a global hotspot for the emergence and spread of antimicrobial resistance (AMR). Understanding AMR in Southeast Asia is crucial for assessing how to control AMR on an international scale. Here we (i) describe the current AMR situation in Southeast Asia, (ii) explore the mechanisms that make Southeast Asia a focal region for the emergence of AMR, and (iii) propose ways in which Southeast Asia could contribute to a global solution.

Moore KA, Simpson JA, Scoullar MJL, McGready R, Fowkes FJI. 2017. Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis. Lancet Glob Health, 5 (11), pp. e1101-e1112. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: 2·6 million stillbirths occur annually worldwide. The association between malaria in pregnancy and stillbirth has yet to be comprehensively quantified. We aimed to quantify the association between malaria in pregnancy and stillbirth, and to assess the influence of malaria endemicity on the association. METHODS: We did a systematic review of the association between confirmed malaria in pregnancy and stillbirth. We included population-based cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths), and randomised controlled trials of malaria in pregnancy interventions, identified before Feb 28, 2017. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We pooled estimates of the association between malaria in pregnancy and stillbirth using meta-analysis. We used meta-regression to assess the influence of endemicity. The study protocol is registered with PROSPERO, protocol number CRD42016038742. FINDINGS: We included 59 studies of 995 records identified, consisting of 141 415 women and 3387 stillbirths. Plasmodium falciparum malaria detected at delivery in peripheral samples increased the odds of stillbirth (odds ratio [OR] 1·81 [95% CI 1·42-2·30]; I2=26·1%; 34 estimates), as did P falciparum detected in placental samples (OR 1·95 [1·48-2·57]; I2=33·6%; 31 estimates). P falciparum malaria detected and treated during pregnancy was also associated with stillbirth, but to a lesser extent (OR 1·47 [95% CI 1·13-1·92]; 19 estimates). Plasmodium vivax malaria increased the odds of stillbirth when detected at delivery (2·81 [0·77-10·22]; three estimates), but not when detected and treated during pregnancy (1·09 [0·76-1·57]; four estimates). The association between P falciparum malaria in pregnancy and stillbirth was two times greater in areas of low-to-intermediate endemicity than in areas of high endemicity (ratio of ORs 1·96 [95% CI 1·34-2·89]). Assuming all women with malaria are still parasitaemic at delivery, an estimated 20% of the 1 059 700 stillbirths in malaria-endemic sub-Saharan Africa are attributed to P falciparum malaria in pregnancy; the population attributable fraction decreases to 12%, assuming all women with malaria are treated during pregnancy. INTERPRETATION: P falciparum and P vivax malaria in pregnancy both increase stillbirth risk. The risk of malaria-associated stillbirth is likely to increase as endemicity declines. There is a pressing need for context-appropriate, evidence-based interventions for malaria in pregnancy in low-endemicity settings. FUNDING: Australian Commonwealth Government, National Health and Medical Research Council, Australian Research Council.

von Seidlein L, Sack D, Azman AS, Ivers LC, Lopez AL, Deen JL. 2017. Cholera outbreak in Yemen. Lancet Gastroenterol Hepatol, 2 (11), pp. 777. | Read more

de Kock M, Tarning J, Barnes KI, Denti P. 2017. Response to "Lactation Status and Studies of Pyrimethamine Pharmacokinetics in Pregnancy". CPT Pharmacometrics Syst Pharmacol, 6 (11), pp. 731. | Read more

Salam AP, Horby PW. 2017. The breadth of viruses in human semen Emerging Infectious Diseases, 23 (11), pp. 1922-1924. | Show Abstract | Read more

© 2017, Centers for Disease Control and Prevention (CDC). All rights reserved. Zika virus RNA is frequently detected in the semen of men after Zika virus infection. To learn more about persistence of viruses in genital fluids, we searched PubMed for relevant articles. We found evidence that 27 viruses, across a broad range of virus families, can be found in human semen.

Ho NT, Hoang VMT, Le NNT, Nguyen DT, Tran A, Kaki D, Tran PM, Thompson CN, Ngo MNQ, Truong KH et al. 2017. A spatial and temporal analysis of paediatric central nervous system infections from 2005 to 2015 in Ho Chi Minh City, Vietnam. Epidemiol Infect, 145 (15), pp. 3307-3317. | Show Abstract | Read more

Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.

Seale AC, Blencowe H, Bianchi-Jassir F, Embleton N, Bassat Q, Ordi J, Menéndez C, Cutland C, Briner C, Berkley JA et al. 2017. Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses. Clin Infect Dis, 65 (suppl_2), pp. S125-S132. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Background: There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. Results: We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS. Conclusions: GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination.

Zellweger RM, Basnyat B, Shrestha P, Prajapati KG, Dongol S, Sharma PK, Koirala S, Darton TC, Dolecek C, Thompson CN et al. 2017. A 23-year retrospective investigation of Salmonella Typhi and Salmonella Paratyphi isolated in a tertiary Kathmandu hospital. PLoS Negl Trop Dis, 11 (11), pp. e0006051. | Show Abstract | Read more

BACKGROUND: Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period. METHODS: We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms. RESULTS: Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates. CONCLUSIONS: Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy.

De Silva AP, Baranage DDS, Padeniya A, Sigera PC, De Alwis S, Abayadeera AU, Mahipala PG, Jayasinghe KS, Dondorp AM, Haniffa R. 2017. Critical Care Junior Doctors' Profile in a Lower Middle-income Country: A National Cross-sectional Survey. Indian J Crit Care Med, 21 (11), pp. 733-739. | Show Abstract | Read more

Background and Aims: Retention of junior doctors in specialties such as critical care is difficult, especially in resource-limited settings. This study describes the profile of junior doctors in adult state intensive care units in Sri Lanka, a lower middle-income country. Materials and Methods: This was a national cross-sectional survey using an anonymous self-administered electronic questionnaire. Results: Five hundred and thirty-nine doctors in 93 Intensive Care Units (ICUs) were contacted, generating 207 responses. Just under half of the respondents (93, 47%) work exclusively in ICUs. Most junior doctors (150, 75.8%) had no previous exposure to anesthesia and 134 (67.7%) had no previous ICU experience while 116 (60.7%) ICU doctors wished to specialize in critical care. However, only a few (12, 6.3%) doctors had completed a critical care diploma course. There was a statistically significant difference (P < 0.05) between the self-assessed confidence of anesthetic background junior doctors and non-anesthetists. The overall median competency for doctors improves with the length of ICU experience and is statistically significant (P < 0.05). ICU postings were less happy and more stressful compared to the last non-ICU posting (P < 0.05 for both). The vast majority, i.e., 173 (88.2%) of doctors felt the care provided for patients in their ICUs was good, very good, or excellent while 71 doctors (36.2%) would be happy to recommend the ICU where they work to a relative with the highest possible score of 10. Conclusion: Measures to improve training opportunities for these doctors and strategies to improve their retention in ICUs need to be addressed.

malERA Refresh Consultative Panel on Insecticide and Drug Resistance. 2017. malERA: An updated research agenda for insecticide and drug resistance in malaria elimination and eradication. PLoS Med, 14 (11), pp. e1002450. | Show Abstract | Read more

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated-too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination.

Tosas Auguet O, Stabler RA, Betley J, Preston MD, Dhaliwal M, Gaunt M, Ioannou A, Desai N, Karadag T, Batra R et al. 2017. Frequent undetected MRSA ward-based transmission linked to patient sharing between hospitals. Clin Infect Dis, | Show Abstract | Read more

Background: Recent evidence suggests hospital transmission of methicillin-resistant Staphylococcus aureus (MRSA) is uncommon in UK centers that have implemented sustained infection control programmes. We investigated whether a healthcare-network analysis could shed light on transmission paths currently sustaining MRSA levels in UK hospitals. Methods: A cross-sectional observational study was performed in two NHS hospital groups and a general district hospital in South-East London. All MRSA patients identified at inpatient, outpatient and community settings between 1st November 2011 and 29th February 2012 were included. We identified genetically-defined MRSA transmission clusters in individual hospitals and across the healthcare-network, and examined genetic differentiation of ST22 MRSA isolates within and between hospitals and inpatient or outpatient and community settings, as informed by average and median pairwise single nucleotide polymorphisms (SNPs) and SNP-based proportions of nearly identical isolates ('I'). Results: 248/610 (40.7%) MRSA patients were linked in 90 transmission-clusters, of which 27 spanned multiple hospitals. Analysis of a large 32 patient ST22-MRSA cluster showed that 26/32 patients (81·3%) had multiple contacts with one another during ward stays at any hospital. No residential, outpatient or significant community healthcare contacts were identified. Genetic differentiation between ST22 MRSA inpatient isolates from different hospitals was less than between inpatient isolates from the same hospitals (p ≤ 0.01). Conclusions: There is evidence of frequent ward-based transmission of MRSA brought about by frequent patient admissions to multiple hospitals. Limiting in-ward transmission requires sharing of MRSA-status data between hospitals.

Halder JB, Benton J, Julé AM, Guérin PJ, Olliaro PL, Basáñez M-G, Walker M. 2017. Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing. PLoS Negl Trop Dis, 11 (10), pp. e0006053. | Show Abstract | Read more

BACKGROUND: Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)'s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance. METHODOLOGY: We performed a systematic literature review to identify studies concluding after 2000 that collected IPD suitable for estimating drug efficacy against STH. We included studies that administered a variety of anthelmintics with follow ups less than 60 days after treatment. We estimated the number of IPD and extracted cohort- and study-level meta-data. PRINCIPAL FINDINGS: We estimate that there exist individual data on approximately 35,000 participants from 129 studies conducted in 39 countries, including 34 out of 103 countries where PCT is recommended. We find significant heterogeneity in diagnostic methods, times of outcome assessment, and the reported measure of efficacy. We also quantify cohorts comprising pre-school age children, pregnant women, and co-infected participants, including with HIV. CONCLUSIONS: We argue that establishing a global IPD repository would improve the capacity to monitor and evaluate the efficacy of anthelmintic drugs, respond to changes and safeguard the ongoing effectiveness of PCT. Establishing a fair, transparent data governance policy will be key for the engagement of the global STH community.

van der Meer AJ, Zeerleder S, Blok DC, Kager LM, Lede IO, Rahman W, Afroz R, Ghose A, Visser CE, Zahed ASM et al. 2017. Neutrophil extracellular traps in patients with pulmonary tuberculosis. Respir Res, 18 (1), pp. 181. | Show Abstract | Read more

Tuberculosis is a devastating infectious disease causing many deaths worldwide. Recent investigations have implicated neutrophil extracellular traps (NETs) in the host response to tuberculosis. The aim of the current study was to obtain evidence for NETs release in the circulation during human tuberculosis. For this we measured the plasma concentrations of nucleosomes in conjunction with neutrophil elastase, in 64 patients with active pulmonary tuberculosis and 32 healthy controls. Patients with active tuberculosis had elevated plasma levels of nucleosomes and elastase when compared with local healthy blood donors. Furthermore nucleosome and elastase levels showed a positive correlation. These findings provide the first evidence for the release of NETs in the circulation of patients with active pulmonary tuberculosis.

Agweyu A, Oliwa J, Gathara D, Muinga N, Allen E, Lilford RJ, English M. 2017. Comparable outcomes among trial and non-trial participants in a clinical trial of antibiotics for childhood pneumonia: A retrospective cohort study. J Clin Epidemiol, | Show Abstract | Read more

OBJECTIVE: We compared characteristics and outcomes of children enrolled in a randomized controlled trial (RCT) comparing oral amoxicillin and benzyl penicillin for the treatment of chest indrawing pneumonia versus children who received routine care to determine the external validity of the trial results. STUDY DESIGN AND SETTING: We undertook a retrospective cohort study of children aged 2 - 59 months admitted in six Kenyan hospitals. Data for non-trial participants were extracted from inpatient records upon conclusion of the RCT. Mortality among trial versus non-trial participants was compared in multivariate models. RESULTS: 1709 children were included, of whom 527 were enrolled in the RCT and 1182 received routine care. History of a wheeze was more common among trial participants (35.4% versus 11.2%; p<0.01), while dehydration was more common among non-trial participants (8.6% versus 5.9%; p=0.05). Other patient characteristics were balanced between the two groups. Among those with available outcome data, 14/1140 (1.2%) non-trial participants died compared to 4/527 (0.8%) enrolled in the trial (adjusted odds ratio 0.7; 95% confidence interval 0.2 to 2.1). CONCLUSION: Patient characteristics were similar and mortality was low among trial and non-trial participants. These findings support the revised World Health Organization treatment recommendations for chest indrawing pneumonia.

Awab GR, Imwong M, Bancone G, Jeeyapant A, Day NPJ, White NJ, Woodrow CJ. 2017. Chloroquine-Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial. Am J Trop Med Hyg, 97 (6), pp. 1782-1787. | Show Abstract | Read more

Afghanistan's national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25-0.54) (intention-to-treat analysis). Protection against recurrence was greater in the first 6 months of follow-up (HR 0.082; 95% CI 0.029-0.23) than later (HR 0.65, 95% CI 0.41-1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however, in none of these cases did hemoglobin fall by ≥ 2 g/dL or to below 7 g/dL, and genotyping did not detect any cases of Mediterranean variant G6PD deficiency. PQ 0.25 mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point-of-care phenotypic tests for G6PD deficiency.

Lim R, Tripura R, J Peto T, Sareth M, Sanann N, Davoeung C, Nguon C, Cheah PY. 2017. Drama as a community engagement strategy for malaria in rural Cambodia. Wellcome Open Res, 2 pp. 95. | Show Abstract | Read more

Background: Countries in Southeast Asia are working to eliminate multidrug-resistant falciparum malaria, a major cause of mortality in tropical regions. Malaria is declining but transmission persists in many rural areas and among forest workers and isolated populations. In these remote communities, conventional health services and education are limited. Mobilising and educating these populations require new approaches as many people are illiterate and do not attend village meetings. This article describes a qualitative study to assess the feasibility of a drama project as a community engagement strategy. Methods: A drama project was conducted in twenty villages in Cambodia with three key messages: to use insecticide-treated bednets and repellents, to get early diagnosis and treatment, and to learn about risks of forest-acquired malaria. Qualitative interviews were conducted with the drama team members, village malaria workers, local health staffs and villagers, to explore the feasibility of using drama to engage the community and the associated challenges. Results: 29 people were interviewed, which included 18 semi-structured interviews and one focus group discussion. Analysis of the interviews resulted in development of the following seven themes: i) exposure to malaria and engagement activities, ii) readiness and barriers to participation, iii) understanding and learning about malaria using drama, iv) entertainment value and engagement method preferences, v) challenges to community engagement, vi) future participation and vii) sustainability. The event saw a very positive response, with an encouraging average participation rate of 66%. The project faced several challenges including logistic problems, rescheduling due to raining season, and time- and budget-constraints. Conclusions: Our evaluation demonstrated that the drama project was feasible in promoting awareness and understanding of malaria prevention and control. Audience members perceived drama as entertaining and as the preferred choice of engagement activity. Participatory drama could be considered as part of the community engagement for malaria elimination.

Chernet A, Utzinger J, Sydow V, Probst-Hensch N, Paris DH, Labhardt ND, Neumayr A. 2017. Prevalence rates of six selected infectious diseases among African migrants and refugees: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis, pp. 1-15. | Show Abstract | Read more

The objective of this paper was to systematically review the literature on the prevalence of selected infectious diseases among migrants/refugees of African origin and to provide policy makers and health care professionals with evidence-based information. We pursued a systematic review and meta-analysis to determine the prevalence of six selected infectious diseases (i.e., syphilis, helminthiasis, schistosomiasis, intestinal protozoa infections, hepatitis B, and hepatitis C) among migrants/refugees of African origin. Three electronic databases (i.e., PubMed, EMBASE, and ISI Web of Science) were searched without language restrictions. Relevant data were extracted and random-effects meta-analyses conducted. Only adjusted estimates were analyzed to help account for heterogeneity and potential confounding. We assessed the quality of evidence using the GRADE approach. The results were stratified by geographical region. Ninety-six studies were included. The evidence was of low quality due to the small numbers of countries, infectious diseases, and participants included. African migrants/refugees had median (with 95% confidence interval [95% CI]) prevalence for syphilis, helminthiasis, schistosomiasis, intestinal protozoa infection, hepatitis B, and hepatitis C of 6.0% [95% CI: 2.0-7.0%], 13.0% [95% CI: 9.5-14.5%], 14.0% [95% CI: 13.0-17.0%], 15.0% [95% CI: 10.5-21.0%], 10.0% [95% CI: 6.0-14.0%], and 3.0% [95% CI: 1.0-4.0%], respectively. We found high heterogeneity regardless of the disease (I 2; minimum 97.5%, maximum 99.7%). The relatively high prevalence of some infectious diseases among African migrants/refugees warrants for systematic screening. The large heterogeneity of the available published data does not allow for stratifying such screening programs according to the geographical origin of African migrants/refugees.

Duyen HTL, Cerny D, Trung DT, Pang J, Velumani S, Toh YX, Qui PT, Hao NV, Simmons C, Haniffa M et al. 2017. Skin dendritic cell and T cell activation associated with dengue shock syndrome. Sci Rep, 7 (1), pp. 14224. | Show Abstract | Read more

The pathogenesis of severe dengue remains unclear, particularly the mechanisms underlying the plasma leakage that results in hypovolaemic shock in a small proportion of individuals. Maximal leakage occurs several days after peak viraemia implicating immunological pathways. Skin is a highly vascular organ and also an important site of immune reactions with a high density of dendritic cells (DCs), macrophages and T cells. We obtained skin biopsies and contemporaneous blood samples from patients within 24 hours of onset of dengue shock syndrome (DSS), and from healthy controls. We analyzed cell subsets by flow cytometry, and soluble mediators and antibodies by ELISA; the percentage of migratory CD1a+ dermal DCs was significantly decreased in the DSS patients, and skin CD8+ T cells were activated, but there was no accumulation of dengue-specific antibodies. Inflammatory monocytic cells were not observed infiltrating the skin of DSS cases on whole-mount histology, although CD14dim cells disappeared from blood.

Taylor AR, Schaffner SF, Cerqueira GC, Nkhoma SC, Anderson TJC, Sriprawat K, Pyae Phyo A, Nosten F, Neafsey DE, Buckee CO. 2017. Quantifying connectivity between local Plasmodium falciparum malaria parasite populations using identity by descent. PLoS Genet, 13 (10), pp. e1007065. | Citations: 1 (Scopus) | Show Abstract | Read more

With the rapidly increasing abundance and accessibility of genomic data, there is a growing interest in using population genetic approaches to characterize fine-scale dispersal of organisms, providing insight into biological processes across a broad range of fields including ecology, evolution and epidemiology. For sexually recombining haploid organisms such as the human malaria parasite P. falciparum, however, there have been no systematic assessments of the type of data and methods required to resolve fine scale connectivity. This analytical gap hinders the use of genomics for understanding local transmission patterns, a crucial goal for policy makers charged with eliminating this important human pathogen. Here we use data collected from four clinics with a catchment area spanning approximately 120 km of the Thai-Myanmar border to compare the ability of divergence (FST) and relatedness based on identity by descent (IBD) to resolve spatial connectivity between malaria parasites collected from proximal clinics. We found no relationship between inter-clinic distance and FST, likely due to sampling of highly related parasites within clinics, but a significant decline in IBD-based relatedness with increasing inter-clinic distance. This association was contingent upon the data set type and size. We estimated that approximately 147 single-infection whole genome sequenced parasite samples or 222 single-infection parasite samples genotyped at 93 single nucleotide polymorphisms (SNPs) were sufficient to recover a robust spatial trend estimate at this scale. In summary, surveillance efforts cannot rely on classical measures of genetic divergence to measure P. falciparum transmission on a local scale. Given adequate sampling, IBD-based relatedness provides a useful alternative, and robust trends can be obtained from parasite samples genotyped at approximately 100 SNPs.

Morgan MC, Maina B, Waiyego M, Mutinda C, Aluvaala J, Maina M, English M. 2017. Pulse oximetry values of neonates admitted for care and receiving routine oxygen therapy at a resource-limited hospital in Kenya. J Paediatr Child Health, | Show Abstract | Read more

AIM: There are 2.7 million neonatal deaths annually, 75% of which occur in sub-Saharan Africa and South Asia. Effective treatment of hypoxaemia through tailored oxygen therapy could reduce neonatal mortality and prevent oxygen toxicity. METHODS: We undertook a two-part prospective study of neonates admitted to a neonatal unit in Nairobi, Kenya, between January and December 2015. We determined the prevalence of hypoxaemia and explored associations of clinical risk factors and signs of respiratory distress with hypoxaemia and mortality. After staff training on oxygen saturation (SpO2 ) target ranges, we enrolled a consecutive sample of neonates admitted for oxygen and measured SpO2 at 0, 6, 12, 18 and 24 h post-admission. We estimated the proportion of neonates outside the target range (≥34 weeks: ≥92%; <34 weeks: 89-93%) with 95% confidence intervals (CIs). RESULTS: A total of 477 neonates were enrolled. Prevalence of hypoxaemia was 29.2%. Retractions (odds ratio (OR) 2.83, 95% CI 1.47-5.47), nasal flaring (OR 2.68, 95% CI 1.51-4.75), and grunting (OR 2.47, 95% CI 1.27-4.80) were significantly associated with hypoxaemia. Nasal flaring (OR 2.85, 95% CI 1.25-6.54), and hypoxaemia (OR 3.06, 95% CI 1.54-6.07) were significantly associated with mortality; 64% of neonates receiving oxygen were out of range at ≥2 time points and 43% at ≥3 time points. CONCLUSION: There is a high prevalence of hypoxaemia at admission and a strong association between hypoxaemia and mortality in this Kenyan neonatal unit. Many neonates had out of range SpO2 values while receiving oxygen. Further research is needed to test strategies aimed at improving the accuracy of oxygen provision in low-resource settings.

Gonçalves BP, Kapulu MC, Sawa P, Guelbéogo WM, Tiono AB, Grignard L, Stone W, Hellewell J, Lanke K, Bastiaens GJH et al. 2017. Examining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity. Nat Commun, 8 (1), pp. 1133. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

A detailed understanding of the human infectious reservoir is essential for improving malaria transmission-reducing interventions. Here we report a multi-regional assessment of population-wide malaria transmission potential based on 1209 mosquito feeding assays in endemic areas of Burkina Faso and Kenya. Across both sites, we identified 39 infectious individuals. In high endemicity settings, infectious individuals were identifiable by research-grade microscopy (92.6%; 25/27), whilst one of three infectious individuals in the lowest endemicity setting was detected by molecular techniques alone. The percentages of infected mosquitoes in the different surveys ranged from 0.05 (4/7716) to 1.6% (121/7749), and correlate positively with transmission intensity. We also estimated exposure to malaria vectors through genetic matching of blood from 1094 wild-caught bloodfed mosquitoes with that of humans resident in the same houses. Although adults transmitted fewer parasites to mosquitoes than children, they received more mosquito bites, thus balancing their contribution to the infectious reservoir.

Dahal P, Simpson JA, Dorsey G, Guérin PJ, Price RN, Stepniewska K. 2017. Statistical methods to derive efficacy estimates of anti-malarials for uncomplicated Plasmodium falciparum malaria: pitfalls and challenges. Malar J, 16 (1), pp. 430. | Show Abstract | Read more

The Kaplan-Meier (K-M) method is currently the preferred approach to derive an efficacy estimate from anti-malarial trial data. In this approach event times are assumed to be continuous and estimates are generated on the assumption that there is only one cause of failure. In reality, failures are captured at pre-scheduled time points and patients can fail treatment due to a variety of causes other than the primary endpoint, commonly termed competing risk events. Ignoring these underlying assumptions can potentially distort the derived efficacy estimates and result in misleading conclusions. This review details the evolution of statistical methods used to derive anti-malarial efficacy for uncomplicated Plasmodium falciparum malaria and assesses the limitations of the current practices. Alternative approaches are explored and their implementation is discussed using example data from a large multi-site study.

Woods K, Nic-Fhogartaigh C, Arnold C, Boutthasavong L, Phuklia W, Lim C, Chanthongthip A, Tulsiani SM, Craig SB, Burns M-A et al. 2017. A comparison of two molecular methods for diagnosing leptospirosis from three different sample types in patients presenting with fever in Laos. Clin Microbiol Infect, | Show Abstract | Read more

OBJECTIVES: To compare two molecular assays (rrs quantitative PCR (qPCR) versus a combined 16SrRNA and LipL32 qPCR) on different sample types for diagnosing leptospirosis in febrile patients presenting to Mahosot Hospital, Vientiane, Laos. METHODS: Serum, buffy coat and urine samples were collected on admission, and follow-up serum ∼10 days later. Leptospira spp. culture and microscopic agglutination tests (MAT) were performed as reference standards. Bayesian latent class modelling was performed to estimate sensitivity and specificity of each diagnostic test. RESULTS: In all, 787 patients were included in the analysis: 4/787 (0.5%) were Leptospira culture positive, 30/787 (3.8%) were MAT positive, 76/787 (9.7%) were rrs qPCR positive and 20/787 (2.5%) were 16SrRNA/LipL32 qPCR positive for pathogenic Leptospira spp. in at least one sample. Estimated sensitivity and specificity (with 95% CI) of 16SrRNA/LipL32 qPCR on serum (53.9% (33.3%-81.8%); 99.6% (99.2%-100%)), buffy coat (58.8% (34.4%-90.9%); 99.9% (99.6%-100%)) and urine samples (45.0% (27.0%-66.7%); 99.6% (99.3%-100%)) were comparable with those of rrs qPCR, except specificity of 16SrRNA/LipL32 qPCR on urine samples was significantly higher (99.6% (99.3%-100%) vs. 92.5% (92.3%-92.8%), p <0.001). Sensitivities of MAT (16% (95% CI 6.3%-29.4%)) and culture (25% (95% CI 13.3%-44.4%)) were low. Mean positive Cq values showed that buffy coat samples were more frequently inhibitory to qPCR than either serum or urine (p <0.001). CONCLUSIONS: Serum and urine are better samples for qPCR than buffy coat, and 16SrRNA/LipL32 qPCR performs better than rrs qPCR on urine. Quantitative PCR on admission is a reliable rapid diagnostic tool, performing better than MAT or culture, with significant implications for clinical and epidemiological investigations of this global neglected disease.

Pisani L, Roozeman J-P, Simonis FD, Giangregorio A, van der Hoeven SM, Schouten LR, Horn J, Neto AS, Festic E, Dondorp AM et al. 2017. Risk stratification using SpO2/FiO2 and PEEP at initial ARDS diagnosis and after 24 h in patients with moderate or severe ARDS. Ann Intensive Care, 7 (1), pp. 108. | Show Abstract | Read more

BACKGROUND: We assessed the potential of risk stratification of ARDS patients using SpO2/FiO2 and positive end-expiratory pressure (PEEP) at ARDS onset and after 24 h. METHODS: We used data from a prospective observational study in patients admitted to a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Risk stratification was by cutoffs for SpO2/FiO2 and PEEP. The primary outcome was in-hospital mortality. Patients with moderate or severe ARDS with a length of stay of > 24 h were included in this study. Patients were assigned to four predefined risk groups: group I (SpO2/FiO2 ≥ 190 and PEEP < 10 cm H2O), group II (SpO2/FiO2 ≥ 190 and PEEP ≥ 10 cm), group III (SpO2/FiO2 < 190 and PEEP < 10 cm H2O) and group IV (SpO2/FiO2 < 190 and PEEP ≥ 10 cm H2O). RESULTS: The analysis included 456 patients. SpO2/FiO2 and PaO2/FiO2 had a strong relationship (P < 0.001, R 2 = 0.676) that could be described in a linear regression equation (SpO2/FiO2 = 42.6 + 1.0 * PaO2/FiO2). Risk stratification at initial ARDS diagnosis resulted in groups that had no differences in in-hospital mortality. Risk stratification at 24 h resulted in groups with increasing mortality rates. The association between group assignment at 24 h and outcome was confounded by several factors, including APACHE IV scores, arterial pH and plasma lactate levels, and vasopressor therapy. CONCLUSIONS: In this cohort of patients with moderate or severe ARDS, SpO2/FiO2 and PaO2/FiO2 have a strong linear relationship. In contrast to risk stratification at initial ARDS diagnosis, risk stratification using SpO2/FiO2 and PEEP after 24 h resulted in groups with worsening outcomes. Risk stratification using SpO2/FiO2 and PEEP could be practical, especially in resource-limited settings.

Darton TC, Jones C, Dongol S, Voysey M, Blohmke CJ, Shrestha R, Karkey A, Shakya M, Arjyal A, Waddington CS et al. 2017. Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal. Front Microbiol, 8 (OCT), pp. 2031. | Show Abstract | Read more

New diagnostic tests for enteric fever are urgently needed to assist with timely antimicrobial treatment of patients and to measure the efficacy of prevention measures such as vaccination. In a novel translational approach, here we use two recently developed controlled human infection models (CHIM) of enteric fever to evaluate an antibody-in-lymphocyte supernatant (ALS) assay, which can detect recent IgA antibody production by circulating B cells inex vivomononuclear cell culture. We calculated the discriminative ability of the ALS assay to distinguish diagnosed cases in the two CHIM studies in Oxford, prior to evaluating blood culture-confirmed diagnoses of patients presenting with fever to hospital in an endemic areas of Kathmandu, Nepal. Antibody responses to membrane preparations and lipopolysaccharide provided good sensitivity (>90%) for diagnosing systemic infection after oral challenge withSalmonellaTyphi orS. Paratyphi A. Assay specificity was moderate (~60%) due to imperfect sensitivity of blood culture as the reference standard and likely unrecognized subclinical infection. These findings were augmented through the translation of the assay into the endemic setting in Nepal. Anti-MP IgA responses again exhibited good sensitivity (86%) but poor specificity (51%) for detecting blood culture-confirmed enteric fever cases (ROC AUC 0.79, 95%CI 0.70-0.88). Patients with anti-MP IgA ALS titers in the upper quartile exhibited a clinical syndrome synonymous with enteric fever. While better reference standards are need to assess enteric fever diagnostics, routine use of this ALS assay could be used to rule out infection and has the potential to double the laboratory detection rate of enteric fever in this setting over blood culture alone.

Adhikari B, Phommasone K, Pongvongsa T, Kommarasy P, Soundala X, Henriques G, White NJ, Day NPJ, Dondorp AM, von Seidlein L et al. 2017. Factors associated with population coverage of targeted malaria elimination (TME) in southern Savannakhet Province, Lao PDR. Malar J, 16 (1), pp. 424. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Targeted malaria elimination (TME) in Lao PDR (Laos) included three rounds of mass drug administrations (MDA) against malaria followed by quarterly blood surveys in two villages in Nong District at Savannakhet Province. The success of MDA largely depends upon the efficacy of the anti-malarial drug regimen, local malaria epidemiology and the population coverage. In order to explore the reasons for participation in TME, a quantitative survey was conducted after the completion of the three rounds of MDA. METHODS: The survey was conducted in two villages with a total of 158 households in July and August 2016. Among the 973 villagers eligible for participation in the MDA, 158 (16.2%) adults (> 18 years) were selected, one each from every household for the interviews using a quantitative questionnaire. RESULTS: 150/158 (94.9%) respondents participated at least in one activity (taking medicine or testing their blood) of TME. 141/150 (94.0%) respondents took part in the MDA and tested their blood in all three rounds. 17/158 (10.7%) were partial or non-participants in three rounds of MDA. Characteristics of respondents which were independently associated with completion of three rounds of MDA included: attending TME meetings [AOR = 12.0 (95% CI 1.1-20.5) (p = 0.03)], knowing that malaria can be diagnosed through blood tests [AOR = 5.6 (95% CI 1.0-32.3) (p = 0.05)], all members from household participated [AOR = 4.2 (95% CI 1.3-14.0) (p = 0.02)], liking all aspects of TME [AOR = 17.2 (95% CI 1.6-177.9) (p = 0.02)] and the perception that TME was important [AOR = 14.9 (95% CI 1.3-171.2) (p = 0.03)]. CONCLUSION: Complete participation in TME was significantly associated with participation in community engagement activities, knowledge that the blood tests were for malaria diagnosis, family members' participation at TME and perceptions that TME was worthwhile. A responsive approach to community engagement that includes formative research and the involvement of community members may increase the uptake of the intervention.

Vellinga NAR, Boerma EC, Koopmans M, Donati A, Dubin A, Shapiro NI, Pearse RM, van der Voort PHJ, Dondorp AM, Bafi T et al. 2017. Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis. Crit Care, 21 (1), pp. 255. | Show Abstract | Read more

BACKGROUND: Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. METHODS: This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. RESULTS: In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). CONCLUSIONS: In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. TRIAL REGISTRATION:, NCT01179243 . Registered on August 3, 2010.

Diep NTN, Thai PQ, Trang NNM, Jäger J, Fox A, Horby P, Phuong HVM, Anh DD, Mai LETQ, VAN Doorn HR, Nadjm B. 2017. Strongyloides stercoralis seroprevalence in Vietnam. Epidemiol Infect, 145 (15), pp. 3214-3218. | Show Abstract | Read more

Strongyloidiasis is a neglected tropical disease caused by the roundworm Strongyloides stercoralis affecting 30-100 million people worldwide. Many Southeast-Asian countries report a high prevalence of S. stercoralis infection, but there are little data from Vietnam. Here, we evaluated the seroprevalence of S. stercoralis related to geography, sex and age in Vietnam through serological testing of anonymized sera. Sera (n = 1710, 1340 adults and 270 children) from an anonymized age-stratified serum bank from four regions in Vietnam between 2012 and 2013 were tested using a commercial Strongyloides ratti immunoglobulin G ELISA. Seroreactivity was found in 29·1% (390/1340) of adults and 5·5% (15/270) of children. Male adults were more frequently seroreactive than females (33·3% vs. 24·9%, P = 0·001). The rural central highlands had the highest seroprevalence (42·4% of adults). Seroreactivity in the other regions was 29·9% (Hue) and 26·0% and 18·2% in the large urban centres of Hanoi and Ho Chi Minh City, respectively. We conclude that seroprevalence of S. stercoralis was high in the Vietnamese adult population, especially in rural areas.

Haniffa R, Mukaka M, Munasinghe SB, De Silva AP, Jayasinghe KSA, Beane A, de Keizer N, Dondorp AM. 2017. Simplified prognostic model for critically ill patients in resource limited settings in South Asia. Crit Care, 21 (1), pp. 250. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Current critical care prognostic models are predominantly developed in high-income countries (HICs) and may not be feasible in intensive care units (ICUs) in lower- and middle-income countries (LMICs). Existing prognostic models cannot be applied without validation in LMICs as the different disease profiles, resource availability, and heterogeneity of the population may limit the transferability of such scores. A major shortcoming in using such models in LMICs is the unavailability of required measurements. This study proposes a simplified critical care prognostic model for use at the time of ICU admission. METHODS: This was a prospective study of 3855 patients admitted to 21 ICUs from Bangladesh, India, Nepal, and Sri Lanka who were aged 16 years and over and followed to ICU discharge. Variables captured included patient age, admission characteristics, clinical assessments, laboratory investigations, and treatment measures. Multivariate logistic regression was used to develop three models for ICU mortality prediction: model 1 with clinical, laboratory, and treatment variables; model 2 with clinical and laboratory variables; and model 3, a purely clinical model. Internal validation based on bootstrapping (1000 samples) was used to calculate discrimination (area under the receiver operating characteristic curve (AUC)) and calibration (Hosmer-Lemeshow C-Statistic; higher values indicate poorer calibration). Comparison was made with the Acute Physiology and Chronic Health Evaluation (APACHE) II and Simplified Acute Physiology Score (SAPS) II models. RESULTS: Model 1 recorded the respiratory rate, systolic blood pressure, Glasgow Coma Scale (GCS), blood urea, haemoglobin, mechanical ventilation, and vasopressor use on ICU admission. Model 2, named TropICS (Tropical Intensive Care Score), included emergency surgery, respiratory rate, systolic blood pressure, GCS, blood urea, and haemoglobin. Model 3 included respiratory rate, emergency surgery, and GCS. AUC was 0.818 (95% confidence interval (CI) 0.800-0.835) for model 1, 0.767 (0.741-0.792) for TropICS, and 0.725 (0.688-0.762) for model 3. The Hosmer-Lemeshow C-Statistic p values were less than 0.05 for models 1 and 3 and 0.18 for TropICS. In comparison, when APACHE II and SAPS II were applied to the same dataset, AUC was 0.707 (0.688-0.726) and 0.714 (0.695-0.732) and the C-Statistic was 124.84 (p < 0.001) and 1692.14 (p < 0.001), respectively. CONCLUSION: This paper proposes TropICS as the first multinational critical care prognostic model developed in a non-HIC setting.

Munster VJ, Wells D, Lambe T, Wright D, Fischer RJ, Bushmaker T, Saturday G, van Doremalen N, Gilbert SC, de Wit E, Warimwe GM. 2017. Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model. NPJ Vaccines, 2 (1), pp. 28. | Show Abstract | Read more

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic virus that causes severe respiratory disease in humans with a case fatality rate close to 40%, but for which no vaccines are available. Here, we evaluated the utility of ChAdOx1, a promising replication-deficient simian adenovirus vaccine vector platform with an established safety profile in humans and dromedary camels, for MERS-CoV vaccine development. Using a transgenic lethal BALB/c MERS-CoV mouse model we showed that single dose intranasal or intramuscular immunisation with ChAdOx1 MERS, encoding full-length MERS-CoV Spike glycoprotein, is highly immunogenic and confers protection against lethal viral challenge. Immunogenicity and efficacy were comparable between immunisation routes. Together these data provide support for further evaluation of ChAdOx1 MERS vaccine in humans and dromedary camels, the animal reservoir of infection.

Lan NPH, Hien NH, Le Thi Phuong T, Thanh DP, Thieu NTV, Ngoc DTT, Tuyen HT, Vinh PV, Ellington MJ, Thwaites GE et al. 2017. Phenotypic and genotypic characteristics of ESBL and AmpC producing organisms associated with bacteraemia in Ho Chi Minh City, Vietnam. Antimicrob Resist Infect Control, 6 (1), pp. 105. | Show Abstract | Read more

BACKGROUND: Broad-spectrum antimicrobials are commonly used as empirical therapy for infections of presumed bacterial origin. Increasing resistance to these antimicrobial agents has prompted the need for alternative therapies and more effective surveillance. Better surveillance leads to more informed and improved delivery of therapeutic interventions, potentially leading to better treatment outcomes. METHODS: We screened 1017 Gram negative bacteria (excludingPseudomonasspp. andAcinetobacterspp.) isolated between 2011 and 2013 from positive blood cultures for susceptibility against third generation cephalosporins, ESBL and/or AmpC production, and associated ESBL/AmpC genes, at the Hospital for Tropical Diseases in Ho Chi Minh City. RESULTS: Phenotypic screening found that 304/1017 (30%) organisms were resistance to third generation cephalosporins; 172/1017 (16.9%) of isolates exhibited ESBL activity, 6.2% (63/1017) had AmpC activity, and 0.5% (5/1017) had both ESBL and AmpC activity.E. coliandAeromonasspp. were the most common organisms associated with ESBL and AmpC phenotypes, respectively.Nearly half of the AmpC producers harboured an ESBL gene. There was no significant difference (p > 0.05) between the antimicrobial resistance phenotypes of the organisms associated with community and hospital-acquired infections. CONCLUSION: AmpC and ESBL producing organisms were commonly associated with bloodstream infections in this setting, with antimicrobial resistant organisms being equally distributed between infections originating from the community and healthcare settings.Aeromonasspp., which was associated with bloodstream infections in cirrhotic/hepatitis patients, were the most abundant AmpC producing organism. We conclude that empirical monotherapy with third generation cephalosporins may not be optimum in this setting.

McLean ARD, Stanisic D, McGready R, Chotivanich K, Clapham C, Baiwog F, Pimanpanarak M, Siba P, Mueller I, King CL et al. 2017. P. falciparum infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission. PLoS One, 12 (10), pp. e0186577. | Show Abstract | Read more

INTRODUCTION: During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. Plasmodium falciparum infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear. METHODS: Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four P. falciparum antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral P. falciparum infection during pregnancy or placental P. falciparum infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between P. falciparum infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG. RESULTS: Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental P. falciparum infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log2 units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed. DISCUSSION: Primigravid women may be at risk of impaired maternofetal antibody transport with placental P. falciparum infection. Direct effects of P. falciparum on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.

Franzen SRP, Chandler C, Siribaddana S, Atashili J, Angus B, Lang T. 2017. Strategies for developing sustainable health research capacity in low and middle-income countries: a prospective, qualitative study investigating the barriers and enablers to locally led clinical trial conduct in Ethiopia, Cameroon and Sri Lanka. BMJ Open, 7 (10), pp. e017246. | Show Abstract | Read more

OBJECTIVES: In 2013, the WHO stated that unless low-income and middle-income countries (LMICs) become producers of research, health goals would be hard to achieve. Among the capacities required to build a local evidence base, ability to conduct clinical trials is important. There is no evidence-based guidance for the best ways to develop locally led trial capacity. This research aims to identify the barriers and enablers to locally led clinical trial conduct in LMICs and determine strategies for their sustainable development. DESIGN: Prospective, multiple case study design consisting of interviews (n=34), focus group discussions (n=13) and process mapping exercises (n=10). SETTING: Case studies took place in Ethiopia (2011), Cameroon (2012) and Sri Lanka (2013). PARTICIPANTS: Local health researchers with previous experiences of clinical trials or stakeholders with an interest in trials were purposively selected through registration searches and snowball sampling (n=100). PRIMARY AND SECONDARY OUTCOME MEASURES: Discussion notes and transcripts were analysed using thematic coding analysis. Key themes and mechanisms were identified. RESULTS: Institutions and individuals were variably successful at conducting trials, but there were strong commonalities in the barriers and enablers across all levels and functions of the research systems. Transferable mechanisms were summarised into the necessary conditions for trial undertaking, which included: awareness of research, motivation, knowledge and technical skills, leadership capabilities, forming collaborations, inclusive trial operations, policy relevance and uptake and macro and institutional strengthening. CONCLUSIONS: Barriers and enablers to locally led trial undertaking exist at all levels and functions of LMIC research systems. Establishing the necessary conditions to facilitate this research will require multiple, coordinated interventions that seek to resolve them in a systemic manner. The strategies presented in the discussion provide an evidence-based framework for a self-sustaining capacity development approach. This represents an important contribution to the literature that will be relevant for research funders, users and producers.

Snow RW, Sartorius B, Kyalo D, Maina J, Amratia P, Mundia CW, Bejon P, Noor AM. 2017. The prevalence of Plasmodium falciparum in sub-Saharan Africa since 1900. Nature, 550 (7677), pp. 515-518. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Malaria transmission is influenced by climate, land use and deliberate interventions. Recent declines have been observed in malaria transmission. Here we show that the African continent has witnessed a long-term decline in the prevalence of Plasmodium falciparum from 40% prevalence in the period 1900-1929 to 24% prevalence in the period 2010-2015, a trend that has been interrupted by periods of rapidly increasing or decreasing transmission. The cycles and trend over the past 115 years are inconsistent with explanations in terms of climate or deliberate intervention alone. Previous global initiatives have had minor impacts on malaria transmission, and a historically unprecedented decline has been observed since 2000. However, there has been little change in the high transmission belt that covers large parts of West and Central Africa. Previous efforts to model the changing patterns of P. falciparum transmission intensity in Africa have been limited to the past 15 years or have used maps drawn from historical expert opinions. We provide quantitative data, from 50,424 surveys at 36,966 geocoded locations, that covers 115 years of malaria history in sub-Saharan Africa; inferring from these data to future trends, we would expect continued reductions in malaria transmission, punctuated with resurgences.

Pigott DM, Deshpande A, Letourneau I, Morozoff C, Reiner RC, Kraemer MUG, Brent SE, Bogoch II, Khan K, Biehl MH et al. 2017. Local, national, and regional viral haemorrhagic fever pandemic potential in Africa: a multistage analysis. Lancet, 390 (10113), pp. 2662-2672. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Predicting when and where pathogens will emerge is difficult, yet, as shown by the recent Ebola and Zika epidemics, effective and timely responses are key. It is therefore crucial to transition from reactive to proactive responses for these pathogens. To better identify priorities for outbreak mitigation and prevention, we developed a cohesive framework combining disparate methods and data sources, and assessed subnational pandemic potential for four viral haemorrhagic fevers in Africa, Crimean-Congo haemorrhagic fever, Ebola virus disease, Lassa fever, and Marburg virus disease. METHODS: In this multistage analysis, we quantified three stages underlying the potential of widespread viral haemorrhagic fever epidemics. Environmental suitability maps were used to define stage 1, index-case potential, which assesses populations at risk of infection due to spillover from zoonotic hosts or vectors, identifying where index cases could present. Stage 2, outbreak potential, iterates upon an existing framework, the Index for Risk Management, to measure potential for secondary spread in people within specific communities. For stage 3, epidemic potential, we combined local and international scale connectivity assessments with stage 2 to evaluate possible spread of local outbreaks nationally, regionally, and internationally. FINDINGS: We found epidemic potential to vary within Africa, with regions where viral haemorrhagic fever outbreaks have previously occurred (eg, western Africa) and areas currently considered non-endemic (eg, Cameroon and Ethiopia) both ranking highly. Tracking transitions between stages showed how an index case can escalate into a widespread epidemic in the absence of intervention (eg, Nigeria and Guinea). Our analysis showed Chad, Somalia, and South Sudan to be highly susceptible to any outbreak at subnational levels. INTERPRETATION: Our analysis provides a unified assessment of potential epidemic trajectories, with the aim of allowing national and international agencies to pre-emptively evaluate needs and target resources. Within each country, our framework identifies at-risk subnational locations in which to improve surveillance, diagnostic capabilities, and health systems in parallel with the design of policies for optimal responses at each stage. In conjunction with pandemic preparedness activities, assessments such as ours can identify regions where needs and provisions do not align, and thus should be targeted for future strengthening and support. FUNDING: Paul G Allen Family Foundation, Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development.

Gimenez AM, Lima LC, Françoso KS, Denapoli PMA, Panatieri R, Bargieri DY, Thiberge J-M, Andolina C, Nosten F, Renia L et al. 2017. Vaccine Containing the Three Allelic Variants of thePlasmodium vivaxCircumsporozoite Antigen Induces Protection in Mice after Challenge with a Transgenic Rodent Malaria Parasite. Front Immunol, 8 (OCT), pp. 1275. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Plasmodium vivax is the most common species that cause malaria outside of the African continent. The development of an efficacious vaccine would contribute greatly to control malaria. Recently, using bacterial and adenoviral recombinant proteins based on theP. vivaxcircumsporozoite protein (CSP), we demonstrated the possibility of eliciting strong antibody-mediated immune responses to each of the three allelic forms ofP. vivaxCSP (PvCSP). In the present study, recombinant proteins representing the PvCSP alleles (VK210, VK247, andP. vivax-like), as well as a hybrid polypeptide, named PvCSP-All epitopes, were generated. This hybrid containing the conserved C-terminal of the PvCSP and the three variant repeat domains in tandem were successfully produced in the yeastPichia pastoris. After purification and biochemical characterization, they were used for the experimental immunization of C57BL/6 mice in a vaccine formulation containing the adjuvant Poly(I:C). Immunization with a recombinant protein expressing all three different allelic forms in fusion elicited high IgG antibody titers reacting with all three different allelic variants of PvCSP. The antibodies targeted both the C-terminal and repeat domains of PvCSP and recognized the native protein on the surface ofP. vivaxsporozoites. More importantly, mice that received the vaccine formulation were protected after challenge with chimericPlasmodium bergheisporozoites expressing CSP repeats ofP. vivaxsporozoites (Pb/PvVK210). Our results suggest that it is possible to elicit protective immunity against one of the most common PvCSP alleles using soluble recombinant proteins expressed byP. pastoris. These recombinant proteins are promising candidates for clinical trials aiming to develop a multiallele vaccine againstP. vivaxmalaria.

Andrews D, Chetty Y, Cooper BS, Virk M, Glass SK, Letters A, Kelly PA, Sudhanva M, Jeyaratnam D. 2017. Multiplex PCR point of care testing versus routine, laboratory-based testing in the treatment of adults with respiratory tract infections: a quasi-randomised study assessing impact on length of stay and antimicrobial use. BMC Infect Dis, 17 (1), pp. 671. | Show Abstract | Read more

BACKGROUND: Laboratory-based respiratory pathogen (RP) results are often available too late to influence clinical decisions such as hospitalisation or antibiotic treatment due to time delay in transport of specimens and testing schedules. Ward-based i.e. point of care (POC) testing providing rapid results may alter the clinical management pathway. METHODS: FilmArray® RP polymerase chain reaction (PCR) systems were placed in three in-patient and out-patient medical areas. Patients presenting with influenza-like illness /upper respiratory tract infection +/- lower RTI were recruited between January-July 2015. FilmArray® POC testing occurred on even days of the month (intervention) or routine, laboratory-based RP PCR testing +/- atypical serology on odd days (control). The primary outcome was length of hospital stay. The secondary outcomes were impact on the use of antimicrobials, readmissions, all-cause mortality, length of ward stay and turn-around time (TAT) (time to result from admission). RESULTS: Of 606 eligible patients, 545 (89.9%) were included; 211 in the control arm and 334 in the intervention arm. 20% of control arm patients and 24% of intervention arm patients had an RP detected. POC testing was not associated with the primary outcome measure, length of stay, but reduced the TAT from 39.5 h to 19.0 h, p < 0.001. Only the prescribing decision differed between study arms, p < 0.001. When antivirals were given, the intervention was associated with a reduction in the median time to the first dose of 36 h and allowed appropriate treatment of mycoplasma infection. CONCLUSIONS: We found no association between respiratory PCR POC testing and length of stay or most of the secondary outcomes except the antimicrobial prescribing decision. This was probably due to a delay in initiating FilmArray® testing. Despite this, POC testing allowed time-critical antivirals to be given significantly faster, appropriate mycoplasma treatment and results were available considerably faster than routine, laboratory-based testing. Ward-staff of all grades performed POC testing without difficulty suggesting potential use across many divergent healthcare settings. Further studies evaluating the implementation of rapid respiratory PCR POC testing and the effect on length of stay and antimicrobial use are required. TRIAL REGISTRATION: ISRCTN10470967 , Retrospectively Registered, 30/6/2015.

Cao P, Klonis N, Zaloumis S, Dogovski C, Xie SC, Saralamba S, White LJ, Fowkes FJI, Tilley L, Simpson JA, McCaw JM. 2017. A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum. Antimicrob Agents Chemother, 61 (12), pp. AAC.00618-17-AAC.00618-17. | Show Abstract | Read more

Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimization of dosing regimens and the development of strategies to prolong the life span of current first-line treatment options. Recent short-drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic (PK-PD) paradigm in which the killing rate depends only on drug concentration. Here, we introduce a dynamic stress model of parasite killing and show through application to 3D7 laboratory strain viability data that the inclusion of a time-dependent parasite stress response dramatically improves the model's explanatory power compared to that of a traditional PK-PD model. Our model demonstrates that the previously reported hypersensitivity of early-ring-stage parasites of the 3D7 strain to dihydroartemisinin compared to other parasite stages is due primarily to a faster development of stress rather than a higher maximum achievable killing rate. We also perform in vivo simulations using the dynamic stress model and demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions for in vivo parasite clearance. Given the important role that PK-PD models play in the design of clinical trials for the evaluation of alternative drug dosing regimens, our novel model will contribute to the further development and improvement of antimalarial therapies.

Parker DM, Landier J, Thu AM, Lwin KM, Delmas G, Nosten FH, Malaria Elimination Task Force Group. 2017. Scale up of aPlasmodium falciparumelimination program and surveillance system in Kayin State, Myanmar. Wellcome Open Res, 2 pp. 98. | Citations: 1 (Scopus) | Show Abstract | Read more

Background: Myanmar has one of the largest malaria burdens in the Greater Mekong Subregion (GMS). Throughout the GMS,Plasmodium falciparumparasites are increasingly resistant to artemisinin combination therapies. Given that there are no current alternative treatment therapies, one proposed solution to the threat of untreatableP. falciparummalaria is to eliminate the parasite from the region. Several small-scale elimination projects have been piloted in the GMS, including along the Myanmar-Thailand border. Following the success of the pilot elimination project along the Myanmar-Thailand border, there was a scale up to a broad area of Eastern Kayin State, Myanmar. Here we describe the establishment of the scale up elimination project in Easter Kayin State.Methods:The scale up relied on geographic reconnaissance and a geographic information system, community engagement, generalized access to community-based early diagnosis and treatment, near real-time epidemiological surveillance, cross sectional malaria prevalence surveys and targeted mass drug administration in villages with high prevalence ofP. falciparummalaria. Molecular markers of drug resistance were also monitored in individuals with symptomatic and asymptomatic infections.Discussion:This protocol illustrates the establishment of an elimination project and operational research in a remote, rural area encompassing several armed groups, multiple political organizations and a near-absent health care infrastructure. The establishment of the project relied on a strong rapport with the target community, on-the-ground knowledge (through geographic surveys and community engagement), rapid decision making and an approach that was flexible enough to quickly adapt to a complex landscape. The elimination project is ongoing, now over three years in operation, and assessment of the impact of this operational research will follow. This project has relevance not only for other malaria elimination projects but also for operational research aimed at eliminating other diseases.

Cheah PY, Day NPJ. 2017. Data sharing: experience from a tropical medicine research unit. Lancet, 390 (10103), pp. 1642. | Citations: 1 (Scopus) | Read more

Le T, Thwaites G, Wolbers M. 2017. Itraconazole or Amphotericin B for Talaromycosis. N Engl J Med, 377 (14), pp. 1403. | Read more

Malla L, Perera-Salazar R, McFadden E, Ogero M, Stepniewska K, English M. 2017. Handling missing data in propensity score estimation in comparative effectiveness evaluations: a systematic review. J Comp Eff Res, | Show Abstract | Read more

AIM: Even though systematic reviews have examined how aspects of propensity score methods are used, none has reviewed how the challenge of missing data is addressed with these methods. This review therefore describes how missing data are addressed with propensity score methods in observational comparative effectiveness studies. METHODS: Published articles on observational comparative effectiveness studies were extracted from MEDLINE and EMBASE databases. RESULTS: Our search yielded 167 eligible articles. Majority of these studies (114; 68%) conducted complete case analysis with only 53 of them stating this in the methods. Only 16 articles reported use of multiple imputation. CONCLUSION: Few researchers use correct methods for handling missing data or reported missing data methodology which may lead to reporting biased findings.

O'Hara GA, McNaughton AL, Maponga T, Jooste P, Ocama P, Chilengi R, Mokaya J, Liyayi MI, Wachira T, Gikungi DM et al. 2017. Hepatitis B virus infection as a neglected tropical disease. PLoS Negl Trop Dis, 11 (10), pp. e0005842. | Read more

Salter SJ, Turner C, Watthanaworawit W, de Goffau MC, Wagner J, Parkhill J, Bentley SD, Goldblatt D, Nosten F, Turner P. 2017. A longitudinal study of the infant nasopharyngeal microbiota: The effects of age, illness and antibiotic use in a cohort of South East Asian children. PLoS Negl Trop Dis, 11 (10), pp. e0005975. | Show Abstract | Read more

A longitudinal study was undertaken in infants living in the Maela refugee camp on the Thailand-Myanmar border between 2007 and 2010. Nasopharyngeal swabs were collected monthly, from birth to 24 months of age, with additional swabs taken if the infant was diagnosed with pneumonia according to WHO clinical criteria. At the time of collection, swabs were cultured for Streptococcus pneumoniae and multiple serotype carriage was assessed. The bacterial 16S rRNA gene profiles of 544 swabs from 21 infants were analysed to see how the microbiota changes with age, respiratory infection, antibiotic consumption and pneumococcal acquisition. The nasopharyngeal microbiota is a somewhat homogenous community compared to that of other body sites. In this cohort it is dominated by five taxa: Moraxella, Streptococcus, Haemophilus, Corynebacterium and an uncharacterized Flavobacteriaceae taxon of 93% nucleotide similarity to Ornithobacterium. Infant age correlates with certain changes in the microbiota across the cohort: Staphylococcus and Corynebacterium are associated with the first few months of life while Moraxella and the uncharacterised Flavobacteriaceae increase in proportional abundance with age. Respiratory illness and antibiotic use often coincide with an unpredictable perturbation of the microbiota that differs from infant to infant and in different illness episodes. The previously described interaction between Dolosigranulum and Streptococcus was observed in these data. Monthly sampling demonstrates that the nasopharyngeal microbiota is in flux throughout the first two years of life, and that in this refugee camp population the pool of potential bacterial colonisers may be limited.

Pokharel S, Basnyat B, Arjyal A, Mahat SP, Kc RK, Bhuju A, Poudyal B, Kestelyn E, Shrestha R, Phuong DNT et al. 2017. Co-trimoxazole versus azithromycin for the treatment of undifferentiated febrile illness in Nepal: study protocol for a randomized controlled trial. Trials, 18 (1), pp. 450. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Undifferentiated febrile illness (UFI) includes typhoid and typhus fevers and generally designates fever without any localizing signs. UFI is a great therapeutic challenge in countries like Nepal because of the lack of available point-of-care, rapid diagnostic tests. Often patients are empirically treated as presumed enteric fever. Due to the development of high-level resistance to traditionally used fluoroquinolones against enteric fever, azithromycin is now commonly used to treat enteric fever/UFI. The re-emergence of susceptibility of Salmonella typhi to co-trimoxazole makes it a promising oral treatment for UFIs in general. We present a protocol of a randomized controlled trial of azithromycin versus co-trimoxazole for the treatment of UFI. METHODS/DESIGN: This is a parallel-group, double-blind, 1:1, randomized controlled trial of co-trimoxazole versus azithromycin for the treatment of UFI in Nepal. Participants will be patients aged 2 to 65 years, presenting with fever without clear focus for at least 4 days, complying with other study criteria and willing to provide written informed consent. Patients will be randomized either to azithromycin 20 mg/kg/day (maximum 1000 mg/day) in a single daily dose and an identical placebo or co-trimoxazole 60 mg/kg/day (maximum 3000 mg/day) in two divided doses for 7 days. Patients will be followed up with twice-daily telephone calls for 7 days or for at least 48 h after they become afebrile, whichever is later; by home visits on days 2 and 4 of treatment; and by hospital visits on days 7, 14, 28 and 63. The endpoints will be fever clearance time, treatment failure, time to treatment failure, and adverse events. The estimated sample size is 330. The primary analysis population will be all the randomized population and subanalysis will be repeated on patients with blood culture-confirmed enteric fever and culture-negative patients. DISCUSSION: Both azithromycin and co-trimoxazole are available in Nepal and are extensively used in the treatment of UFI. Therefore, it is important to know the better orally administered antimicrobial to treat enteric fever and other UFIs especially against the background of fluoroquinolone-resistant enteric fever. TRIAL REGISTRATION:, ID: NCT02773407 . Registered on 5 May 2016.

Teparrukkul P, Nilsakul J, Dunachie S, Limmathurotsakul D. 2017. Clinical Epidemiology of Septic Arthritis Caused by Burkholderia pseudomallei and Other Bacterial Pathogens in Northeast Thailand. Am J Trop Med Hyg, 97 (6), pp. 1695-1701. | Show Abstract | Read more

Septic arthritis is a medical emergency, and if not treated appropriately, it can be associated with high morbidity and mortality. Melioidosis, a serious infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is highly endemic in South and Southeast Asia and northern Australia. We reviewed the medical charts of adult patients admitted with bacterial septic arthritis at Sunpasitthiprasong Hospital, Ubon Ratchathani, northeast Thailand from January 2012 to December 2014. Bacterial septic arthritis was defined as one or more hot swollen joints with isolation of a pathogenic organism from an affected joint or from blood. A total of 154 patients with septic arthritis were retrospectively evaluated. The most common causes were B. pseudomallei (48%, N = 74), Streptococcus spp. (29%, N = 44), and Staphylococcus aureus (10%, N = 16). Prevalence of diabetes, bacteremia, and pneumonia was higher in B. pseudomallei septic arthritis than in septic arthritis caused by the other bacteria (all P < 0.01). Seventy three percent (54/74) of patients infected with B. pseudomallei and 69% (55/80) of patients with the other bacteria received effective antimicrobials on the first day of admission (P = 0.60), but in-hospital mortality of the former group was considerably higher (34% versus 14%, P = 0.004). In conclusion, B. pseudomallei septic arthritis is common and associated with high mortality in northeast Thailand. Emergence of Streptococcus arthritis is observed. Difficulty in diagnosing melioidosis and identifying B. pseudomallei in areas where health care workers are not familiar with the disease is discussed. In melioidosis-endemic regions, parenteral ceftazidime could be considered as empirical antimicrobial therapy for patients with septic arthritis and underlying diseases.

Mostowy RJ, Croucher NJ, De Maio N, Chewapreecha C, Salter SJ, Turner P, Aanensen DM, Bentley SD, Didelot X, Fraser C. 2017. Pneumococcal Capsule Synthesis Locus cps as Evolutionary Hotspot with Potential to Generate Novel Serotypes by Recombination. Mol Biol Evol, 34 (10), pp. 2537-2554. | Citations: 1 (Scopus) | Show Abstract | Read more

Diversity of the polysaccharide capsule in Streptococcus pneumoniae-main surface antigen and the target of the currently used pneumococcal vaccines-constitutes a major obstacle in eliminating pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule biosynthesis locus, cps. However, the evolutionary dynamics of the capsule remains not fully understood. Here, using genetic data from 4,519 bacterial isolates, we found cps to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of relaxed purifying selection and positive, diversifying selection acting at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared with the rest of the genome. Diversifying selection was particularly evident in the region of wzd/wze genes, which are known to regulate capsule expression and hence the bacterium's ability to cause disease. Using a novel, capsule-centered approach, we analyzed the evolutionary history of 12 major serogroups. Such analysis revealed their complex diversification scenarios, which were principally driven by recombination with other serogroups and other streptococci. Patterns of recombinational exchanges between serogroups could not be explained by serotype frequency alone, thus pointing to nonrandom associations between co-colonizing serotypes. Finally, we discovered a previously unobserved mosaic serotype 39X, which was confirmed to carry a viable and structurally novel capsule. Adding to previous discoveries of other mosaic capsules in densely sampled collections, these results emphasize the strong adaptive potential of the bacterium by its ability to generate novel antigenic diversity by recombination.

Ing H, Fellmeth G, White J, Stein A, Simpson JA, McGready R. 2017. Validation of the Edinburgh Postnatal Depression Scale (EPDS) on the Thai-Myanmar border. Trop Doct, 47 (4), pp. 339-347. | Show Abstract | Read more

Postnatal depression is common and may have severe consequences for women and their children. Locally validated screening tools are required to identify at-risk women in marginalised populations. The Edinburgh Postnatal Depression Scale (EPDS) is one of the most frequently used tools globally. This cross-sectional study assessed the validity and acceptability of the EPDS in Karen and Burmese among postpartum migrant and refugee women on the Thai-Myanmar border. The EPDS was administered to participants and results compared with a diagnostic interview. Local staff provided feedback on the acceptability of the EPDS through a focus group discussion. Results from 670 women showed high accuracy and reasonable internal consistency of the EPDS. However, acceptability to local staff was low, limiting the utility of the EPDS in this setting despite its good psychometrics. Further work is required to identify a tool that is acceptable and sensitive to cultural manifestations of depression in this vulnerable population.

Teerawattanasook N, Tauran PM, Teparrukkul P, Wuthiekanun V, Dance DAB, Arif M, Limmathurotsakul D. 2017. Capacity and Utilization of Blood Culture in Two Referral Hospitals in Indonesia and Thailand. Am J Trop Med Hyg, 97 (4), pp. 1257-1261. | Show Abstract | Read more

It is generally recommended that sepsis patients should have at least two blood cultures obtained before antimicrobial therapy. From 1995 to 2015, the number of blood cultures taken each year in a 1,100-bed public referral hospital in Ubon Ratchathani northeast Thailand rose from 5,235 to 56,719, whereas the number received in an 840-bed referral public hospital in South Sulawesi, Indonesia, in 2015 was 2,779. The proportion of patients sampled for blood cultures out of all inpatients in South Sulawesi in 2015 (9%; 2,779/30,593) was lower than that in Ubon Ratchathani in 2003 (13%; 8,707/66,515), at a time when health expenditure per capita in the two countries was comparable. Under-use of bacterial cultures may lead to an underestimate and underreporting of the incidence of antimicrobial-resistant infections. Raising capacity and utilization of clinical microbiology laboratories in developing countries, at least at sentinel hospitals, to monitor the antimicrobial resistance situation should be prioritized.

Haselbeck AH, Panzner U, Im J, Baker S, Meyer CG, Marks F. 2017. Current perspectives on invasive nontyphoidal Salmonella disease. Curr Opin Infect Dis, 30 (5), pp. 498-503. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

PURPOSE OF REVIEW: We searched PubMed for scientific literature published in the past 2 years for relevant information regarding the burden of invasive nontyphoidal Salmonella disease and host factors associated with nontyphoidal Salmonella infection and discuss current knowledge on vaccine development. The following search terms were used: Salmonella, non typhoidal/nontyphoidal, NTS, disease, bloodstream infection, invasive, sepsis/septicaemia/septicemia, bacteraemia/bacteremia, gastroenteritis, incidence, prevalence, morbidity, mortality, case fatality, host/risk factor, vaccination, and prevention/control. RECENT FINDINGS: Estimates of the global invasive nontyphoidal Salmonella disease burden have been recently updated; additional data from Africa, Asia, and Latin America are now available. New data bridge various knowledge gaps, particularly with respect to host risk factors and the geographical distribution of iNTS serovars. It has also been observed that Salmonella Typhimurium sequence type 313 is emergent in several African countries. Available data suggest that genetic variation in the sequence type 313 strain has led to increased pathogenicity and human host adaptation. A bivalent efficacious vaccine, targeting Salmonella serovars Typhimurium and Enteritidis, would significantly lower the disease burden in high-risk populations. SUMMARY: The mobilization of surveillance networks, especially in Asia and Latin America, may provide missing data regarding the invasive nontyphoidal Salmonella disease burden and their corresponding antimicrobial susceptibility profiles. Efforts and resources should be directed toward invasive nontyphoidal Salmonella disease vaccine development.

Arabi YM, Al-Omari A, Mandourah Y, Al-Hameed F, Sindi AA, Alraddadi B, Shalhoub S, Almotairi A, Al Khatib K, Abdulmomen A et al. 2017. Critically Ill Patients With the Middle East Respiratory Syndrome: A Multicenter Retrospective Cohort Study. Crit Care Med, 45 (10), pp. 1683-1695. | Show Abstract | Read more

OBJECTIVES: To describe patient characteristics, clinical manifestations, disease course including viral replication patterns, and outcomes of critically ill patients with severe acute respiratory infection from the Middle East respiratory syndrome and to compare these features with patients with severe acute respiratory infection due to other etiologies. DESIGN: Retrospective cohort study. SETTING: Patients admitted to ICUs in 14 Saudi Arabian hospitals. PATIENTS: Critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection (n = 330) admitted between September 2012 and October 2015 were compared to consecutive critically ill patients with community-acquired severe acute respiratory infection of non-Middle East respiratory syndrome etiology (non-Middle East respiratory syndrome severe acute respiratory infection) (n = 222). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Although Middle East respiratory syndrome severe acute respiratory infection patients were younger than those with non-Middle East respiratory syndrome severe acute respiratory infection (median [quartile 1, quartile 3] 58 yr [44, 69] vs 70 [52, 78]; p < 0.001), clinical presentations and comorbidities overlapped substantially. Patients with Middle East respiratory syndrome severe acute respiratory infection had more severe hypoxemic respiratory failure (PaO2/FIO2: 106 [66, 160] vs 176 [104, 252]; p < 0.001) and more frequent nonrespiratory organ failure (nonrespiratory Sequential Organ Failure Assessment score: 6 [4, 9] vs 5 [3, 7]; p = 0.002), thus required more frequently invasive mechanical ventilation (85.2% vs 73.0%; p < 0.001), oxygen rescue therapies (extracorporeal membrane oxygenation 5.8% vs 0.9%; p = 0.003), vasopressor support (79.4% vs 55.0%; p < 0.001), and renal replacement therapy (48.8% vs 22.1%; p < 0.001). After adjustment for potential confounding factors, Middle East respiratory syndrome was independently associated with death compared to non-Middle East respiratory syndrome severe acute respiratory infection (adjusted odds ratio, 5.87; 95% CI, 4.02-8.56; p < 0.001). CONCLUSIONS: Substantial overlap exists in the clinical presentation and comorbidities among patients with Middle East respiratory syndrome severe acute respiratory infection from other etiologies; therefore, a high index of suspicion combined with diagnostic testing is essential component of severe acute respiratory infection investigation for at-risk patients. The lack of distinguishing clinical features, the need to rely on real-time reverse transcription polymerase chain reaction from respiratory samples, variability in viral shedding duration, lack of effective therapy, and high mortality represent substantial clinical challenges and help guide ongoing clinical research efforts.

Tschirhart N, Nosten F, Foster AM. 2017. Migrant tuberculosis patient needs and health system response along the Thailand-Myanmar border. Health Policy Plan, 32 (8), pp. 1212-1219. | Show Abstract | Read more

This article aims to identify how the health system in Tak province, Thailand has responded to migrants' barriers to tuberculosis (TB) treatment. Our qualitatively driven multi-methods project utilized focus group discussions, key informant interviews, and a survey of community health volunteers to collect data in 2014 from multiple perspectives. Migrants identified legal status and transportation difficulties as the primary barriers to seeking TB treatment. Lack of financial resources and difficulties locating appropriate and affordable health services in other Thai provinces or across the border in Myanmar further contributed to migrants' challenges. TB care providers responded to barriers to treatment by bringing care out into the community, enhancing patient mobility, providing supportive services, and reaching out to potential patients. Interventions to improve migrant access and adherence to TB treatment necessarily extend outside of the health system and require significant resources to expand equitable access to treatment. Although this research is specific to the Thailand-Myanmar border, we anticipate that the findings will contribute to broader conversations around the inputs that are necessary to address disparities and inequities. Our study suggests that migrants need to be provided with resources that help stabilize their financial situation and overcome difficulties associated with their legal status in order to access and continue TB treatment.

Peto T, Tripura R, Seidlein LV. 2017. Model citizen. Lancet Glob Health, 5 (10), pp. e973. | Read more

Brady OJ, Slater HC, Pemberton-Ross P, Wenger E, Maude RJ, Ghani AC, Penny MA, Gerardin J, White LJ, Chitnis N et al. 2017. Model citizen - Authors' reply. Lancet Glob Health, 5 (10), pp. e974. | Read more

Imwong M, Hien TT, Thuy-Nhien NT, Dondorp AM, White NJ. 2017. Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam. Lancet Infect Dis, 17 (10), pp. 1022-1023. | Citations: 7 (Web of Science Lite) | Read more

Zhang Z, Geskus RB, Kattan MW, Zhang H, Liu T. 2017. Nomogram for survival analysis in the presence of competing risks. Ann Transl Med, 5 (20), pp. 403. | Show Abstract | Read more

Clinical research usually involves time-to-event survival analysis, in which the presence of a competing event is prevalent. It is acceptable to use the conventional Cox proportional hazard regression to model cause-specific hazard. However, this cause-specific hazard cannot directly translate to the cumulative incidence function, and the latter is usually clinically relevant. The subdistribution hazard regression directly quantifies the impact of covariates on the cumulative incidence. When estimating the subdistribution hazard, subjects experiencing competing event continue to contribute to the risk set, and censoring weights are assigned to them after the competing event time. The weights are the conditional probability that a subject remains uncensored, and can be modelled to depend on the covariates of a subject. The first option to perform regression on the subdistribution hazard was the crr() function in the cmprsk package. However, it is not straightforward to draw a nomogram, which is a user-friendly tool for risk prediction, with the crr() function. To overcome this problem, we show an alternative method to use a nomogram function based on result of subdistribution hazard modeling.

Horby P, Denis E, Kayem ND, Reis A, Rojek A, Salam AP, Olliaro P. 2017. A training curriculum for conducting clinical research during outbreaks TROPICAL MEDICINE & INTERNATIONAL HEALTH, 22 pp. 167-168.

Musicha P, Cornick JE, Bar-Zeev N, French N, Masesa C, Denis B, Kennedy N, Mallewa J, Gordon MA, Msefula CL et al. 2017. Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study. Lancet Infect Dis, 17 (10), pp. 1042-1052. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND: Bacterial bloodstream infection is a common cause of morbidity and mortality in sub-Saharan Africa, yet few facilities are able to maintain long-term surveillance. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme has done sentinel surveillance of bacteraemia since 1998. We report long-term trends in bloodstream infection and antimicrobial resistance from this surveillance. METHODS: In this surveillance study, we analysed blood cultures that were routinely taken from adult and paediatric patients with fever or suspicion of sepsis admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi from 1998 to 2016. The hospital served an urban population of 920 000 in 2016, with 1000 beds, although occupancy often exceeds capacity. The hospital admits about 10 000 adults and 30 000 children each year. Antimicrobial susceptibility tests were done by the disc diffusion method according to British Society of Antimicrobial Chemotherapy guidelines. We used the Cochran-Armitage test for trend to examine trends in rates of antimicrobial resistance, and negative binomial regression to examine trends in icidence of bloodstream infection over time. FINDINGS: Between Jan 1, 1998, and Dec 31, 2016, we isolated 29 183 pathogens from 194 539 blood cultures. Pathogen detection decreased significantly from 327·1/100 000 in 1998 to 120·2/100 000 in 2016 (p<0·0001). 13 366 (51·1%) of 26 174 bacterial isolates were resistant to the Malawian first-line antibiotics amoxicillin or penicillin, chloramphenicol, and co-trimoxazole; 68·3% of Gram-negative and 6·6% of Gram-positive pathogens. The proportions of non-Salmonella Enterobacteriaceae with extended spectrum beta-lactamase (ESBL) or fluoroquinolone resistance rose significantly after 2003 to 61·9% in 2016 (p<0·0001). Between 2003 and 2016, ESBL resistance rose from 0·7% to 30·3% in Escherichia coli, from 11·8% to 90·5% in Klebsiella spp and from 30·4% to 71·9% in other Enterobacteriaceae. Similarly, resistance to ciprofloxacin rose from 2·5% to 31·1% in E coli, from 1·7% to 70·2% in Klebsiella spp and from 5·9% to 68·8% in other Enterobacteriaceae. By contrast, more than 92·0% of common Gram-positive pathogens remain susceptible to either penicillin or chloramphenicol. Meticillin-resistant Staphylococcus aureus (MRSA) was first reported in 1998 at 7·7% and represented 18·4% of S aureus isolates in 2016. INTERPRETATION: The rapid expansion of ESBL and fluoroquinolone resistance among common Gram-negative pathogens, and the emergence of MRSA, highlight the growing challenge of bloodstream infections that are effectively impossible to treat in this resource-limited setting. FUNDING: Wellcome Trust, H3ABionet, Southern Africa Consortium for Research Excellence (SACORE).

Inzaule SC, Hamers RL, Paredes R, Yang C, Schuurman R, de Wit TFR. 2017. The evolving landscape of HIV drug resistance diagnostics for expanding testing in resource-limited settings AIDS Reviews, 19 (4), pp. 179-189. | Show Abstract

© 2017, Publicaciones Permanyer. All rights reserved. Global scale-up of antiretroviral treatment has dramatically changed the prospects of HIV/AIDS disease, rendering life-long chronic care and treatment a reality for millions of HIV-infected patients. Affordable technologies to monitor antiretroviral treatment are needed to ensure long-term durability of limited available drug regimens. HIV drug resistance tests can complement existing strategies in optimizing clinical decision-making for patients with treatment failure, in addition to facilitating population-based surveillance of HIV drug resistance. This review assesses the current landscape of HIV drug resistance technologies and discusses the strengths and limitations of existing assays available for expanding testing in resource-limited settings. These include sequencing-based assays (Sanger sequencing assays and nextgeneration sequencing), point mutation assays, and genotype-free data-based prediction systems. Sanger assays are currently considered the gold standard genotyping technology, though only available at a limited number of resource-limited setting reference and regional laboratories, but high capital and test costs have limited their wide expansion. Point mutation assays present opportunities for simplified laboratory assays, but HIV genetic variability, extensive codon redundancy at or near the mutation target sites with limited multiplexing capability have restricted their utility. Next-generation sequencing, despite high costs, may have potential to reduce the testing cost significantly through multiplexing in high-throughput facilities, although the level of bioinformatics expertise required for data analysis is currently still complex and expensive and lacks standardization. Web-based genotype-free prediction systems may provide enhanced antiretroviral treatment decision-making without the need for laboratory testing, but require further clinical field evaluation and implementation scientific research in resource-limited settings.

Jin C, Gibani MM, Moore M, Juel HB, Jones E, Meiring J, Harris V, Gardner J, Nebykova A, Kerridge SA et al. 2017. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet, 390 (10111), pp. 2472-2480. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with, number NCT02324751, and is ongoing. FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

Clapham HE, Cummings DAT, Johansson MA. 2017. Immune status alters the probability of apparent illness due to dengue virus infection: Evidence from a pooled analysis across multiple cohort and cluster studies. PLoS Negl Trop Dis, 11 (9), pp. e0005926. | Show Abstract | Read more

Dengue is an important vector-borne pathogen found across much of the world. Many factors complicate our understanding of the relationship between infection with one of the four dengue virus serotypes, and the observed incidence of disease. One of the factors is a large proportion of infections appear to result in no or few symptoms, while others result in severe infections. Estimates of the proportion of infections that result in no symptoms (inapparent) vary widely from 8% to 100%, depending on study and setting. To investigate the sources of variation of these estimates, we used a flexible framework to combine data from multiple cohort studies and cluster studies (follow-up around index cases). Building on previous observations that the immune status of individuals affects their probability of apparent disease, we estimated the probability of apparent disease among individuals with different exposure histories. In cohort studies mostly assessing infection in children, we estimated the proportion of infections that are apparent as 0.18 (95% Credible Interval, CI: 0.16, 0.20) for primary infections, 0.13 (95% CI: 0.05, 0.17) for individuals infected in the year following a first infection (cross-immune period), and 0.41 (95% CI: 0.36, 0.45) for those experiencing secondary infections after this first year. Estimates of the proportion of infections that are apparent from cluster studies were slightly higher than those from cohort studies for both primary and secondary infections, 0.22 (95% CI: 0.15, 0.29) and 0.57 (95% CI: 0.49, 0.68) respectively. We attempted to estimate the apparent proportion by serotype, but current published data were too limited to distinguish the presence or absence of serotype-specific differences. These estimates are critical for understanding dengue epidemiology. Most dengue data come from passive surveillance systems which not only miss most infections because they are asymptomatic and often underreported, but will also vary in sensitivity over time due to the interaction between previous incidence and the symptomatic proportion, as shown here. Nonetheless the underlying incidence of infection is critical to understanding susceptibility of the population and estimating the true burden of disease, key factors for effectively targeting interventions. The estimates shown here help clarify the link between past infection, observed disease, and current transmission intensity.

Do LAH, Pellet J, van Doorn HR, Tran AT, Nguyen BH, Tran TTL, Tran QH, Vo QB, Tran Dac NA, Trinh HN et al. 2017. Host Transcription Profile in Nasal Epithelium and Whole Blood of Hospitalized Children Under 2 Years of Age With Respiratory Syncytial Virus Infection. J Infect Dis, 217 (1), pp. 134-146. | Show Abstract | Read more

Background: Most insights into the cascade of immune events after acute respiratory syncytial virus (RSV) infection have been obtained from animal experiments or in vitro models. Methods: In this study, we investigated host gene expression profiles in nasopharyngeal (NP) swabs and whole blood samples during natural RSV and rhinovirus (hRV) infection (acute versus early recovery phase) in 83 hospitalized patients <2 years old with lower respiratory tract infections. Results: Respiratory syncytial virus infection induced strong and persistent innate immune responses including interferon signaling and pathways related to chemokine/cytokine signaling in both compartments. Interferon-α/β, NOTCH1 signaling pathways and potential biomarkers HIST1H4E, IL7R, ISG15 in NP samples, or BCL6, HIST2H2AC, CCNA1 in blood are leading pathways and hub genes that were associated with both RSV load and severity. The observed RSV-induced gene expression patterns did not differ significantly in NP swab and blood specimens. In contrast, hRV infection did not as strongly induce expression of innate immunity pathways, and significant differences were observed between NP swab and blood specimens. Conclusions: We conclude that RSV induced strong and persistent innate immune responses and that RSV severity may be related to development of T follicular helper cells and antiviral inflammatory sequelae derived from high activation of BCL6.

Njunge JM, Oyaro IN, Kibinge NK, Rono MK, Kariuki SM, Newton CR, Berkley JA, Gitau EN. 2017. Cerebrospinal fluid markers to distinguish bacterial meningitis from cerebral malaria in children Wellcome Open Research, 2 pp. 47-47. | Read more

Seale AC, Gordon NC, Islam J, Peacock SJ, Scott JAG. 2017. AMR Surveillance in low and middle-income settings - A roadmap for participation in the Global Antimicrobial Surveillance System (GLASS) Wellcome Open Research, 2 pp. 92-92. | Show Abstract | Read more

© 2017 Seale AC et al. Drug-resistant infections caused by bacteria with increasing antimicrobial resistance (AMR) threaten our ability to treat life-threatening conditions. Tackling AMR requires international collaboration and partnership. An early and leading priority to do this is to strengthen AMR surveillance, particularly in low-income countries where the burden of infectious diseases is highest and where data are most limited. The World Health Organization (WHO) has developed the Global AMR Surveillance System (GLASS) as one of a number of measures designed to tackle the problem of AMR, and WHO member states have been encouraged to produce National Action Plans for AMR by 2017. However, low-income countries are unlikely to have the resources or capacity to implement all the components in the GLASS manual. To facilitate their efforts, we developed a guideline that is aligned to the GLASS procedures, but written specifically for implementation in low-income countries. The guideline allows for flexibility across different systems, but has sufficient standardisation of core protocols to ensure that, if followed, data will be valid and comparable. This will ensure that the surveillance programme can provide health intelligence data to inform evidence-based interventions at local, nat ional and international levels.

Bonell A, Lubell Y, Newton PN, Crump JA, Paris DH. 2017. Estimating the burden of scrub typhus: A systematic review. PLoS Negl Trop Dis, 11 (9), pp. e0005838. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known. METHODS: We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000. FINDINGS: In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%-27.9% (median 22.2% IQR 18.6-25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes. INTERPRETATION: Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8-10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

Trieu HT, Anh NTK, Vuong HNT, Dao TTM, Hoa NTX, Tuong VNC, Dinh PT, Wills B, Qui PT, Van Tan L et al. 2017. Long-term outcome in survivors of neonatal tetanus following specialist intensive care in Vietnam. BMC Infect Dis, 17 (1), pp. 646. | Show Abstract | Read more

BACKGROUND: Neonatal tetanus continues to occur in many resource-limited settings but there are few data regarding long-term neurological outcome from the disease, especially in settings with critical care facilities. METHODS: We assessed long-term outcome following neonatal tetanus in infants treated in a pediatric intensive care unit in southern Vietnam. Neurological and neurodevelopmental testing was performed in 17 survivors of neonatal tetanus and 18 control children from the same communities using tools previously validated in Vietnamese children. RESULTS: The median age of children assessed was 36 months. Eight neonatal tetanus survivors and 9 community control cases aged < 42 months were tested using the Bayley III Scales of Infant and Toddler Development (Bayley III-VN) and 8 neonatal tetanus survivors and 9 community controls aged ≥42 months were tested using the Movement Assessment Battery for Children. No significant reductions in growth indices or neurodevelopmental scores were shown in survivors of neonatal tetanus compared to controls although there was a trend towards lower scores in neonatal tetanus survivors. Neurological examination was normal in all children except for two neonatal tetanus survivors with perceptive deafness and one child with mild gross motor abnormality. Neonatal tetanus survivors who had expienced severe disease (Ablett grade ≥ 3) had lower total Bayley III-VN scores than those with mild disease (15 (IQR 14-18) vs 24 (IQR 19-27), p = 0.05) with a significantly lower cognitive domain score (3 (IQR 2-6) severe disease vs 7 (IQR 7-8) mild disease, p = 0.02). CONCLUSIONS: Neonatal tetanus is associated with long-term sequelae in those with severe disease. In view of these findings, prevention of neonatal tetanus should remain a priority.

Thao NTT, Donato C, Trang VTH, Kien NT, Trang PMMT, Khanh TQ, Nguyet DT, Sessions OM, Cuong HQ, Lan PT et al. 2017. Evolution and Spatiotemporal Dynamics of Enterovirus A71 Subgenogroups in Vietnam. J Infect Dis, 216 (11), pp. 1371-1379. | Show Abstract | Read more

Background: Enterovirus A71 (EV-A71) is the major cause of severe hand, foot, and mouth disease and viral encephalitis in children across the Asia-Pacific region, including in Vietnam, which has experienced a high burden of disease in recent years. Multiple subgenogroups (C1, C4, C5, and B5) concurrently circulate in the region with a large variation in epidemic severity. The relative differences in their evolution and epidemiology were examined within Vietnam and globally. Methods: A total of 752 VP1 gene sequences were analyzed (413 generated in this study combined with 339 obtained from GenBank), collected from patients in 36 provinces in Vietnam during 2003-2013, along with epidemiological metadata. Globally representative VP1 gene datasets of subgenogroups were used to coestimate time-resolved phylogenies and relative genetic diversity to infer virus origins and regional transmission network. Results: Despite frequent virus migration between countries, the highest genetic diversity of individual subgenogroups was maintained independently for several years in specific Asian countries representing genogroup-specific sources of EV-A71 diversity. Conclusion: This study highlights a persistent transmission network of EV-A71, with specific Asian countries seeding other countries in the region and beyond, emphasizing the need for improved EV-A71 surveillance and detailed genetic and antigenic characterization.

Dunachie SJ, Jenjaroen K, Reynolds CJ, Quigley KJ, Sergeant R, Sumonwiriya M, Chaichana P, Chumseng S, Ariyaprasert P, Lassaux P et al. 2017. Infection with Burkholderia pseudomallei - immune correlates of survival in acute melioidosis. Sci Rep, 7 (1), pp. 12143. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine.

Bhutta ZA, Berkley JA, Bandsma RHJ, Kerac M, Trehan I, Briend A. 2017. Severe childhood malnutrition NATURE REVIEWS DISEASE PRIMERS, 3 pp. 17067-17067. | Read more

White NJ, Watson J, Ashley EA. 2017. Split dosing of artemisinins does not improve antimalarial therapeutic efficacy. Sci Rep, 7 (1), pp. 12132. | Show Abstract | Read more

It has been suggested recently, based on pharmacokinetic-pharmacodynamic modelling exercises, that twice daily dosing of artemisinins increases malaria parasite killing and so could "dramatically enhance and restore drug effectiveness" in artemisinin resistant P. falciparum malaria infections. It was recommended that split dosing should be incorporated into all artemisinin combination regimen designs. To explain why parasite clearance rates were not faster with split dose regimens it was concluded that splenic malaria parasite clearance capacity was readily exceeded, resulting in the accumulation of dead parasites in the circulation, that parasite clearance was therefore an unreliable measure of drug efficacy, and instead that human immunity is the primary determinant of clearance rates. To test these various hypotheses we performed a logistic meta-regression analysis of cure rates from all falciparum malaria treatment trials (n = 40) with monotherapy arms containing artemisinin or a derivative (76 arms). There was no evidence that split dosing enhanced cure rates.

Cheong E, Roberts T, Rattanavong S, Riley TV, Newton PN, Dance DAB. 2017. Clostridium difficile infection in the Lao People's Democratic Republic: first isolation and review of the literature. BMC Infect Dis, 17 (1), pp. 635. | Show Abstract | Read more

BACKGROUND: Current knowledge of the epidemiology of Clostridium difficile infection in Asia, and in particular the Greater Mekong Subregion, is very limited. Only a few studies from Thailand and Vietnam have been reported from the region with variable testing methods and results, and no studies from Lao People's Democratic Republic (PDR). Therefore we investigated the presence of C. difficile in a single centre in the Lao PDR and determined the ribotypes present. METHOD: Seventy unformed stool samples from hospital inpatients at Mahosot Hospital, Vientiane, were tested for the presence of C. difficile using selective differential agar and confirmed by latex agglutination. C. difficile isolates were further characterised by ribotyping and toxin gene detection. RESULTS: C. difficile was isolated from five of the 70 patients, and five different ribotypes were identified (014, 017, 020, QX 107 and QX 574). CONCLUSION: This is the first isolation of C. difficile from human stool samples in the Lao PDR. These results will add to the limited amount of data on C. difficile in the region. In addition, we hope this information will alert clinicians to the presence of C. difficile in the country and will help inform future investigations into the epidemiology and diagnosis of C. difficile in Lao PDR.

Darton TC, Baker S, Randall A, Dongol S, Karkey A, Voysey M, Carter MJ, Jones C, Trappl K, Pablo J et al. 2017. Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array. Front Microbiol, 8 (SEP), pp. 1794. | Show Abstract | Read more

Current diagnostic tests for typhoid fever, the disease caused by Salmonella Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 S. Typhi antigens in sera from 41 participants challenged with oral S. Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort (n = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid (n = 100) from other febrile bacteremia (n = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever.

Ouma PO, Agutu NO, Snow RW, Noor AM. 2017. Univariate and multivariate spatial models of health facility utilisation for childhood fevers in an area on the coast of Kenya. Int J Health Geogr, 16 (1), pp. 34. | Show Abstract | Read more

BACKGROUND: Precise quantification of health service utilisation is important for the estimation of disease burden and allocation of health resources. Current approaches to mapping health facility utilisation rely on spatial accessibility alone as the predictor. However, other spatially varying social, demographic and economic factors may affect the use of health services. The exclusion of these factors can lead to the inaccurate estimation of health facility utilisation. Here, we compare the accuracy of a univariate spatial model, developed only from estimated travel time, to a multivariate model that also includes relevant social, demographic and economic factors. METHODS: A theoretical surface of travel time to the nearest public health facility was developed. These were assigned to each child reported to have had fever in the Kenya demographic and health survey of 2014 (KDHS 2014). The relationship of child treatment seeking for fever with travel time, household and individual factors from the KDHS2014 were determined using multilevel mixed modelling. Bayesian information criterion (BIC) and likelihood ratio test (LRT) tests were carried out to measure how selected factors improve parsimony and goodness of fit of the time model. Using the mixed model, a univariate spatial model of health facility utilisation was fitted using travel time as the predictor. The mixed model was also used to compute a multivariate spatial model of utilisation, using travel time and modelled surfaces of selected household and individual factors as predictors. The univariate and multivariate spatial models were then compared using the receiver operating area under the curve (AUC) and a percent correct prediction (PCP) test. RESULTS: The best fitting multivariate model had travel time, household wealth index and number of children in household as the predictors. These factors reduced BIC of the time model from 4008 to 2959, a change which was confirmed by the LRT test. Although there was a high correlation of the two modelled probability surfaces (Adj R 2 = 88%), the multivariate model had better AUC compared to the univariate model; 0.83 versus 0.73 and PCP 0.61 versus 0.45 values. CONCLUSION: Our study shows that a model that uses travel time, as well as household and individual-level socio-demographic factors, results in a more accurate estimation of use of health facilities for the treatment of childhood fever, compared to one that relies on only travel time.

Malla L, Perera-Salazar R, McFadden E, English M. 2017. Comparative effectiveness of injectable penicillin versus a combination of penicillin and gentamicin in children with pneumonia characterised by indrawing in Kenya: protocol for an observational study. BMJ Open, 7 (9), pp. e016784. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: WHO treatment guidelines are widely recommended for guiding treatment for millions of children with pneumonia every year across multiple low-income and middle-income countries. Guidelines are based on synthesis of available evidence that provides moderate certainty in evidence of effects for forms of pneumonia that can result in hospitalisation. However, trials have included fewer children from Africa than other settings, and it is suggested that African children with pneumonia have higher mortality. Thus, despite improving access to recommended treatments and deployment with high coverage of childhood vaccines, pneumonia remains one of the top causes of mortality for children in Kenya. Establishing whether there are benefits of alternative treatment regimens to help reduce mortality would require pragmatic clinical trials. However, these remain relatively expensive and time consuming. This protocol describes an approach to using secondary analysis of a new, large observational dataset as a potentially cheaper and quicker way to examine the comparative effectiveness of penicillin versus penicillin plus gentamicin in treatment of indrawing pneumonia. Addressing this question is important, as although it is now recommended that this form of pneumonia is treated with oral medication as an outpatient, it remains associated with non-trivial mortality that may be higher outside trial populations. METHODS AND ANALYSIS: We will use a large observational dataset that captures data on all admissions to 13 Kenyan county hospitals. These data represent the findings of clinicians in practice and, because the system was developed for large observational research, pose challenges of non-random treatment allocation and missing data. To overcome these challenges, this analysis will use a rigorous approach to study design, propensity score methods and multiple imputation to minimise bias. ETHICS AND DISSEMINATION: The primary data are held by hospitals participating in the Kenyan Clinical Information Network project with de-identifed data shared with the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme for agreed analyses. The use of data for the analysis described received ethical clearance from the KEMRI scientific and ethical review committee. The findings of this analysis will be published.

Brent AJ, Mugo D, Musyimi R, Mutiso A, Morpeth S, Levin M, Scott JAG. 2017. Bacteriological diagnosis of childhood TB: a prospective observational study. Sci Rep, 7 (1), pp. 11808. | Show Abstract | Read more

Childhood TB diagnosis is challenging. Studies in adults suggest Microscopic Observation Drug Susceptibility (MODS) culture or the Xpert MTB/RIF assay might be used to expand bacteriological diagnosis. However data from children are more limited. We prospectively compared MODS and Xpert MTB/RIF with standard microscopy and culture using the BD MGIT 960 system among 1442 Kenyan children with suspected TB. 97 specimens from 54 children were TB culture-positive: 91 (94%) by MGIT and 74 (76%) by MODS (p = 0.002). 72 (74%) culture-positive and 7 culture-negative specimens were Xpert MTB/RIF positive. Xpert MTB/RIF specificity was 100% (99.7-100%) among 1164 specimens from 892 children in whom TB was excluded, strongly suggesting all Xpert MTB/RIF positives are true positives. The sensitivity of MGIT, MODS and Xpert MTB/RIF was 88%, 71% and 76%, respectively, among all 104 true positive (culture and/or Xpert MTB/RIF positive) specimens. MGIT, MODS and Xpert MTB/RIF on the initial specimen identified 40/51 (78%), 33/51 (65%) and 33/51 (65%) culture-confirmed pulmonary TB cases, respectively; Xpert MTB/RIF detected 5 additional culture-negative cases. The high sensitivity and very high specificity of the Xpert MTB/RIF assay supports its inclusion in the reference standard for bacteriological diagnosis of childhood TB in research and clinical practice.

Adhikari B, Pell C, Phommasone K, Soundala X, Kommarasy P, Pongvongsa T, Henriques G, Day NPJ, Mayxay M, Cheah PY. 2017. Elements of effective community engagement: lessons from a targeted malaria elimination study in Lao PDR (Laos). Glob Health Action, 10 (1), pp. 1366136. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Mass drug (antimalarial) administration (MDA) is currently under study in Southeast Asia as part of a package of interventions referred to as targeted malaria elimination (TME). This intervention relies on effective community engagement that promotes uptake and adherence in target communities (above 80%). OBJECTIVE: Based on the experienced of designing and implementing the community engagement for TME in Laos, in this article we aim to present the elements of effective community engagement for mass antimalarial administration. METHODS: The design and implementation of community engagement, which took place from September 2015 to August 2016 was recorded as field notes, meeting minutes and photographs. These data underwent qualitative content analysis. RESULTS: The community engagement strategy that accompanied TME in Laos was successful in terms of contributing to high levels of participation in mass anti-malarial administration (above 85%). Based on the experience of designing and implementing the community engagement, five key elements were identified: (1) stakeholder and authority engagement, which proceeded from national level, to regional/district and local level; (2) local human resources, particularly the recruitment of local volunteers who were integral to the design and implementation of activities in the study villages; (3) formative research, to rapidly gain insight into the local social and economic context; (4) responsiveness whereby the approach was adapted according to the needs of the community and their responses to the various study components; and (5) sharing control/leadership with the community in terms of decisions on the organization of TME activities. CONCLUSIONS: The community engagement that accompanied TME in Laos had to deal with challenges of implementing a complex study in remote and linguistically isolated villages. Despite these challenges, the study recorded high population coverage. Lessons learnt from this experience are useful for studies and intervention programs in diverse contexts.

Nyikuri MM, Tsofa B, Okoth P, Barasa EW, Molyneux S. 2017. "We are toothless and hanging, but optimistic": sub county managers' experiences of rapid devolution in coastal Kenya. Int J Equity Health, 16 (1), pp. 113. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In March 2013, Kenya transitioned from a centralized to a devolved system of governance. Within the health sector, this entailed the transfer of service provision functions to 47 newly formed semi-autonomous counties, while policy and regulatory functions were retained at the national level. The devolution process was rapid rather than progressive. METHODS: We conducted qualitative research within one county to examine the early experiences of devolution in the health sector. We specifically focused on the experience of change from the perspective of sub-county managers, who form the link between county level managers and health facility managers. We collected data by observing a diverse range of management meetings, support supervision visits and outreach activities involving sub-county managers between May 2013 and June 2015, conducting informal interviews wherever we could. Informal observations and interviews were supplemented by fifteen tape recorded in depth interviews with purposively selected sub-county managers from three sub-counties. RESULTS: We found that sub county managers as with many other health system actors were anxious about and ill-prepared for the unexpectedly rapid devolution of health functions to the newly created county government. They experienced loss of autonomy and resources in addition to confused lines of accountability within the health system. However, they harnessed individual, team and stakeholder resources to maintain their jobs, and continued to play a central role in supporting peripheral facility managers to cope with change. CONCLUSIONS: Our study illustrates the importance in accelerated devolution contexts for: 1) mid-level managers to adopt new ways of working and engagement with higher and lower levels in the system; 2) clear lines of communication during reforms to these actors and 3) anticipating and managing the effect of change on intangible software issues such as trust and motivation. More broadly, we show the value of examining organisational change from the perspective of key actors within the system, and highlight the importance in times of rapid change of drawing upon and working with those already in the system. These actors have valuable tacit knowledge, but tapping into and building on this knowledge to enable positive response in times of health system shocks requires greater attention to sustained software capacity building within the health system.

Tsofa B, Goodman C, Gilson L, Molyneux S. 2017. Devolution and its effects on health workforce and commodities management - early implementation experiences in Kilifi County, Kenya. Int J Equity Health, 16 (1), pp. 169. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND: Decentralisation is argued to promote community participation, accountability, technical efficiency, and equity in the management of resources, and has been a recurring theme in health system reforms for several decades. In 2010, Kenya passed a new constitution that introduced 47 semi-autonomous county governments, with substantial transfer of responsibility for health service delivery from the central government to these counties. Focusing on two key elements of the health system, Human Resources for Health (HRH) and Essential Medicines and Medical Supplies (EMMS) management, we analysed the early implementation experiences of this major governance reform at county level. METHODS: We employed a qualitative case study design, focusing on Kilifi County, and adapted the decision space framework developed by Bossert et al., to guide our inquiry and analysis. Data were collected through document reviews, key informant interviews, and participant and non-participant observations between December 2012 and December 2014. RESULTS: As with other county level functions, HRH and EMMS management functions were rapidly transferred to counties before appropriate county-level structures and adequate capacity to undertake these functions were in place. For HRH, this led to major disruptions in staff salary payments, political interference with HRH management functions and confusion over HRH management roles. There was also lack of clarity over specific roles and responsibilities at county and national government, and of key players at each level. Subsequently health worker strikes and mass resignations were witnessed. With EMMS, significant delays in procurement led to long stock-outs of essential drugs in health facilities. However, when the county finally managed to procure drugs, health facilities reported a better order fill-rate compared to the period prior to devolution. CONCLUSION: The devolved government system in Kenya has significantly increased county level decision-space for HRH and EMMS management functions. However, harnessing the full potential benefits of this increased autonomy requires targeted interventions to clarify the roles and responsibilities of different actors at all levels of the new system, and to build capacity of the counties to undertake certain specific HRH and EMMS management tasks. Capacity considerations should always be central when designing health sector decentralisation policies.

Tsofa B, Molyneux S, Gilson L, Goodman C. 2017. How does decentralisation affect health sector planning and financial management? a case study of early effects of devolution in Kilifi County, Kenya. Int J Equity Health, 16 (1), pp. 151. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: A common challenge for health sector planning and budgeting has been the misalignment between policies, technical planning and budgetary allocation; and inadequate community involvement in priority setting. Health system decentralisation has often been promoted to address health sector planning and budgeting challenges through promoting community participation, accountability, and technical efficiency in resource management. In 2010, Kenya passed a new constitution that introduced 47 semi-autonomous devolved county governments, and a substantial transfer of responsibility for healthcare from the central government to these counties. METHODS: This study analysed the effects of this major political decentralization on health sector planning, budgeting and overall financial management at county level. We used a qualitative, case study design focusing on Kilifi County, and were guided by a conceptual framework which drew on decentralisation and policy analysis theories. Qualitative data were collected through document reviews, key informant interviews, and participant and non-participant observations conducted over an eighteen months' period. RESULTS: We found that the implementation of devolution created an opportunity for local level prioritisation and community involvement in health sector planning and budgeting hence increasing opportunities for equity in local level resource allocation. However, this opportunity was not harnessed due to accelerated transfer of functions to counties before county level capacity had been established to undertake the decentralised functions. We also observed some indication of re-centralisation of financial management from health facility to county level. CONCLUSION: We conclude by arguing that, to enhance the benefits of decentralised health systems, resource allocation, priority setting and financial management functions between central and decentralised units are guided by considerations around decision space, organisational structure and capacity, and accountability. In acknowledging the political nature of decentralisation polices, we recommend that health sector policy actors develop a broad understanding of the countries' political context when designing and implementing technical strategies for health sector decentralisation.

Ataíde R, Powell R, Moore K, McLean A, Phyo AP, Nair S, White M, Anderson TJ, Beeson JG, Simpson JA et al. 2017. Declining Transmission and Immunity to Malaria and Emerging Artemisinin Resistance in Thailand: A Longitudinal Study. J Infect Dis, 216 (6), pp. 723-731. | Show Abstract | Read more

Background: Reductions in malaria transmission decrease naturally acquired immunity, which may influence the emergence of Plasmodium falciparum artemisinin-resistant phenotypes and genotypes over time. Methods: Antibodies specific for P. falciparum antigens were determined in uncomplicated hyperparasitemic malaria patients over a 10-year period of declining malaria transmission and emerging artemisinin resistance in northwestern Thailand. We investigated the association between antibody levels and both parasite clearance time (PCt½) and artemisinin resistance-associated kelch13 genotypes over time. Results: Immunity to P. falciparum declined prior to 2004, preceding the emergence of artemisinin resistance-associated genotypes and phenotypes (maximum mean change in antibody level per year: anti-MSP142 = -0.17; 95% confidence interval [CI] = -.31 to -.04; P = .01). In this period of declining immunity, and in the absence of kelch13 mutations, PCt½ increased. Between 2007 and 2011, levels of antibodies fluctuated, and higher antibody levels were associated with faster PCt½ (maximum yearly change in PCt½, in hours: EBA140rII = -0.39; 95% CI = -.61 to -.17; P < .001). Conclusions: Understanding the impact of changing transmission and immunity on the emergence of artemisinin resistance is important particularly as increased malaria control and elimination activities may enhance immunological conditions for the expansion of artemisinin-resistant P. falciparum.

Kosaisavee V, Suwanarusk R, Chua ACY, Kyle DE, Malleret B, Zhang R, Imwong M, Imerbsin R, Ubalee R, Sámano-Sánchez H et al. 2017. Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi. Blood, 130 (11), pp. 1357-1363. | Citations: 2 (Scopus) | Show Abstract | Read more

Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date, only a single case of naturally acquired P cynomolgi has been found in humans. In this study, we show that whereas P cynomolgi merozoites invade monkey red blood cells indiscriminately in vitro, in humans, they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234). This likely contributes to the paucity of detectable zoonotic cynomolgi malaria. We further describe postinvasion morphologic and rheologic alterations in P cynomolgi-infected human reticulocytes that are strikingly similar to those observed for P vivax These observations stress the value of P cynomolgi as a model in the development of blood stage vaccines against vivax malaria.

Thuy DB, Campbell J, Hoang NVM, Trinh TTT, Duong HTH, Hieu NC, Duy NHA, Hao NV, Baker S, Thwaites GE et al. 2017. A one-year prospective study of colonization with antimicrobial-resistant organisms on admission to a Vietnamese intensive care unit. PLoS One, 12 (9), pp. e0184847. | Show Abstract | Read more

There is a paucity of data regarding initial bacterial colonization on admission to Intensive Care Units (ICUs) in low and middle-income countries (LMICs). Patients admitted to ICUs in LMICs are at high-risk of subsequent infection with antimicrobial-resistant organisms (AROs). We conducted a prospective, observational study at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam from November 2014 to January 2016 to assess the colonization and antimicrobial susceptibility of Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas spp. and Acinetobacter spp. among adult patients within 48 hours of ICU admission. We found the admission colonization prevalence (with at least one of the identified organisms) was 93.7% (785/838) and that of AROs was 63.1% (529/838). The colonization frequency with AROs among patients admitted from the community was comparable to those transferred from other hospitals (62.2% vs 63.8%). Staphylococcus aureus was the most commonly isolated bacteria from nasal swabs (13.1%, 110/838) and the methicillin-resistant Staphylococcus aureus nasal colonization prevalence was 8.6% (72/838). We isolated Escherichia coli from rectal swabs from almost all enrolled patients (88.3%, 740/838) and 52.1% (437/838) of patients were colonized by extended spectrum β-lactamase producing Escherichia coli. Notably, Klebsiella pneumoniae was the most frequently isolated bacteria from the tracheal swabs (11.8%, 18/153). Vietnamese ICU patients have a high rate of colonization with AROs and are thus at risk of subsequent infections with these organisms if good infection control practices are not in place.

Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. 2017. Snakebite envenoming. Nat Rev Dis Primers, 3 pp. 17063. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Snakebite envenoming is a neglected tropical disease that kills >100,000 people and maims >400,000 people every year. Impoverished populations living in the rural tropics are particularly vulnerable; snakebite envenoming perpetuates the cycle of poverty. Snake venoms are complex mixtures of proteins that exert a wide range of toxic actions. The high variability in snake venom composition is responsible for the various clinical manifestations in envenomings, ranging from local tissue damage to potentially life-threatening systemic effects. Intravenous administration of antivenom is the only specific treatment to counteract envenoming. Analgesics, ventilator support, fluid therapy, haemodialysis and antibiotic therapy are also used. Novel therapeutic alternatives based on recombinant antibody technologies and new toxin inhibitors are being explored. Confronting snakebite envenoming at a global level demands the implementation of an integrated intervention strategy involving the WHO, the research community, antivenom manufacturers, regulatory agencies, national and regional health authorities, professional health organizations, international funding agencies, advocacy groups and civil society institutions.

Baniya S, Holden C, Basnyat B. 2017. Reentry High Altitude Pulmonary Edema in the Himalayas. High Alt Med Biol, 18 (4), pp. 425-427. | Show Abstract | Read more

Baniya, Santosh, Christopher Holden, and Buddha Basnyat. Reentry high altitude pulmonary edema in the Himalayas. High Alt Med Biol. 18:425-427, 2017.-Reentry high altitude pulmonary edema (HAPE), a subset of HAPE, is a well recognized, life-threatening illness documented almost exclusively in the North and South Americans, who live at high altitude (>2500 m) and return to their homes after a brief sojourn of days to months at lower altitude. This phenomenon has not been reported in Sherpas or other people of Tibetan origin in Nepal or India. And it has rarely been reported from Tibet. In this study we document a case of reentry HAPE in Manang region (3500 m) of Nepal in a 7-year-old Nepali boy of Tibetan ancestry who fell ill when he ascended to his village (Manang, 3500 m) from Besisahar (760 m) in 1 day in a motor vehicle after spending the winter (December to March) at Besisahar with his family. With more motorable road access to high altitude settlements in the Himalayas, reentry HAPE may need to be strongly considered by healthcare professionals in local residents of high altitude; otherwise life-threatening complications may ensue as in our case report.

Macharia PM, Odera PA, Snow RW, Noor AM. 2017. Spatial models for the rational allocation of routinely distributed bed nets to public health facilities in Western Kenya. Malar J, 16 (1), pp. 367. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In high to moderate malaria transmission areas of Kenya, long-lasting insecticidal nets (LLINs) are provided free of charge to pregnant women and infants during routine antenatal care (ANC) and immunization respectively. Quantities of LLINs distributed to clinics are quantified based on a combination of monthly consumption data and population size of target counties. However, this approach has been shown to lead to stock-outs in targeted clinics. In this study, a novel LLINs need quantification approach for clinics in the routine distribution system was developed. The estimated need was then compared to the actual allocation to identify potential areas of LLIN over- or under-allocation in the high malaria transmission areas of Western Kenya. METHODS: A geocoded database of public health facilities was developed and linked to monthly LLIN allocation. A network analysis approach was implemented using the location of all public clinics and topographic layers to model travel time. Estimated travel time, socio-economic and ANC attendance data were used to model clinic catchment areas and the probability of ANC service use within these catchments. These were used to define the number of catchment population who were likely to use these clinics for the year 2015 equivalent to LLIN need. Actual LLIN allocation was compared with the estimated need. Clinics were then classified based on whether allocation matched with the need, and if not, whether they were over or under-allocated. RESULTS: 888 (70%) public health facilities were allocated 591,880 LLINs in 2015. Approximately 682,377 (93%) pregnant women and infants were likely to have attended an LLIN clinic. 36% of the clinics had more LLIN than was needed (over-allocated) while 43% had received less (under-allocated). Increasing efficiency of allocation by diverting over supply of LLIN to clinics with less stock and fully covering 43 clinics that did not receive nets in 2015 would allow for complete matching of need with distribution. CONCLUSION: The proposed spatial modelling framework presents a rationale for equitable allocation of routine LLINs and could be used for quantification of other maternal and child health commodities applicable in different settings. Western Kenya region received adequate LLINs for routine distribution in line with government of Kenya targets, however, the model shows important inefficiencies in the allocation of the LLINs at clinic level.

Lohy Das J, Dondorp AM, Nosten F, Phyo AP, Hanpithakpong W, Ringwald P, Lim P, White NJ, Karlsson MO, Bergstrand M, Tarning J. 2017. Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia. AAPS J, 19 (6), pp. 1842-1854. | Show Abstract | Read more

Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin-resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing.

Sumonwiriya M, Paris DH, Sunyakumthorn P, Anantatat T, Jenjaroen K, Chumseng S, Im-Erbsin R, Tanganuchitcharnchai A, Jintaworn S, Blacksell SD et al. 2017. Strong interferon-gamma mediated cellular immunity to scrub typhus demonstrated using a novel whole cell antigen ELISpot assay in rhesus macaques and humans. PLoS Negl Trop Dis, 11 (9), pp. e0005846. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Scrub typhus is a febrile infection caused by the obligate intracellular bacterium Orientia tsutsugamushi, which causes significant morbidity and mortality across the Asia-Pacific region. The control of this vector-borne disease is challenging due to humans being dead-end hosts, vertical maintenance of the pathogen in the vector itself, and a potentially large rodent reservoir of unclear significance, coupled with a lack of accurate diagnostic tests. Development of an effective vaccine is highly desirable. This however requires better characterization of the natural immune response of this neglected but important disease. Here we implement a novel IFN-γ ELISpot assay as a tool for studying O. tsutsugamushi induced cellular immune responses in an experimental scrub typhus rhesus macaque model and human populations. Whole cell antigen for O. tsutsugamushi (OT-WCA) was prepared by heat inactivation of Karp-strain bacteria. Rhesus macaques were infected intradermally with O. tsutsugamushi. Freshly isolated peripheral blood mononuclear cells (PBMC) from infected (n = 10) and uninfected animals (n = 5) were stimulated with OT-WCA, and IFN-γ secreting cells quantitated by ELISpot assay at five time points over 28 days. PBMC were then assayed from people in a scrub typhus-endemic region of Thailand (n = 105) and responses compared to those from a partially exposed population in a non-endemic region (n = 14), and to a naïve population in UK (n = 12). Mean results at Day 0 prior to O. tsutsugamushi infection were 12 (95% CI 0-25) and 15 (2-27) spot-forming cells (SFC)/106 PBMC for infected and control macaques respectively. Strong O. tsutsugamushi-specific IFN-γ responses were seen post infection, with ELISpot responses 20-fold higher than baseline at Day 7 (mean 235, 95% CI 200-270 SFC/106 PBMC), 105-fold higher at Day 14 (mean 1261, 95% CI 1,097-1,425 SFC/106 PBMC), 125-fold higher at Day 21 (mean 1,498, 95% CI 1,496-1,500 SFC/106 PBMC) and 118-fold higher at Day 28 (mean 1,416, 95% CI 1,306-1,527 SFC/106 PBMC). No significant change was found in the control group at any time point compared to baseline. Humans from a scrub typhus endemic region of Thailand had mean responses of 189 (95% CI 88-290) SFC/106 PBMC compared to mean responses of 40 (95% CI 9-71) SFC/106 PBMC in people from a non-endemic region and 3 (95% CI 0-7) SFC/106 PBMC in naïve controls. In summary, this highly sensitive assay will enable field immunogenicity studies and further characterization of the host response to O. tsutsugamushi, and provides a link between human and animal models to accelerate vaccine development.

Ley B, Bancone G, von Seidlein L, Thriemer K, Richards JS, Domingo GJ, Price RN. 2017. Methods for the field evaluation of quantitative G6PD diagnostics: a review. Malar J, 16 (1), pp. 361. | Show Abstract | Read more

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at risk of severe haemolysis following the administration of 8-aminoquinoline compounds. Primaquine is the only widely available 8-aminoquinoline for the radical cure of Plasmodium vivax. Tafenoquine is under development with the potential to simplify treatment regimens, but point-of-care (PoC) tests will be needed to provide quantitative measurement of G6PD activity prior to its administration. There is currently a lack of appropriate G6PD PoC tests, but a number of new tests are in development and are likely to enter the market in the coming years. As these are implemented, they will need to be validated in field studies. This article outlines the technical details for the field evaluation of novel quantitative G6PD diagnostics such as sample handling, reference testing and statistical analysis. Field evaluation is based on the comparison of paired samples, including one sample tested by the new assay at point of care and one sample tested by the gold-standard reference method, UV spectrophotometry in an established laboratory. Samples can be collected as capillary or venous blood; the existing literature suggests that potential differences in capillary or venous blood are unlikely to affect results substantially. The collection and storage of samples is critical to ensure preservation of enzyme activity, it is recommended that samples are stored at 4 °C and testing occurs within 4 days of collection. Test results can be visually presented as scatter plot, Bland-Altman plot, and a histogram of the G6PD activity distribution of the study population. Calculating the adjusted male median allows categorizing results according to G6PD activity to calculate standard performance indicators and to perform receiver operating characteristic (ROC) analysis.

Ayieko P, Irimu G, English M. 2017. Effect of enhanced feedback to hospitals that are part of an emerging clinical information network on uptake of revised childhood pneumonia treatment policy: study protocol for a cluster randomized trial. Trials, 18 (1), pp. 416. | Show Abstract | Read more

BACKGROUND: The national pneumonia treatment guidelines in Kenya changed in February 2016 but such guideline changes are often characterized by prolonged delays in affecting practice. We designed an enhanced feedback intervention, delivered within an ongoing clinical network that provides a general form of feedback, aimed at improving and sustaining uptake of the revised pneumonia treatment policy. The objective was to determine whether an enhanced feedback intervention will improve correctness of classification and treatment of childhood pneumonia, compared to an existing approach to feedback, after nationwide treatment policy change and within an existing hospital network. METHODS/DESIGN: A pragmatic, cluster randomized trial conducted within a clinical network of 12 Kenyan county referral hospitals providing inpatient pediatric care to children (aged 2-59 months) with acute medical conditions between March and November 2016. The intervention comprised enhanced feedback (monthly written feedback incorporating goal setting, and action planning delivered by a senior clinical coordinator for selected pneumonia indicators) and this was compared to standard feedback (2-monthly written feedback on multiple quality of pediatric care indicators) both delivered within a clinical network promoting clinical leadership linked to mentorship and peer-to-peer support, and improved use of health information on service delivery. The 12 hospitals were randomized to receive either enhanced feedback (n = 6) or standard feedback (n = 6) delivered over a 9-month period following nationwide pneumonia treatment policy change. The primary outcome is the proportion of all admitted patients with pneumonia (fulfilling criteria for treatment with orally administered amoxicillin) who are correctly classified and treated in the first 24 h. The secondary outcome will be measured over the course of the admission as any change in treatment for pneumonia after the first 24 h. DISCUSSION: This trial protocol employs a pragmatic trial design during a period of nationwide change in treatment guidelines to address two high-priority areas within implementation research: promoting adoption of health policies and optimizing effectiveness of feedback. TRIAL REGISTRATION:, ID: NCT02817971 . Registered retrospectively on 27 June 2016.

Ujka K, Bruno RM, Bastiani L, Bernardi E, Sdringola P, Dikic N, Basyal B, Bhandari SS, Basnyat B, Cogo A, Pratali L. 2017. Relationship Between Occupational Physical Activity and Subclinical Vascular Damage in Moderate-Altitude Dwellers. High Alt Med Biol, 18 (3), pp. 249-257. | Show Abstract | Read more

Ujka, Kristian, Rosa Maria Bruno, Luca Bastiani, Eva Bernardi, Paolo Sdringola, Nenad Dikic, Bikash Basyal, Sanjeeb Sundarshan Bhandari, Buddha Basnyat, Annalisa Cogo, and Lorenza Pratali. Relationship between occupational physical activity and subclinical vascular damage in moderate-altitude dwellers. High Alt Med Biol. 18:249-257, 2017. BACKGROUND: Occupational physical activity (OPA) has been associated with increased cardiovascular (CV) events. The aim of this study was to investigate the association between OPA and markers of subclinical vascular damage among a moderate-altitude population living in the rural village of Chaurikharka (Nepal; 2600 m sea level). METHODS: Seventy-two individuals (age 42 ± 15 years, ranges 15-85 years, 23 men) were enrolled. Physical activity (PA) was evaluated using the International Physical Activity Questionnaire (IPAQ). Carotid-femoral pulse wave velocity (PWV), carotid ultrasound assessment, and flow-mediated dilation (FMD) were performed. RESULTS: OPA was 9860 ± 5385 Metabolic Equivalent of Task (MET)-minutes/week, representing 77% of total energy expenditure, with 97% of the population performing high-intensity PA. In the univariate analysis, OPA was significantly associated with PWV (β = 0.474, p = 0.001) and carotid stiffness (CS) (β = 0.29, p = 0.019). In the multivariate analysis, including age, sex, oxygen saturation, mean blood pressure, low-density lipoprotein (LDL), and OPA, OPA remained an independent predictor of PWV (β = 0.403, p = 0.001) but not of CS (β = 0.028, p = 0.8). OPA remained an independent predictor of PWV independently from the Framingham risk score (FRS). CONCLUSION: High-intensity OPA shows a positive, independent association with aortic stiffness in Himalayan moderate-altitude dwellers. This study suggests how vigorous OPA performed in moderate altitude may be a CV risk factor.

Landier J, Kajeechiwa L, Thwin MM, Parker DM, Chaumeau V, Wiladphaingern J, Imwong M, Miotto O, Patumrat K, Duanguppama J et al. 2017. Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar. Wellcome Open Res, 2 pp. 81. | Citations: 2 (Scopus) | Show Abstract | Read more

Background: Artemisinin and partner drug-resistant falciparum malaria is expanding over the Greater Mekong Sub-region (GMS). Eliminating falciparum malaria in the GMS while drugs still retain enough efficacy could prevent global spread of antimalarial resistance. Eliminating malaria rapidly requires targeting the reservoir of asymptomatic parasite carriers. This pilot trial aimed to evaluate the acceptability, safety, feasibility and effectiveness of mass-drug administration (MDA) in reducing malaria in four villages in Eastern Myanmar.Methods:Villages with ≥30% malaria prevalence were selected. Long-lasting insecticidal bednets (LLINs) and access to malaria early diagnosis and treatment (EDT) were provided. Two villages received MDA immediately and two were followed for nine months pre-MDA. MDA consisted of a 3-day supervised course of  dihydroartemisinin-piperaquine and single low-dose primaquine administered monthly for three months. Adverse events (AE) were monitored by interviews and consultations. Malaria prevalence was assessed by ultrasensitive PCR quarterly for 24 months. Symptomatic malaria incidence,entomological indices, and antimalarial resistance markers were monitored.Results:MDA was well tolerated. There were no serious AE and mild to moderate AE were reported in 5.6%(212/3931) interviews. In the smaller villages, participation to three MDA courses was 61% and 57%, compared to 28% and 29% in the larger villages. Baseline prevalence was higher in intervention than in control villages (18.7% (95%CI=16.1-21.6) versus 6.8%(5.2-8.7), p<0.0001) whereas three months after starting MDA, prevalence was lower in intervention villages (0.4%(0.04-1.3) versus 2.7%(1.7-4.1), p=0.0014). After nine months the difference was no longer significant (2.0%(1.0-3.5) versus 0.9%(0.04-1.8), p=0.10). M0-M9 symptomatic falciparum incidence was similar between intervention and control. Before/after MDA comparisons showed that asymptomaticP. falciparumcarriage and anopheline vector positivity decreased significantly whereas prevalence of the artemisinin-resistance molecular marker remained stable.Conclusions:This MDA was safe and feasible, and, could accelerate elimination ofP. falciparum in addition to EDT and LLINs when community participation was sufficient.

Omedo I, Mogeni P, Rockett K, Kamau A, Hubbart C, Jeffreys A, Ochola-Oyier LI, de Villiers EP, Gitonga CW, Noor AM et al. 2017. Geographic-genetic analysis of Plasmodium falciparum parasite populations from surveys of primary school children in Western Kenya Wellcome Open Research, 2 pp. 29-29. | Show Abstract | Read more

© 2017 Omedo I et al. Background. Malaria control, and finally malaria elimination, requires the identification and targeting of residual foci or hotspots of transmission. However, the level of parasite mixing within and between geographical locations is likely to impact the effectiveness and durability of control interventions and thus should be taken into consideration when developing control programs. Methods. In order to determine the geographic-genetic patterns of Plasmodium falciparum parasite populations at a sub-national level in Kenya, we used the Sequenom platform to genotype 111 genome-wide distributed single nucleotide polymorphic (SNP) positions in 2486 isolates collected from children in 95 primary schools in western Kenya. We analysed these parasite genotypes for genetic structure using principal component analysis and assessed local and global clustering using statistical measures of spatial autocorrelation. We further examined the region for spatial barriers to parasite movement as well as directionality in the patterns of parasite movement. Results. We found no evidence of population structure and little evidence of spatial autocorrelation of parasite genotypes (correlation coefficients < 0.03 among parasite pairs in distance classes of 1km, 2km and 5km; p value < 0.01). An analysis of the geographical distribution of allele frequencies showed weak evidence of variation in distribution of alleles, with clusters representing a higher than expected number of samples with the major allele being identified for 5 SNPs. Furthermore, we found no evidence of the existence of spatial barriers to parasite movement within the region, but observed directional movement of parasites among schools in two separate sections of the region studied. Conclusions. Our findings illustrate a pattern of high parasite mixing within the study region. If this mixing is due to rapid gene flow, then “one-off” targeted interventions may not be currently effective at the sub-national scale in Western Kenya, due to the high parasite movement that is likely to lead to re-introduction of infection from surrounding regions. However repeated targeted interventions may reduce transmission in the surrounding regions.

Soontarawirat I, Andolina C, Paul R, Day NPJ, Nosten F, Woodrow CJ, Imwong M. 2017. Plasmodium vivax genetic diversity and heterozygosity in blood samples and resulting oocysts at the Thai-Myanmar border. Malar J, 16 (1), pp. 355. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Polyclonal blood-stage infections of Plasmodium vivax are frequent even in low transmission settings, allowing meiotic recombination between heterologous parasites. Empirical data on meiotic products are however lacking. This study examined microsatellites in oocysts derived by membrane feeding of mosquitoes from blood-stage P. vivax infections at the Thai-Myanmar border. METHODS: Blood samples from patients presenting with vivax malaria were fed to Anopheles cracens by membrane feeding and individual oocysts from midguts were obtained by dissection after 7 days. DNA was extracted from oocysts and parental blood samples and tested by microsatellite analysis. RESULTS: A focused study of eight microsatellite markers was undertaken for nine blood stage infections from 2013, for which derived oocysts were studied in six cases. One or more alleles were successfully amplified for 131 oocysts, revealing high levels of allelic diversity in both blood and oocyst stages. Based on standard criteria for defining minor alleles, there was evidence of clear deviation from random mating (inbreeding) with relatively few heterozygous oocysts compared to variance across the entire oocyst population (FIT = 0.89). The main explanation appeared to be natural compartmentalisation at mosquito (FSC = 0.27) and human stages (FCT = 0.68). One single human case produced a total of 431 successfully amplified loci (across 70 oocysts) that were homozygous and identical to parental alleles at all markers, indicating clonal infection and transmission. Heterozygous oocyst alleles were found at 15/176 (8.5%) successfully amplified loci in the other five cases. There was apparently reduced oocyst heterozygosity in individual oocysts compared to diversity within individual mosquitoes (FIS = 0.55), but this may simply reflect the difficulty of detecting minor alleles in oocysts, given the high rate of amplification failure. Inclusion of minor allele peaks (irrespective of height) when matching peaks were found in related blood or oocyst samples, added 11 minor alleles for 9 oocysts, increasing the number of heterozygous loci to 26/176 (14.8%; p = 0.096). CONCLUSION: There was an apparently low level of heterozygous oocysts but this can be explained by a combination of factors: relatively low complexity of parental infection, natural compartmentalisation in humans and mosquitoes, and the methodological challenge of detecting minor alleles.

Rojek A, Horby P, Dunning J. 2017. Insights from clinical research completed during the west Africa Ebola virus disease epidemic. Lancet Infect Dis, 17 (9), pp. e280-e292. | Citations: 2 (Scopus) | Show Abstract | Read more

The west Africa Ebola virus disease (EVD) epidemic was extraordinary in scale. Now that the epidemic has ended, it is a relevant time to examine published studies with direct relevance to clinical care and, more broadly, to examine the implications of the clinical research response mounted. Clinically relevant research includes literature detailing risk factors for and clinical manifestations of EVD, laboratory and other investigation findings in patients, experimental vaccine and therapeutic clinical trials, and analyses of survivor syndrome. In this Review, we discuss new insights from patient-oriented research completed during the west Africa epidemic, identify ongoing knowledge gaps, and suggest priorities for future research.

Caillet C, Sichanh C, Assemat G, Malet-Martino M, Sommet A, Bagheri H, Sengxeu N, Mongkhonmath N, Mayxay M, Syhakhang L et al. 2017. Role of Medicines of Unknown Identity in Adverse Drug Reaction-Related Hospitalizations in Developing Countries: Evidence from a Cross-Sectional Study in a Teaching Hospital in the Lao People's Democratic Republic. Drug Saf, 40 (9), pp. 809-821. | Show Abstract | Read more

INTRODUCTION: The health dangers of medicines of unknown identity (MUIs) [loose pharmaceutical units repackaged in individual bags without labelling of their identity] have been suspected in L/MICs. Using visual and analytical tools to identify MUIs, we investigated the frequency of, and factors associated with, adverse drug reaction (ADR)-related hospitalizations in a central hospital in Vientiane Capital, Lao People's Democratic Republic (PDR). METHODS: All unplanned admissions, except for acute trauma and intentional overdose, were prospectively recorded during a 7-week period in 2013, leading to include 453 adults hospitalized for ≥24 h. The patients or their relatives were interviewed to complete the study questionnaire. MUIs suspected of being involved in ADR(s) were identified through comparison of visual characteristics of tablets/capsules with that of reference medicines (photograph tool), and by proton nuclear magnetic resonance and mass spectrometry analyses. Factors associated with ADRs were identified by multivariate logistic regression. RESULTS: The frequency of hospitalizations related to an ADR was 5.1% (23/453, 95% confidence interval [CI] 3.1-7.1). Forty-eight (12.8%) patients used MUI(s) in the last 2 weeks preceding hospitalization. They were more likely to be hospitalized because of an ADR (adjusted odds ratio 4.5, 95% CI 1.7-11.5) than patients using medicines of known identity. MUIs were mainly involved in bleeding gastroduodenal ulcers. The photograph tool led to the misidentifications because of look-alike pharmaceutical units in the medicines photograph collection. CONCLUSION: According to the results of this study, there is a need to ensure appropriate labelling of medicines at dispensing and to provide well-suited tools to identify MUIs in clinical settings to improve drug safety and patients' care in developing countries with limited capacities for drug analysis.

Malina T, Krecsák L, Westerström A, Szemán-Nagy G, Gyémánt G, M-Hamvas M, Rowan EG, Harvey AL, Warrell DA, Pál B et al. 2017. Individual variability of venom from the European adder (Vipera berus berus) from one locality in Eastern Hungary. Toxicon, 135 pp. 59-70. | Citations: 1 (Scopus) | Show Abstract | Read more

We have revealed intra-population variability among venom samples from several individual European adders (Vipera berus berus) within a defined population in Eastern Hungary. Individual differences in venom pattern were noticed, both gender-specific and age-related, by one-dimensional electrophoresis. Gelatin zymography demonstrated that these individual venoms have different degradation profiles indicating varying protease activity in the specimens from adders of different ages and genders. Some specimens shared a conserved region of substrate degradation, while others had lower or extremely low protease activity. Phospholipase A2 activity of venoms was similar but not identical. Interspecimen diversity of the venom phospholipase A2-spectra (based on the components' molecular masses) was detected by MALDI-TOF MS. The lethal toxicity of venoms (LD50) also showed differences among individual snakes. Extracted venom samples had varying neuromuscular paralysing effect on chick biventer cervicis nerve-muscle preparations. The paralysing effect of venom was lost when calcium in the physiological salt solution was replaced by strontium; indicating that the block of twitch responses to nerve stimulation is associated with the activity of a phospholipase-dependent neurotoxin. In contrast to the studied V. b. berus venoms from different geographical regions so far, this is the first V. b. berus population discovered to have predominantly neurotoxic neuromuscular activity. The relevance of varying venom yields is also discussed. This study demonstrates that individual venom variation among V. b. berus living in particular area of Eastern Hungary might contribute to a wider range of clinical manifestations of V. b. berus envenoming than elsewhere in Europe.

English M, Irimu G, Nyamai R, Were F, Garner P, Opiyo N. 2017. Developing guidelines in low-income and middle-income countries: lessons from Kenya. Arch Dis Child, 102 (9), pp. 846-851. | Show Abstract | Read more

There are few examples of sustained nationally organised, evidence-informed clinical guidelines development processes in Sub-Saharan Africa. We describe the evolution of efforts from 2005 to 2015 to support evidence-informed decision making to guide admission hospital care practices in Kenya. The approach to conduct reviews, present evidence, and structure and promote transparency of consensus-based procedures for making recommendations improved over four distinct rounds of policy making. Efforts to engage important voices extended from government and academia initially to include multiple professional associations, regulators and practitioners. More than 100 people have been engaged in the decision-making process; an increasing number outside the research team has contributed to the conduct of systematic reviews, and 31 clinical policy recommendations has been developed. Recommendations were incorporated into clinical guideline booklets that have been widely disseminated with a popular knowledge and skills training course. Both helped translate evidence into practice. We contend that these efforts have helped improve the use of evidence to inform policy. The systematic reviews, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approaches and evidence to decision-making process are well understood by clinicians, and the process has helped create a broad community engaged in evidence translation together with a social or professional norm to use evidence in paediatric care in Kenya. Specific sustained efforts should be made to support capacity and evidence-based decision making in other African settings and clinical disciplines.

Rueangweerayut R, Bancone G, Harrell EJ, Beelen AP, Kongpatanakul S, Möhrle JJ, Rousell V, Mohamed K, Qureshi A, Narayan S et al. 2017. Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers. Am J Trop Med Hyg, 97 (3), pp. 702-711. | Citations: 2 (Scopus) | Show Abstract | Read more

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [N = 3]) and primaquine (-1.25 to -3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

Van Toi P, Pouplin T, Tho NDK, Phuong PN, Chau TTH, Thuong Thuong NT, Heemskerk D, Hien TT, Thwaites GE. 2017. High-performance liquid chromatography with time-programmed fluorescence detection for the quantification of Levofloxacin in human plasma and cerebrospinal fluid in adults with tuberculous meningitis. J Chromatogr B Analyt Technol Biomed Life Sci, 1061-1062 pp. 256-262. | Show Abstract | Read more

An accurate and reliable high-performance liquid chromatography with time-programmed fluorescence detection was developed and validated to measure levofloxacin in human plasma and cerebrospinal fluid (CSF). After solid phase extraction process using Evolute® ABN 96 fixed well plate; levofloxacin and internal standard-enoxacin were separated using a mobile phase consisting of phosphate buffer 10mM with 0.025% triethylamine pH 3.0 - acetonitrile (88:12, v/v) on a Purosphere RP-8e column (5μm, 125×4.0mm) at a flow rate of 1.2mL/min at 35°C. The excitation/emission wavelengths were set to 269/400nm and 294/500nm, for enoxacin and levofloxacin, respectively. The method was linear over the concentration range of 0.02 to 20.0μg/mL with a limit of detection of 0.01μg/mL. The relative standard deviation of intra-assay and inter-assay precision for levofloxacin at four quality controls concentrations (0.02, 0.06, 3.0 and 15.0μg/mL) were less than 7% and the accuracies ranged from 96.75% to 101.9% in plasma, and from 93.00% to 98.67% in CSF. The validated method was successfully applied to quantify levofloxacin in a considerable quantity of plasma (826) and CSF (477) samples collected from 232 tuberculous meningitis patients, and the preliminary intensive pharmacokinetics analysis from 14 tuberculous meningitis patients in Vietnam is described in this paper.

Rabaa MA, Girerd-Chambaz Y, Duong Thi Hue K, Vu Tuan T, Wills B, Bonaparte M, van der Vliet D, Langevin E, Cortes M, Zambrano B et al. 2017. Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy. Elife, 6 | Show Abstract | Read more

This study defined the genetic epidemiology of dengue viruses (DENV) in two pivotal phase III trials of the tetravalent dengue vaccine, CYD-TDV, and thereby enabled virus genotype-specific estimates of vaccine efficacy (VE). Envelope gene sequences (n = 661) from 11 DENV genotypes in 10 endemic countries provided a contemporaneous global snapshot of DENV population genetics and revealed high amino acid identity between the E genes of vaccine strains and wild-type viruses from trial participants, including at epitope sites targeted by virus neutralising human monoclonal antibodies. Post-hoc analysis of all CYD14/15 trial participants revealed a statistically significant genotype-level VE association within DENV-4, where efficacy was lowest against genotype I. In subgroup analysis of trial participants age 9-16 years, VE estimates appeared more balanced within each serotype, suggesting that genotype-level heterogeneity may be limited in older children. Post-licensure surveillance is needed to monitor vaccine performance against the backdrop of DENV sequence diversity and evolution.

Keyes LE, Sallade TD, Duke C, Starling J, Sheets A, Pant S, Young DS, Twillman D, Regmi N, Phelan B et al. 2017. Blood Pressure and Altitude: An Observational Cohort Study of Hypertensive and Nonhypertensive Himalayan Trekkers in Nepal. High Alt Med Biol, 18 (3), pp. 267-277. | Show Abstract | Read more

Keyes, Linda E., Thomas Douglas Sallade, Charles Duke, Jennifer Starling, Alison Sheets, Sushil Pant, David S. Young, David Twillman, Nirajan Regmi, Benoit Phelan, Purshotam Paudel, Matthew McElwee, Luke Mather, Devlin Cole, Theodore McConnell, and Buddha Basnyat. Blood pressure and altitude: an observational cohort study of hypertensive and nonhypertensive Himalayan trekkers in Nepal. High Alt Med Biol. 18:267-277, 2017. OBJECTIVES: To determine how blood pressure (BP) changes with altitude in normotensive versus hypertensive trekkers. Secondary aims were to evaluate the prevalence of severe hypertension (BP ≥180/100 mmHg) and efficacy of different antihypertensive agents at high altitude. METHODS: This was an observational cohort study of resting and 24-hour ambulatory BP in normotensive and hypertensive trekkers at 2860, 3400, and 4300 m in Nepal. RESULTS: We enrolled 672 trekkers age 18 years and older, 60 with a prior diagnosis of hypertension. Mean systolic and diastolic BP did not change between altitudes in normotensive or hypertensive trekkers, but was higher in those with hypertension. However, there was large interindividual variability. At 3400 m, the majority (60%, n = 284) of normotensive participants had a BP within 10 mmHg of their BP at 2860 m, while 21% (n = 102) increased and 19% (n = 91) decreased. The pattern was similar between 3400 and 4300 m (64% [n = 202] no change, 21% [n = 65] increased, 15% [n = 46] decreased). BP decreased in a greater proportion of hypertensive trekkers versus normotensives (36% [n = 15] vs. 21% at 3400 m, p = 0.01 and 30% [n = 7] vs. 15% at 4300 m, p = 0.05). Severe hypertension occurred in both groups, but was asymptomatic. In a small subset of participants, 24-hour ambulatory BP monitoring showed that nocturnal BP decreased in normotensive (n = 4) and increased in hypertensive trekkers (n = 4). CONCLUSIONS: Most travelers, including those with well-controlled hypertension, can be reassured that their BP will remain relatively stable at high altitude. Although extremely elevated BP may be observed at high altitude in normotensive and hypertensive people, it is unlikely to be symptomatic. The ideal antihypertensive regimen at high altitude remains unclear.

Meiring JE, Gibani M, TyVAC Consortium Meeting Group:. 2017. The Typhoid Vaccine Acceleration Consortium (TyVAC): Vaccine effectiveness study designs: Accelerating the introduction of typhoid conjugate vaccines and reducing the global burden of enteric fever. Report from a meeting held on 26-27 October 2016, Oxford, UK. Vaccine, 35 (38), pp. 5081-5088. | Show Abstract | Read more

Typhoid fever is estimated to cause between 11.9-26.9 million infections globally each year with 129,000-216,510 deaths. Access to improved water sources have reduced disease incidence in parts of the world but the use of efficacious vaccines is seen as an important public health tool for countries with a high disease burden. A new generation of Vi typhoid conjugate vaccines (TCVs), licensed for use in young children and expected to provide longer lasting protection than previous vaccines, are now available. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has convened a working group to review the evidence on TCVs and produce an updated WHO position paper for all typhoid vaccines in 2018 that will inform Gavi, the Vaccine Alliance's future vaccine investment strategies for TCVs. The Typhoid Vaccine Acceleration Consortium (TyVAC) has been formed through a $36.9 million funding program from the Bill & Melinda Gates Foundation to accelerate the introduction of TCVs into Gavi-eligible countries. In October 2016, a meeting was held to initiate planning of TCV effectiveness studies that will provide the data required by policy makers and stakeholders to support decisions on TCV use in countries with a high typhoid burden. Discussion topics included (1) the latest evidence and data gaps in typhoid epidemiology; (2) WHO and Gavi methods and data requirements; (3) data on TCV efficacy; (4) cost effectiveness analysis for TCVs from mathematical models; (5) TCV delivery and effectiveness study design. Specifically, participants were asked to comment on study design in 3 sites for which population-based typhoid surveillance is underway. The conclusion of the meeting was that country-level decision making would best be informed by the respective selected sites in Africa and Asia vaccinating children aged from 9-months to 15-years-old, employing either an individual or cluster randomized design with design influenced by population characteristics, transmission dynamics, and statistical considerations.

Shrestha GS, Kwizera A, Lundeg G, Baelani JI, Azevedo LCP, Pattnaik R, Haniffa R, Gavrilovic S, Mai NTH, Kissoon N et al. 2017. International Surviving Sepsis Campaign guidelines 2016: the perspective from low-income and middle-income countries. Lancet Infect Dis, 17 (9), pp. 893-895. | Citations: 3 (Web of Science Lite) | Read more

Hernández-de-Diego R, de Villiers EP, Klingström T, Gourlé H, Conesa A, Bongcam-Rudloff E. 2017. The eBioKit, a stand-alone educational platform for bioinformatics. PLoS Comput Biol, 13 (9), pp. e1005616. | Show Abstract | Read more

Bioinformatics skills have become essential for many research areas; however, the availability of qualified researchers is usually lower than the demand and training to increase the number of able bioinformaticians is an important task for the bioinformatics community. When conducting training or hands-on tutorials, the lack of control over the analysis tools and repositories often results in undesirable situations during training, as unavailable online tools or version conflicts may delay, complicate, or even prevent the successful completion of a training event. The eBioKit is a stand-alone educational platform that hosts numerous tools and databases for bioinformatics research and allows training to take place in a controlled environment. A key advantage of the eBioKit over other existing teaching solutions is that all the required software and databases are locally installed on the system, significantly reducing the dependence on the internet. Furthermore, the architecture of the eBioKit has demonstrated itself to be an excellent balance between portability and performance, not only making the eBioKit an exceptional educational tool but also providing small research groups with a platform to incorporate bioinformatics analysis in their research. As a result, the eBioKit has formed an integral part of training and research performed by a wide variety of universities and organizations such as the Pan African Bioinformatics Network (H3ABioNet) as part of the initiative Human Heredity and Health in Africa (H3Africa), the Southern Africa Network for Biosciences (SAnBio) initiative, the Biosciences eastern and central Africa (BecA) hub, and the International Glossina Genome Initiative.

Gordon SB, Rylance J, Luck A, Jambo K, Ferreira DM, Manda-Taylor L, Bejon P, Ngwira B, Littler K, Seager Z et al. 2017. A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi. Wellcome Open Res, 2 pp. 70. | Show Abstract | Read more

Controlled human infection model (CHIM) studies have pivotal importance in vaccine development, being useful for proof of concept, pathogenesis, down-selection and immunogenicity studies.  To date, however, they have seldom been carried out in low and middle income countries (LMIC), which is where the greatest burden of vaccine preventable illness is found.  This workshop discussed the benefits and barriers to CHIM studies in Malawi.  Benefits include improved vaccine effectiveness and host country capacity development in clinical, laboratory and governance domains.  Barriers include acceptability, safety and regulatory issues. The report suggests a framework by which ethical, laboratory, scientific and governance issues may be addressed by investigators considering or planning CHIM in LMIC.

Abubakar A, Van de Vijver FJR, Hassan AS, Fischer R, Nyongesa MK, Kabunda B, Berkley JA, Stein A, Newton CR. 2017. Cumulative Psychosocial Risk is a Salient Predictor of Depressive Symptoms among Vertically HIV-Infected and HIV-Affected Adolescents at the Kenyan Coast. Ann Glob Health, 83 (5-6), pp. 743-752. | Show Abstract | Read more

BACKGROUND: Little is known of mental health outcomes among vertically HIV-infected or HIV-affected adolescents in Africa. OBJECTIVES: The current study set out to describe depressive symptoms and their correlates among vertically HIV-infected and HIV-affected adolescents at the Kenyan Coast. METHODS: 130 adolescents (vertically HIV-infected [n = 44], HIV-affected [n = 53], and unexposed [n = 33]) and their caregivers participated in this cross-sectional study. An adapted version of the Beck Depression Inventory-11 (BDI) was administered to examine depressive symptoms in both adolescents and caregivers, together with measures of sociodemographic, medical, and anthropometric characteristics. FINDINGS: Our analysis indicated a main effect of HIV status on mean BDI scores in HIV-infected (18.4 [SD = 8.3) and HIV-affected (16.8 [SD = 7.3]) adolescents compared to the community controls (12.0 [SD = 7.9]), F (2, 127) = 6.704, P = .002, η2 = .095. Post hoc analysis showed that BDI scores of HIV-infected adolescents were higher than those of community controls (P < .001). Similarly, HIV-affected adolescents had BDI scores that were higher than those of community controls (P = .007). However, there was no difference in BDI scores between HIV-infected and HIV-affected adolescents (P = .304). A path analytic model indicated that cumulative psychosocial risk (orphanhood, family poverty, and caregiver depressive symptoms) were positive predictors of BDI scores among adolescents, while nutritional status had a limited role. CONCLUSIONS: Both HIV-infected and HIV-affected adolescents are at a high risk of experiencing depressive symptoms, largely due to the multiple psychosocial risk factors in their environment. The provision of adequate psychosocial support and counseling needs to become an integral part of the care program for adolescents from families living with HIV/AIDS at the Kenyan coast and other similar settings.

Bui TTT, Tran TT, Nghiem MN, Rahman P, Tran TTT, Dinh MNH, Le MH, Nguyen VVC, Thwaites G, Rahman M. 2017. Molecular characterization of hepatitis B virus in Vietnam. BMC Infect Dis, 17 (1), pp. 601. | Show Abstract | Read more

BACKGROUND: Hepatitis B virus (HBV) infection is a major public health problem globally. HBV genotypes and subgenotypes influence disease transmission, progression, and treatment outcome. A study was conducted among treatment naive chronic HBV patients in southern Vietnam to determine the genotypes and subgenotypes of HBV. METHODS: A prospective, exploratory study was conducted among treatment naïve chronic HBV patients attending at the Hospital for Tropical Diseases, in Ho Chi Minh City, Vietnam during 2012, 2014 and 2016. HBV DNA positive samples (systematically selected 2% of all treatment naïve chronic patients during 2012 and 2014, and 8% of all treatment naïve chronic patients during 2016) were subjected to whole genome sequencing (WGS) either by Sanger or Illumina sequencing. WGS was used to define genotype, sub-genotype, recombination, and the prevalence of drug resistance and virulence-associated mutations. RESULTS: One hundred thirty five treatment naïve chronic HBV patients including 18 from 2012, 24 from 2014, and 93 from 2016 were enrolled. Of 135 sequenced viruses, 72.6% and 27.4% were genotypes B and C respectively. Among genotype B isolates, 87.8% and 12.2% were subgenotypes B4 and B2 respectively. A G1896A mutation in the precore gene was present in 30.6% of genotype B isolates. The genotype C isolates were all subgenotype C1 and 78.4% (29/37) of them had at least one basal core promoter (BCP) mutation. A1762T and G1764 T mutations and a double mutation (A1762T and G1764 T) in the BCP region were significantly more frequent in genotype C1 isolates (p < 0.001). CONCLUSION: HBV genotype B including subgenotype B4 is predominant in southern Vietnam. However, one fourth of the chronic HBV infections were caused by subgenotype C1.

Oseni Z, Than HH, Kolakowska E, Chalmers L, Hanboonkunupakarn B, McGready R. 2017. Video-based feedback as a method for training rural healthcare workers to manage medical emergencies: a pilot study. BMC Med Educ, 17 (1), pp. 149. | Show Abstract | Read more

BACKGROUND: Video-based feedback has been shown to aid knowledge retention, skills learning and improve team functionality. We explored the use of video-based feedback and low fidelity simulation for training rural healthcare workers along the Thailand-Myanmar border and Papua New Guinea (PNG) to manage medical emergencies effectively. METHODS: Twenty-four study participants were recruited from three Shoklo Malaria Research Unit clinics along the Thailand-Myanmar border and eight participants from Kudjip Nazarene Hospital, PNG. The teams were recorded on video managing a simulated medical emergency scenario and the video was used to aid feedback and assess performance using Observed Structured Clinical Examination (OSCE) scoring and Team Emergency Assessment Measure (TEAM) questionnaire. The process was repeated post-feedback at both sites and at 6 weeks at the Thailand-Myanmar border site. Thailand-Myanmar border participants' individual confidence levels and baseline knowledge (using OSCE scoring) were assessed before team assessment and feedback at week 1 and repeated post-feedback and at 6 weeks. Focus group discussions (FGD) were held at each Thailand-Myanmar border clinic at week 1 (8 participants at each clinic). RESULTS: Individual paired tests of OSCE scores showed significant improvement post-feedback at week 1 (p < 0.001) and week 6 (p < 0.001) compared to baseline OSCE scores. There was a trend for increased team OSCE scores compared to baseline at week 1 (p = 0.068) and week 6 (p = 0.109) although not significant. Thailand-Myanmar border TEAM scores demonstrated improvement post-feedback mainly in leadership, teamwork and task management which was sustained up to week 6. PNG showed an improvement mainly in teamwork and task management. The global rating of the teams' non-technical performance at both sites improved post feedback and at week 6 on the Thailand-Myanmar border site. Self-rated confidence scores by Thailand-Myanmar border participants increased significantly from baseline following training at week 1 (p = 0.020), and while higher at 6 weeks follow up than at baseline, this was not significant (p = 0.471). The FGD revealed majority of participants felt that watching the video recording of their performance and the video-based feedback contributed most to their learning. CONCLUSION: Video-assisted feedback resulted in an improvement in clinical knowledge, confidence and quality of teamwork for managing medical emergencies in two low resource medical facilities in South East Asia and the South Pacific.

Abdad MY, Abdallah RA, Karkouri KE, Beye M, Stenos J, Owen H, Unsworth N, Robertson I, Blacksell SD, Nguyen T-T et al. 2017. Rickettsia gravesii sp. nov.: a novel spotted fever group rickettsia in Western Australian Amblyomma triguttatum triguttatum ticks. Int J Syst Evol Microbiol, 67 (9), pp. 3156-3161. | Show Abstract | Read more

A rickettsial organism harboured by Amblyomma triguttatum ticks on Barrow Island, Western Australia, was discovered after reports of possible rickettsiosis among local workers. Subsequent isolation of this rickettsia (strain BWI-1) in cell culture and analysis of its phylogenetic, genotypic and phenotypic relationships with type strains of Rickettsia species with standing in nomenclature suggested that it was sufficiently divergent to warrant its classification as a new species. Multiple gene comparison of strain BWI-1 revealed degrees of sequence similarity with Rickettsia raoultii, its closest relative, of 99.58, 98.89, 97.03, 96.93 and 95.73 % for the 16S rRNA, citrate synthase, ompA, ompB and sca4 genes, respectively. Serotyping in mice also demonstrated that strain BWI-1T was distinct from Rickettsia raoultii. Thus, we propose the naming of a new species, Rickettsia gravesii sp. nov., based on its novel genotypic and phenotypic characteristics. Strain BWI-1T was deposited in the ATCC, CSUR and ARRL collections under reference numbers VR-1664, CSUR R172 and RGBWI-1, respectively.

Bancone G, Kalnoky M, Chu CS, Chowwiwat N, Kahn M, Malleret B, Wilaisrisak P, Rénia L, Domingo GJ, Nosten F. 2017. The G6PD flow-cytometric assay is a reliable tool for diagnosis of G6PD deficiency in women and anaemic subjects. Sci Rep, 7 (1), pp. 9822. | Show Abstract | Read more

Glucose-6-phosphate dehydrogenase (G6PD) activity is essential for redox equilibrium of red blood cells (RBCs) and, when compromised, the RBCs are more susceptible to haemolysis. 8-aminoquinolines (primaquine and tafenoquine) are used for the radical curative treatment of Plasmodium vivax malaria and can cause haemolysis in G6PD deficient subjects. Haemolytic risk is dependent on treatment dose and patient G6PD status but ultimately it correlates with the number of G6PD deficient RBCs. The G6PD spectrophotometric assay reliably identifies deficient subjects but is less reliable in heterozygous females, especially when other blood conditions are present. In this work we analysed samples with a range of G6PD phenotypes and haematologic conditions from 243 healthy volunteers of Asian or African-American heritage using both the spectrophotomeric assay and the G6PD flow-cytometric assay. Overall 18.5% of subjects (29.3% of Asian females) presented with anaemia, associated with decreased RBCs volume (MCV) and reticulocytosis; the flow-cytometric assay showed good correlation with the spectrophotometric assay (Pearson's r 0.918-0.957) and was less influenced by haemoglobin concentration, number of RBCs and number of reticulocytes. This resulted in more precise quantification of the number of G6PD deficient RBCs and presumably higher predictive power of drug induced haemolytic risk.

Douglas NM, Poespoprodjo JR, Patriani D, Malloy MJ, Kenangalem E, Sugiarto P, Simpson JA, Soenarto Y, Anstey NM, Price RN. 2017. Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study. PLoS Med, 14 (8), pp. e1002379. | Show Abstract | Read more

BACKGROUND: Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia. METHODS AND FINDINGS: Routinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%-34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%-30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%-50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4-24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15-2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%-38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%-32.3%) in those prescribed either a low (≥1.5 mg/kg and <5 mg/kg) or high (≥5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86-0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85-0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up. CONCLUSIONS: Unsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.

Nguyen VH, Dubot-Pérès A, Russell FM, Dance DAB, Vilivong K, Phommachan S, Syladeth C, Lai J, Lim R, Morpeth M et al. 2017. Acute respiratory infections in hospitalized children in Vientiane, Lao PDR - the importance of Respiratory Syncytial Virus. Sci Rep, 7 (1), pp. 9318. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

The Human respiratory syncytial virus (RSV) is one of the most important viral pathogens, causing epidemics of acute respiratory infection (ARI), especially bronchiolitis and pneumonia, in children worldwide. To investigate the RSV burden in Laos, we conducted a one-year study in children <5 years old admitted to Mahosot Hospital, Vientiane Capital, to describe clinical and epidemiological characteristics and predictive factors for severity of RSV-associated ARI. Pooled nasal and throat swabs were tested using multiplex real-time PCR for 33 respiratory pathogens (FTD® kit). A total of 383 patients were included, 277 (72.3%) of whom presented with pneumonia. 377 (98.4%) patients were positive for at least one microorganism, of which RSV was the most common virus (41.0%), with a peak observed between June and September, corresponding to the rainy season. Most RSV inpatients had pneumonia (84.1%), of whom 35% had severe pneumonia. Children <3-months old were a high-risk group for severe pneumonia, independently of RSV infection. Our study suggests that RSV infection is frequent in Laos and commonly associated with pneumonia in hospitalized young children. Further investigations are required to provide a better overall view of the Lao nationwide epidemiology and public health burden of RSV infection over time.

Abdi AI, Hodgson SH, Muthui MK, Kivisi CA, Kamuyu G, Kimani D, Hoffman SL, Juma E, Ogutu B, Draper SJ et al. 2017. Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure. BMC Infect Dis, 17 (1), pp. 585. | Show Abstract | Read more

BACKGROUND: The PfEMP1 family of Plasmodium falciparum antigens play a key role in pathogenesis of severe malaria through their insertion into the surface of parasite infected erythrocytes, and adhesion to host cells. Previous studies have suggested that parasites expressing PfEMP1 subclasses group A and DC8, associated with severe malaria, may have a growth advantage in immunologically naïve individuals. However, this idea has not been tested in longitudinal studies. METHODS: Here we assessed expression of the var genes encoding PfEMP1, in parasites sampled from volunteers with varying prior exposure to malaria, following experimental infection by sporozoites (PfSPZ). Using qPCR, we tested for associations between the expression of various var subgroups in surviving parasite populations from each volunteer and 1) the levels of participants' antibodies to infected erythrocytes before challenge infection and 2) the apparent in vivo parasite multiplication rate. RESULTS: We show that 1) expression of var genes encoding for group A and DC8-like PfEMP1 were associated with low levels of antibodies to infected erythrocytes (αIE) before challenge, and 2) expression of a DC8-like CIDRα1.1 domain was associated with higher apparent parasite multiplication rate in a manner that was independent of levels of prior antibodies to infected erythrocytes. CONCLUSIONS: This study provides insight into the role of antibodies to infected erythrocytes surface antigens in the development of naturally acquired immunity and may help explain why specific PfEMP1 variants may be associated with severe malaria. TRIAL REGISTRATION: Pan African Clinical Trial Registry: PACTR201211000433272 . Date of registration: 10th October 2012.

Sharma P, Bhuju A, Tuladhar R, Parry CM, Basnyat B. 2017. Tubo-ovarian abscess infected by Salmonella typhi. BMJ Case Rep, 2017 pp. bcr-2017-221213-bcr-2017-221213. | Show Abstract | Read more

We report a case of a tubo-ovarian abscess infected with Salmonella enterica serotype typhi A 19-year-old Nepalese woman presented to a hospital in Kathmandu with lower abdominal pain, constipation, fever and a non-healing, suppurative surgical wound from an emergency caesarian section performed 2 months previously at 37 weeks of pregnancy. She also had an exploratory laparotomy for an appendix perforation with peritonitis at 25 weeks of gestation. Her wound infection did not respond to cloxacillin and she had an exploratory laparotomy, and a tubo-ovarian abscess was found from which S. typhi was isolated. She had a bilateral salpingo-oophorectomy and responded to 14 days of chloramphenicol. A tubo-ovarian abscess is a rare complication of enteric fever.

Fanello C, Onyamboko M, Lee SJ, Woodrow C, Setaphan S, Chotivanich K, Buffet P, Jauréguiberry S, Rockett K, Stepniewska K et al. 2017. Post-treatment haemolysis in African children with hyperparasitaemic falciparum malaria; a randomized comparison of artesunate and quinine. BMC Infect Dis, 17 (1), pp. 575. | Show Abstract | Read more

BACKGROUND: Parenteral artesunate is the treatment of choice for severe malaria. Recently, haemolytic anaemia occurring 1 to 3 weeks after artesunate treatment of falciparum malaria has been reported in returning travellers in temperate countries. METHODS: To assess these potential safety concerns in African children, in whom most deaths from malaria occur, an open-labelled, randomized controlled trial was conducted in Kinshasa, Democratic Republic of Congo. 217 children aged between 6 months and 14 years with acute uncomplicated falciparum malaria and parasite densities over 100,000/μL were randomly allocated to intravenous artesunate or quinine, hospitalized for 3 days and then followed for 42 days. RESULTS: The immediate reduction in haemoglobin was less with artesunate than with quinine: median (IQR) fall at 72 h 1.4 g/dL (0.90-1.95) vs. 1.7 g/dL (1.10-2.40) (p = 0.009). This was explained by greater pitting then recirculation of once infected erythrocytes. Only 5% of patients (in both groups) had a ≥ 10% reduction in haemoglobin after day 7 (p = 0.1). One artesunate treated patient with suspected concomitant sepsis had a protracted clinical course and required a blood transfusion on day 14. CONCLUSIONS: Clinically significant delayed haemolysis following parenteral artesunate is uncommon in African children hospitalised with acute falciparum malaria and high parasitaemias. TRIAL REGISTRATION: ; Identifier: NCT02092766 (18/03/2014).

Githinji S, Oyando R, Malinga J, Ejersa W, Soti D, Rono J, Snow RW, Buff AM, Noor AM. 2017. Completeness of malaria indicator data reporting via the District Health Information Software 2 in Kenya, 2011-2015. Malar J, 16 (1), pp. 344. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Health facility-based data reported through routine health information systems form the primary data source for programmatic monitoring and evaluation in most developing countries. The adoption of District Health Information Software (DHIS2) has contributed to improved availability of routine health facility-based data in many low-income countries. An assessment of malaria indicators data reported by health facilities in Kenya during the first 5 years of implementation of DHIS2, from January 2011 to December 2015, was conducted. METHODS: Data on 19 malaria indicators reported monthly by health facilities were extracted from the online Kenya DHIS2 database. Completeness of reporting was analysed for each of the 19 malaria indicators and expressed as the percentage of data values actually reported over the expected number; all health facilities were expected to report data for each indicator for all 12 months in a year. RESULTS: Malaria indicators data were analysed for 6235 public and 3143 private health facilities. Between 2011 and 2015, completeness of reporting in the public sector increased significantly for confirmed malaria cases across all age categories (26.5-41.9%, p < 0.0001, in children aged <5 years; 30.6-51.4%, p < 0.0001, in persons aged ≥5 years). Completeness of reporting of new antenatal care (ANC) clients increased from 53.7 to 70.5%, p < 0.0001). Completeness of reporting of intermittent preventive treatment in pregnancy (IPTp) decreased from 64.8 to 53.7%, p < 0.0001 for dose 1 and from 64.6 to 53.4%, p < 0.0001 for dose 2. Data on malaria tests performed and test results were not available in DHIS2 from 2011 to 2014. In 2015, sparse data on microscopy (11.5% for children aged <5 years; 11.8% for persons aged ≥5 years) and malaria rapid diagnostic tests (RDTs) (8.1% for all ages) were reported. In the private sector, completeness of reporting increased significantly for confirmed malaria cases across all age categories (16.7-23.1%, p < 0.0001, in children aged <5 years; 19.4-28.6%, p < 0.0001, in persons aged ≥5 years). Completeness of reporting also improved for new ANC clients (16.2-23.6%, p < 0.0001), and for IPTp doses 1 and 2 (16.6-20.2%, p < 0.0001 and 15.5-20.5%, p < 0.0001, respectively). In 2015, less than 3% of data values for malaria tests performed were reported in DHIS2 from the private sector. CONCLUSIONS: There have been sustained improvements in the completeness of data reported for most key malaria indicators since the adoption of DHIS2 in Kenya in 2011. However, major data gaps were identified for the malaria-test indicator and overall low reporting across all indicators from private health facilities. A package of proven DHIS2 implementation interventions and performance-based incentives should be considered to improve private-sector data reporting.

Chaguza C, Cornick JE, Andam CP, Gladstone RA, Alaerts M, Musicha P, Peno C, Bar-Zeev N, Kamng'ona AW, Kiran AM et al. 2017. Population genetic structure, antibiotic resistance, capsule switching and evolution of invasive pneumococci before conjugate vaccination in Malawi. Vaccine, 35 (35 Pt B), pp. 4594-4602. | Show Abstract | Read more

INTRODUCTION: Pneumococcal infections cause a high death toll in Sub Saharan Africa (SSA) but the recently rolled out pneumococcal conjugate vaccines (PCV) will reduce the disease burden. To better understand the population impact of these vaccines, comprehensive analysis of large collections of pneumococcal isolates sampled prior to vaccination is required. Here we present a population genomic study of the invasive pneumococcal isolates sampled before the implementation of PCV13 in Malawi. MATERIALS AND METHODS: We retrospectively sampled and whole genome sequenced 585 invasive isolates from 2004 to 2010. We determine the pneumococcal population genetic structure and assessed serotype prevalence, antibiotic resistance rates, and the occurrence of serotype switching. RESULTS: Population structure analysis revealed 22 genetically distinct sequence clusters (SCs), which consisted of closely related isolates. Serotype 1 (ST217), a vaccine-associated serotype in clade SC2, showed highest prevalence (19.3%), and was associated with the highest MDR rate (81.9%) followed by serotype 12F, a non-vaccine serotype in clade SC10 with an MDR rate of 57.9%. Prevalence of serotypes was stable prior to vaccination although there was an increase in the PMEN19 clone, serotype 5 ST289, in clade SC1 in 2010 suggesting a potential undetected local outbreak. Coalescent analysis revealed recent emergence of the SCs and there was evidence of natural capsule switching in the absence of vaccine induced selection pressure. Furthermore, majority of the highly prevalent capsule-switched isolates were associated with acquisition of vaccine-targeted capsules. CONCLUSIONS: This study provides descriptions of capsule-switched serotypes and serotypes with potential to cause serotype replacement post-vaccination such as 12F. Continued surveillance is critical to monitor these serotypes and antibiotic resistance in order to design better infection prevention and control measures such as inclusion of emerging replacement serotypes in future conjugate vaccines.

Ojal J, Hammitt LL, Gaitho J, Scott JAG, Goldblatt D. 2017. Pneumococcal conjugate vaccine induced IgG and nasopharyngeal carriage of pneumococci: Hyporesponsiveness and immune correlates of protection for carriage Vaccine, 35 (35), pp. 4652-4657. | Citations: 1 (Scopus) | Show Abstract | Read more

© 2017 The Author(s) Background Prior studies have demonstrated hyporesponsiveness to pneumococcal conjugate vaccines (PCVs) when administered in the presence of homologous carriage. This may be substantially more important in Africa where carriage prevalence is high. Deriving a correlate of protection (CoP) for carriage is important in guiding the future use of extended PCVs as population control of pneumococcal disease by vaccination is now focused principally on its indirect effect. We therefore explored the complex relationship between existing carriage and vaccine responsiveness, and between serum IgG levels and risk of acquisition. Methods We undertook secondary analyses of data from two previously published clinical trials of the safety and immunogenicity of PCV in Kenya. We compared responses to vaccination between serotype-specific carriers and non-carriers at vaccination. We assessed the risk of carriage acquisition in relation to PCV-induced serum IgG levels using either a step- or continuous-risk function. Results For newborns, the immune response among carriers was 51–82% lower than that among non-carriers, depending on serotype. Among toddlers, for serotypes 6B, 14 and 19F the post-vaccination response among carriers was lower by between 29 and 70%. The estimated CoP against acquisition ranged from 0.26 to 1.93 μg/mL across serotypes, however, these thresholds could not be distinguished statistically from a model with constant probability of carriage independent of assay value. Conclusion We have confirmed hyporesponsiveness in an equatorial African setting in both infants and toddlers. Population responses to vaccination are likely to improve with time as carriage prevalence of vaccine serotypes is reduced. We have not found clear correlates of protection against carriage acquisition am ong toddlers in this population. Assessing the potential of new vaccines through the use of CoP against carriage is still difficult as there are no clear-cut serotype specific correlates.

Ojal J, Flasche S, Hammitt LL, Akech D, Kiti MC, Kamau T, Adetifa I, Nurhonen M, Scott JAG, Auranen K. 2017. Sustained reduction in vaccine-type invasive pneumococcal disease despite waning effects of a catch-up campaign in Kilifi, Kenya: A mathematical model based on pre-vaccination data Vaccine, 35 (35), pp. 4561-4568. | Citations: 1 (Scopus) | Show Abstract | Read more

© 2017 The Author(s) Background In 2011, Kenya introduced the 10-valent pneumococcal conjugate vaccine together with a catch-up campaign for children aged < 5 years in Kilifi County. In a post-vaccination surveillance study based in Kilifi, there was a substantial decline in invasive pneumococcal disease (IPD). However, given the continued circulation of the vaccine serotypes it is possible that vaccine-serotype disease may re-emerge once the effects of the catch-up campaign wear off. Methods We developed a compartmental, age-structured dynamic model of pneumococcal carriage and invasive disease for three serotype groups: the 10-valent vaccine serotypes and two groups of non-vaccine serotypes based on their susceptibility to mutual competition. The model was calibrated to age- and serotype-specific data on carriage and IPD in the pre-vaccination era and used to predict carriage prevalence and IPD up to ten years post-vaccination in Kilifi. The model was validated against the observed carriage prevalence after vaccine introduction. Results The model predicts a sustained reduction in vaccine-type pneumococcal carriage prevalence from 33% to 8% in infants and from 30% to 8% in 1–5 year olds over the 10-year period following vaccine introduction. The incidence of IPD is predicted to decline across all age groups resulting in an overall reduction of 56% in the population, corresponding to 10.4 cases per 100,000 per year. The vaccine-type IPD incidence is estimated to decline by 83% while non-vaccine-type IPD incidence is predicted to increase by 52%. The model's predictions of carriage prevalence agrees well with the observed data in the first five years post-vaccination. Conclusion We predict a sustained and substantial decline in IPD through PCV vaccination and that the current regimen is insufficient to fully eliminate vaccine-serotype circulation in the model. We show that the observed impact is likely to be sustained despite waning effects of the catch-up campaign.

Rutledge GG, Marr I, Huang GKL, Auburn S, Marfurt J, Sanders M, White NJ, Berriman M, Newbold CI, Anstey NM et al. 2017. Genomic Characterization of Recrudescent Plasmodium malariae after Treatment with Artemether/Lumefantrine. Emerg Infect Dis, 23 (8), pp. 1300-1307. | Show Abstract | Read more

Plasmodium malariae is the only human malaria parasite species with a 72-hour intraerythrocytic cycle and the ability to persist in the host for life. We present a case of a P. malariae infection with clinical recrudescence after directly observed administration of artemether/lumefantrine. By using whole-genome sequencing, we show that the initial infection was polyclonal and the recrudescent isolate was a single clone present at low density in the initial infection. Haplotypic analysis of the clones in the initial infection revealed that they were all closely related and were presumably recombinant progeny originating from the same infective mosquito bite. We review possible explanations for the P. malariae treatment failure and conclude that a 3-day artemether/lumefantrine regimen is suboptimal for this species because of its long asexual life cycle.

Alam MS, Ley B, Nima MK, Johora FT, Hossain ME, Thriemer K, Auburn S, Marfurt J, Price RN, Khan WA. 2017. Molecular analysis demonstrates high prevalence of chloroquine resistance but no evidence of artemisinin resistance in Plasmodium falciparum in the Chittagong Hill Tracts of Bangladesh. Malar J, 16 (1), pp. 335. | Show Abstract | Read more

BACKGROUND: Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. METHODS: Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. RESULTS: In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. CONCLUSION: This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance.

Jeong C, Peter BM, Basnyat B, Neupane M, Beall CM, Childs G, Craig SR, Novembre J, Di Rienzo A. 2017. Correction: A longitudinal cline characterizes the genetic structure of human populations in the Tibetan plateau. PLoS One, 12 (8), pp. e0183407. | Show Abstract | Read more

[This corrects the article DOI: 10.1371/journal.pone.0175885.].

Ley B, Thriemer K, Jaswal J, Poirot E, Alam MS, Phru CS, Khan WA, Dysoley L, Qi G, Kheong CC et al. 2017. Barriers to routine G6PD testing prior to treatment with primaquine. Malar J, 16 (1), pp. 329. | Show Abstract | Read more

BACKGROUND: Primaquine is essential for the radical cure of vivax malaria, however its broad application is hindered by the risk of drug-induced haemolysis in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency. Rapid diagnostic tests capable of diagnosing G6PD deficiency are now available, but these are not used widely. METHODS: A series of qualitative interviews were conducted with policy makers and healthcare providers in four vivax-endemic countries. Routine G6PD testing is not part of current policy in Bangladesh, Cambodia or China, but it is in Malaysia. The interviews were analysed with regard to respondents perceptions of vivax malaria, -primaquine based treatment for malaria and the complexities of G6PD deficiency. RESULTS: Three barriers to the roll-out of routine G6PD testing were identified in all sites: (a) a perceived low risk of drug-induced haemolysis; (b) the perception that vivax malaria was benign and accordingly treatment with primaquine was not regarded as a priority; and, (c) the additional costs of introducing routine testing. In Malaysia, respondents considered the current test and treat algorithm suitable and the need for an alternative approach was only considered relevant in highly mobile and hard to reach populations. CONCLUSIONS: Greater efforts are needed to increase awareness of the benefits of the radical cure of Plasmodium vivax and this should be supported by economic analyses exploring the cost effectiveness of routine G6PD testing.

Nhung NT, Chansiripornchai N, Carrique-Mas JJ. 2017. Antimicrobial Resistance in Bacterial Poultry Pathogens: A Review. Front Vet Sci, 4 (AUG), pp. 126. | Citations: 1 (Scopus) | Show Abstract | Read more

Antimicrobial resistance (AMR) is a global health threat, and antimicrobial usage and AMR in animal production is one of its contributing sources. Poultry is one of the most widespread types of meat consumed worldwide. Poultry flocks are often raised under intensive conditions using large amounts of antimicrobials to prevent and to treat disease, as well as for growth promotion. Antimicrobial resistant poultry pathogens may result in treatment failure, leading to economic losses, but also be a source of resistant bacteria/genes (including zoonotic bacteria) that may represent a risk to human health. Here we reviewed data on AMR in 12 poultry pathogens, including avian pathogenic Escherichia coli (APEC), Salmonella Pullorum/Gallinarum, Pasteurella multocida, Avibacterium paragallinarum, Gallibacterium anatis, Ornitobacterium rhinotracheale (ORT), Bordetella avium, Clostridium perfringens, Mycoplasma spp., Erysipelothrix rhusiopathiae, and Riemerella anatipestifer. A number of studies have demonstrated increases in resistance over time for S. Pullorum/Gallinarum, M. gallisepticum, and G. anatis. Among Enterobacteriaceae, APEC isolates displayed considerably higher levels of AMR compared with S. Pullorum/Gallinarum, with prevalence of resistance over >80% for ampicillin, amoxicillin, tetracycline across studies. Among the Gram-negative, non-Enterobacteriaceae pathogens, ORT had the highest levels of phenotypic resistance with median levels of AMR against co-trimoxazole, enrofloxacin, gentamicin, amoxicillin, and ceftiofur all exceeding 50%. In contrast, levels of resistance among P. multocida isolates were less than 20% for all antimicrobials. The study highlights considerable disparities in methodologies, as well as in criteria for phenotypic antimicrobial susceptibility testing and result interpretation. It is necessary to increase efforts to harmonize testing practices, and to promote free access to data on AMR in order to improve treatment guidelines as well as to monitor the evolution of AMR in poultry bacterial pathogens.

Devine A, Harvey R, Min AM, Gilder MET, Paw MK, Kang J, Watts I, Hanboonkunupakarn B, Nosten F, McGready R. 2017. Strategies for the prevention of perinatal hepatitis B transmission in a marginalized population on the Thailand-Myanmar border: a cost-effectiveness analysis. BMC Infect Dis, 17 (1), pp. 552. | Show Abstract | Read more

BACKGROUND: Data on the cost effectiveness of hepatitis B virus (HBV) screening and vaccination strategies for prevention of vertical transmission of HBV in resource limited settings is sparse. METHODS: A decision tree model of HBV prevention strategies utilised data from a cohort of 7071 pregnant women on the Thailand-Myanmar border using a provider perspective. All options included universal HBV vaccination for newborns in three strategies: (1) universal vaccination alone; (2) universal vaccination with screening of women during antenatal visits with rapid diagnostic test (RDT) plus HBV immune globulin (HBIG) administration to newborns of HBV surface antigen positive women; and (3) universal vaccination with screening of women during antenatal visits plus HBIG administration to newborns of women testing HBV e antigen positive by confirmatory test. At the time of the study, the HBIG after confirmatory test strategy was used. The costs in United States Dollars (US$), infections averted and incremental cost effectiveness ratios (ICERs) were calculated and sensitivity analyses were conducted. A willingness to pay threshold of US$1200 was used. RESULTS: The universal HBV vaccination was the least costly option at US$4.33 per woman attending the clinic. The HBIG after (RDT) strategy had an ICER of US$716.78 per infection averted. The HBIG after confirmatory test strategy was not cost-effective due to extended dominance. The one-way sensitivity analysis showed that while the transmission parameters and cost of HBIG had the biggest impact on outcomes, the HBIG after confirmatory test only became a cost-effective option when a low test cost was used or a high HBIG cost was used. The probabilistic sensitivity analysis showed that HBIG after RDT had an 87% likelihood of being cost-effective as compared to vaccination only at a willingness to pay threshold of US$1200. CONCLUSIONS: HBIG following confirmatory test is not a cost-effective strategy for preventing vertical transmission of HBV in the Thailand-Myanmar border population. By switching to HBIG following rapid diagnostic test, perinatal infections will be reduced by nearly one third. This strategy may be applicable to similar settings for marginalized populations where the confirmatory test is not logistically possible.

Shabani SH, Zakeri S, Salmanian AH, Amani J, Mehrizi AA, Snounou G, Nosten F, Andolina C, Mourtazavi Y, Djadid ND. 2017. Biological, immunological and functional properties of two novel multi-variant chimeric recombinant proteins of CSP antigens for vaccine development against Plasmodium vivax infection. Mol Immunol, 90 pp. 158-171. | Show Abstract | Read more

The circumsporozoite protein (CSP) of the malaria parasite Plasmodium vivax is a major pre-erythrocyte vaccine candidate. The protein has a central repeat region that belongs to one of repeat families (VK210, VK247, and the P. vivax-like). In the present study, computer modelling was employed to select chimeric proteins, comprising the conserved regions and different arrangements of the repeat elements (VK210 and VK247), whose structure is similar to that of the native counterparts. DNA encoding the selected chimeras (named CS127 and CS712) were synthetically constructed based on E. coli codons, then cloned and expressed. Mouse monoclonal antibodies (mAbs; anti-Pv-210-CDC and -Pv-247-CDC), recognized the chimeric antigens in ELISA, indicating correct conformation and accessibility of the B-cell epitopes. ELISA using IgG from plasma samples collected from 221 Iranian patients with acute P. vivax showed that only 49.32% of the samples reacted to both CS127 and CS712 proteins. The dominant subclass for the two chimeras was IgG1 (48% of the positive responders, OD492=0.777±0.420 for CS127; 48.41% of the positive responders, OD492=0.862±0.423 for CS712, with no statistically significant difference P>0.05; Wilcoxon signed ranks test). Binding assays showed that both chimeric proteins bound to immobilized heparan sulphate and HepG2 hepatocyte cells in a concentration-dependent manner, saturable at 80μg/mL. Additionally, anti-CS127 and -CS712 antibodies raised in mice recognized the native protein on the surface of P. vivax sporozoite with high intensity, confirming the presence of common epitopes between the recombinant forms and the native proteins. In summary, despite structural differences at the molecular level, the expression levels of both chimeras were satisfactory, and their conformational structure retained biological function, thus supporting their potential for use in the development of vivax-based vaccine.

Warrell DA. 2017. Snakebites: reducing their international impact. Med J Aust, 207 (3), pp. 112-113. | Read more

Obiero CW, Seale AC, Jones K, Ngari M, Bendon CL, Morpeth S, Mohammed S, Mturi N, Fegan G, Berkley JA. 2017. Should first-line empiric treatment strategies cover coagulase-negative staphylococcal infections in severely malnourished or HIV-infected children in Kenya? PLoS One, 12 (8), pp. e0182354. | Show Abstract | Read more

BACKGROUND: Bloodstream infection is a common cause of morbidity in children aged <5 years in developing countries. In studies reporting bacteremia in Africa, coagulase-negative Staphylococci (CoNS) are commonly isolated. However, it is currently unclear whether children who are highly susceptible to infection because of severe acute malnutrition (SAM) or HIV should be treated with antimicrobials specifically to cover CoNS. We aimed to determine the clinical significance of CoNS amongst children admitted to a rural hospital in Kenya in relation to nutritional and HIV status. METHODS: Systematically collected clinical and microbiological surveillance data from children aged 6-59 months admitted to Kilifi County Hospital (2007-2013) were analysed. Multivariable regression was used to test associations between CoNS isolation from blood cultures and SAM (MUAC <11.5cm or nutritional oedema (kwashiorkor)), and HIV serostatus; and among children with SAM or HIV, associations between CoNS isolation and mortality, duration of hospitalization and clinical features. RESULTS: CoNS were isolated from blood culture in 906/13,315 (6.8%) children, of whom 135/906 (14.9%) had SAM and 54/906 (6.0%) were HIV antibody positive. CoNS isolation was not associated with SAM (MUAC<11.5cm (aOR 1.11, 95% CI 0.88-1.40) or kwashiorkor (aOR 0.84, 95% CI 0.48-1.49)), or a positive HIV antibody test (aOR 1.25, 95% CI 0.92-1.71). Among children with SAM or a positive HIV antibody test, CoNS isolation was not associated with mortality or prolonged hospitalization. CONCLUSION: In a large, systematic study, there was no evidence that antimicrobial therapy should specifically target CoNS amongst children with SAM or HIV-infection or exposure.

Hoa LNM, Tuan NA, My PH, Huong TTK, Chi NTY, Hau Thu TT, Carrique-Mas J, Duong MT, Tho ND, Hoang ND et al. 2017. Assessing evidence for avian-to-human transmission of influenza A/H9N2 virus in rural farming communities in northern Vietnam. J Gen Virol, 98 (8), pp. 2011-2016. | Show Abstract | Read more

Rural farming communities in northern Vietnam do not routinely practice vaccination for influenza A viruses (IAV) for either humans or poultry, which enables us to study transmission intensity via seroepidemiology. Using samples from a longitudinal cohort of farming households, we determined the number of symptomatic and asymptomatic human infections for seasonal IAV and avian A/H9 over 2 years. As expected, we detected virologically confirmed acute cases of seasonal IAV in humans, as well as large numbers of subclinical seroconversions to A/H1pdm [55/265 (21 %)], A/H3 [95/265 (36 %)] and A/H9 [24/265 (9 %)]. Five of the A/H9 human seroconverters likely represented true infections rather than heterosubtypic immunity, because the individuals seroconverted solely to A/H9. Among co-located poultry, we found significantly higher seroprevalance for A/H5 compared to A/H9 in both chickens and ducks [for northern study sites overall, 337/1105 (30.5 %) seropositive for A/H5 and 123/1105 (11.1 %) seropositive for A/H9].

Nackers F, Cohuet S, le Polain de Waroux O, Langendorf C, Nyehangane D, Ndazima D, Nanjebe D, Karani A, Tumwesigye E, Mwanga-Amumpaire J et al. 2017. Carriage prevalence and serotype distribution of Streptococcus pneumoniae prior to 10-valent pneumococcal vaccine introduction: A population-based cross-sectional study in South Western Uganda, 2014 Vaccine, 35 (39), pp. 5271-5277. | Show Abstract | Read more

© 2017 The Authors Background Information on Streptococcus pneumoniae nasopharyngeal (NP) carriage before the pneumococcal conjugate vaccine (PCV) introduction is essential to monitor impact. The 10-valent PCV (PCV10) was officially introduced throughout Ugandan national childhood immunization programs in 2013 and rolled-out countrywide during 2014. We aimed to measure the age-specific Streptococcus pneumoniae carriage and serotype distribution across all population age groups in the pre-PCV10 era in South Western Uganda. Methods We conducted a two-stage cluster, age-stratified, cross-sectional community-based study in Sheema North sub-district between January and March 2014. One NP swab was collected and analyzed for each participant in accordance with World Health Organization guidelines. Results NP carriage of any pneumococcal serotype was higher among children < 2 years old (77%; n = 387) than among participants aged ≥15 years (8.5%; n = 325) (chi 2 p < 0.001). Of the 623 positive cultures, we identified 49 serotypes among 610 (97.9%) isolates; thirteen (2.1%) isolates were non-typeable. Among < 2 years old, serotypes 6A, 6B, 14, 15B, 19F and 23F accounted for half of all carriers. Carriage prevalence with PCV10 serotypes was 29.4% among individuals aged < 2 years (n = 387), 23.4% in children aged 2–4 years (n = 217), 11.4% in 5–14 years (n = 417), and 0.4% among individuals ≥15 years of age (n = 325). The proportion of carried pneumococci serotypes contained in PCV10 was 38.1% (n = 291), 32.8% (n = 154), 29.4% (n = 156), and 4.4% (n = 22) among carriers aged < 2 years, 2–4 years, 5–14 years and ≥15 years, respectively. Discussion In Sheema district, the proportion of PCV10 serotypes was low ( < 40%), across all age groups, especially among individuals aged 15 years or older ( < 5%). PCV10 introduction is likely to impact transmission among children and to older individuals, but less likely to substantially modify pneumococcal NP ecology among individuals aged 15 years or older.

Mramba L, Ngari M, Mwangome M, Muchai L, Bauni E, Walker AS, Gibb DM, Fegan G, Berkley JA. 2017. A growth reference for mid upper arm circumference for age among school age children and adolescents, and validation for mortality: growth curve construction and longitudinal cohort study. BMJ, 358 pp. j3423. | Show Abstract | Read more

Objectives To construct growth curves for mid-upper-arm circumference (MUAC)-for-age z score for 5-19 year olds that accord with the World Health Organization growth standards, and to evaluate their discriminatory performance for subsequent mortality.Design Growth curve construction and longitudinal cohort study.Setting United States and international growth data, and cohorts in Kenya, Uganda, and Zimbabwe.Participants The Health Examination Survey (HES)/National Health and Nutrition Examination Survey (NHANES) US population datasets (age 5-25 years), which were used to construct the 2007 WHO growth reference for body mass index in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 growth standards age 2-6 years. Validation data were from 685 HIV infected children aged 5-17 years participating in the Antiretroviral Research for Watoto (ARROW) trial in Uganda and Zimbabwe; and 1741 children aged 5-13 years discharged from a rural Kenyan hospital (3.8% HIV infected). Both cohorts were followed-up for survival during one year.Main outcome measures Concordance with WHO 2006 growth standards at age 60 months and survival during one year according to MUAC-for-age and body mass index-for-age z scores.Results The new growth curves transitioned smoothly with WHO growth standards at age 5 years. MUAC-for-age z scores of -2 to -3 and less than-3, compared with -2 or more, was associated with hazard ratios for death within one year of 3.63 (95% confidence interval 0.90 to 14.7; P=0.07) and 11.1 (3.40 to 36.0; P<0.001), respectively, among ARROW trial participants; and 2.22 (1.01 to 4.9; P=0.04) and 5.15 (2.49 to 10.7; P<0.001), respectively, among Kenyan children after discharge from hospital. The AUCs for MUAC-for-age and body mass index-for-age z scores for discriminating subsequent mortality were 0.81 (95% confidence interval 0.70 to 0.92) and 0.75 (0.63 to 0.86) in the ARROW trial (absolute difference 0.06, 95% confidence interval -0.032 to 0.16; P=0.2) and 0.73 (0.65 to 0.80) and 0.58 (0.49 to 0.67), respectively, in Kenya (absolute difference in AUC 0.15, 0.07 to 0.23; P=0.0002).Conclusions The MUAC-for-age z score is at least as effective as the body mass index-for-age z score for assessing mortality risks associated with undernutrition among African school aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.

Pol S, Fox-Lewis S, Cheah PY, Turner C. 2017. "Know your audience": A hospital community engagement programme in a non-profit paediatric hospital in Cambodia. PLoS One, 12 (8), pp. e0182573. | Show Abstract | Read more

OBJECTIVE: The purpose of this evaluation is to explore the impact of the new hospital community engagement programme (comprised of a Young Persons Advisory Group and a Science Café) on community members and other stakeholders, with regard to their attitudes, skills and degree of engagement in a paediatric hospital in Cambodia. DESIGN: Data collection included feedback questionnaires and reflections produced after each YPAG and Science Café event. Further questionnaires and reflective interviews were conducted to gather the views of key stakeholders. Data were analysed by thematic content analysis and numerical data were expressed using descriptive statistics. RESULTS: The vast majority of participants expressed their enjoyment and satisfaction of the hospital community engagement programme. Delivering the programme in the right manner for the target audiences, by prioritising their needs was key to this. Participants valued the programmes in terms of the knowledge delivered around good health practices, the skills developed such as confidence and responsibility for their health, and the provision of opportunities to voice their opinions. All stakeholders recognised the importance of the programme in improving the quality of the healthcare service provided at the hospital. CONCLUSIONS: In order to have a successful hospital community engagement programme, understanding the target audience is essential. The engagement programme must be delivered in the right way to meet the needs of community members, including right communication, right setting, right people and right timing. This will ultimately result in a meaningful programme that is able to empower community members, potentially resulting in lasting change in healthcare practices. In conclusion, the gap between hospitals and the community could narrow, allowing everyone to interact and learn from each other.

Barasa EW, Manyara AM, Molyneux S, Tsofa B. 2017. Recentralization within decentralization: County hospital autonomy under devolution in Kenya. PLoS One, 12 (8), pp. e0182440. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In 2013, Kenya transitioned into a devolved system of government with a central government and 47 semi-autonomous county governments. In this paper, we report early experiences of devolution in the Kenyan health sector, with a focus on public county hospitals. Specifically, we examine changes in hospital autonomy as a result of devolution, and how these have affected hospital functioning. METHODS: We used a qualitative case study approach to examine the level of autonomy that hospitals had over key management functions and how this had affected hospital functioning in three county hospitals in coastal Kenya. We collected data by in-depth interviews of county health managers and hospital managers in the case study hospitals (n = 21). We adopted the framework proposed by Chawla et al (1995) to examine the autonomy that hospitals had over five management domains (strategic management, finance, procurement, human resource, and administration), and how these influenced hospital functioning. FINDINGS: Devolution had resulted in a substantial reduction in the autonomy of county hospitals over the five key functions examined. This resulted in weakened hospital management and leadership, reduced community participation in hospital affairs, compromised quality of services, reduced motivation among hospital staff, non-alignment of county and hospital priorities, staff insubordination, and compromised quality of care. CONCLUSION: Increasing the autonomy of county hospitals in Kenya will improve their functioning. County governments should develop legislation that give hospitals greater control over resources and key management functions.

Arabi YM, Al-Omari A, Mandourah Y, Al-Hameed F, Sindi AA, Alraddadi B, Shalhoub S, Almotairi A, Al Khatib K, Abdulmomen A et al. 2017. Critically Ill Patients With the Middle East Respiratory Syndrome: A Multicenter Retrospective Cohort Study. Crit Care Med, | Show Abstract | Read more

OBJECTIVES: To describe patient characteristics, clinical manifestations, disease course including viral replication patterns, and outcomes of critically ill patients with severe acute respiratory infection from the Middle East respiratory syndrome and to compare these features with patients with severe acute respiratory infection due to other etiologies. DESIGN: Retrospective cohort study. SETTING: Patients admitted to ICUs in 14 Saudi Arabian hospitals. PATIENTS: Critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection (n = 330) admitted between September 2012 and October 2015 were compared to consecutive critically ill patients with community-acquired severe acute respiratory infection of non-Middle East respiratory syndrome etiology (non-Middle East respiratory syndrome severe acute respiratory infection) (n = 222). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Although Middle East respiratory syndrome severe acute respiratory infection patients were younger than those with non-Middle East respiratory syndrome severe acute respiratory infection (median [quartile 1, quartile 3] 58 yr [44, 69] vs 70 [52, 78]; p < 0.001), clinical presentations and comorbidities overlapped substantially. Patients with Middle East respiratory syndrome severe acute respiratory infection had more severe hypoxemic respiratory failure (PaO2/FIO2: 106 [66, 160] vs 176 [104, 252]; p < 0.001) and more frequent nonrespiratory organ failure (nonrespiratory Sequential Organ Failure Assessment score: 6 [4, 9] vs 5 [3, 7]; p = 0.002), thus required more frequently invasive mechanical ventilation (85.2% vs 73.0%; p < 0.001), oxygen rescue therapies (extracorporeal membrane oxygenation 5.8% vs 0.9%; p = 0.003), vasopressor support (79.4% vs 55.0%; p < 0.001), and renal replacement therapy (48.8% vs 22.1%; p < 0.001). After adjustment for potential confounding factors, Middle East respiratory syndrome was independently associated with death compared to non-Middle East respiratory syndrome severe acute respiratory infection (adjusted odds ratio, 5.87; 95% CI, 4.02-8.56; p < 0.001). CONCLUSIONS: Substantial overlap exists in the clinical presentation and comorbidities among patients with Middle East respiratory syndrome severe acute respiratory infection from other etiologies; therefore, a high index of suspicion combined with diagnostic testing is essential component of severe acute respiratory infection investigation for at-risk patients. The lack of distinguishing clinical features, the need to rely on real-time reverse transcription polymerase chain reaction from respiratory samples, variability in viral shedding duration, lack of effective therapy, and high mortality represent substantial clinical challenges and help guide ongoing clinical research efforts.

The HC, Florez de Sessions P, Jie S, Pham Thanh D, Thompson CN, Nguyen Ngoc Minh C, Chu CW, Tran T-A, Thomson NR, Thwaites GE et al. 2017. Assessing gut microbiota perturbations during the early phase of infectious diarrhea in Vietnamese children. Gut Microbes, pp. 1-17. | Show Abstract | Read more

Diarrheal diseases remain the second most common cause of mortality in young children in developing countries. Efforts have been made to explore the impact of diarrhea on bacterial communities in the human gut, but a thorough understanding has been impeded by inadequate resolution in bacterial identification and the examination of only few etiological agents. Here, by profiling an extended region of the 16S rRNA gene in the fecal microbiome, we aimed to elucidate the nature of gut microbiome perturbations during the early phase of infectious diarrhea caused by various etiological agents in Vietnamese children. Fecal samples from 145 diarrheal cases with a confirmed infectious etiology before antimicrobial therapy and 54 control subjects were analyzed. We found that the diarrheal fecal microbiota could be robustly categorized into 4 microbial configurations that either generally resembled or were highly divergent from a healthy state. Factors such as age, nutritional status, breastfeeding, and the etiology of the infection were significantly associated with these microbial community structures. We observed a consistent elevation of Fusobacterium mortiferum, Escherichia, and oral microorganisms in all diarrheal fecal microbiome configurations, proposing similar mechanistic interactions, even in the absence of global dysbiosis. We additionally found that Bifidobacterium pseudocatenulatum was significantly depleted during dysenteric diarrhea regardless of the etiological agent, suggesting that further investigations into the use of this species as a dysentery-orientated probiotic therapy are warranted. Our findings contribute to the understanding of the complex influence of infectious diarrhea on gut microbiome and identify new opportunities for therapeutic interventions.

Mugyenyi CK, Elliott SR, Yap XZ, Feng G, Boeuf P, Fegan G, Osier FFH, Fowkes FJI, Avril M, Williams TN et al. 2017. Declining Malaria Transmission Differentially Impacts the Maintenance of Humoral Immunity to Plasmodium falciparum in Children. J Infect Dis, 216 (7), pp. 887-898. | Show Abstract | Read more

Background: We investigated the poorly understood impact of declining malaria transmission on maintenance of antibodies to Plasmodium falciparum merozoite antigens and infected erythrocytes (IEs), including functional immunity. Methods: In a 3-year longitudinal cohort of 300 Kenyan children, antibodies to different AMA1 and MSP2 alleles of merozoites, IE surface antigens, and antibody functional activities were quantified. Results: Over a period in which malaria transmission declined markedly, AMA1 and MSP2 antibodies decreased substantially; estimated half-lives of antibody duration were 0.8 year and 1-3 years, respectively. However, 69%-74% of children maintained their seropositivity to AMA1 alleles and 42%-52% to MSP2 alleles. Levels and prevalence of antimerozoite antibodies were consistently associated with increasing age and concurrent parasitemia. Antibodies promoting opsonic phagocytosis of merozoites declined rapidly (half-life, 0.15 years). In contrast, complement-fixing antibodies to merozoites did not decline and antibodies to IE surface antigens expressing virulent phenotypes were much better maintained (half-life, 4-10 years). Conclusions: A decline in malaria transmission is associated with reduction in naturally acquired immunity. However, loss of immunity is not universal; some key functional responses and antibodies to IEs were better maintained and these may continue to provide some protection. Findings have implications for malaria surveillance and control measures and informing vaccine development.

Commons RJ, Thriemer K, Humphreys G, Suay I, Sibley CH, Guerin PJ, Price RN. 2017. The Vivax Surveyor: Online mapping database for Plasmodium vivax clinical trials. Int J Parasitol Drugs Drug Resist, 7 (2), pp. 181-190. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Recurrent P. vivax infections are associated with significant morbidity and mortality. Although radical cure can reduce recurrent infection, it is confounded by antimalarial resistance and the lack of safe and effective hypnozoitocidal treatment. This study documents the available literature of published clinical trials of P. vivax, providing an up to date, online, open access tool to view and download available information. METHODS: A systematic review was conducted according to PRISMA guidelines to identify prospective P. vivax therapeutic clinical trials with at least 28 days follow-up published between 1st January 1960 and 12th October 2016. Treatment arms and evidence of chloroquine resistance were mapped to trial sites. RESULTS: Since 1960, a total of 1152 antimalarial clinical trials with a minimum 28 days follow-up have been published, of which 230 (20.0%) enrolled patients with P. vivax and were included. Trials were conducted in 38 countries: 168 (73.0%) in the Asia-Pacific, 13 (5.7%) in Africa and 43 (18.7%) in the Americas. The proportion of antimalarial trials assessing P. vivax rose from 10.7% (12/112) in 1991-1995, to 24.9% (56/225) in 2011-2015. Overall, 188 (81.7%) P. vivax trials included a chloroquine treatment arm, either alone or in combination with primaquine, and 107 (46.5%) trials included a chloroquine treatment arm with early primaquine to assess radical cure. There has been a recent increase in treatment arms with artemisinin derivatives. Of the 131 sites in which chloroquine resistance could be quantified, resistance was present in 59 (45.0%) sites in 15 endemic countries. CONCLUSIONS: Over the last 20 years there has been a substantial increase in clinical research on the treatment of P. vivax, which has generated a greater awareness of the global extent of chloroquine resistance. The WWARN open access, online interactive map provides up to date information of areas where drug resistant P. vivax is emerging.

Atwal S, Giengkam S, Chaemchuen S, Dorling J, Kosaisawe N, VanNieuwenhze M, Sampattavanich S, Schumann P, Salje J. 2017. Evidence for a peptidoglycan-like structure in Orientia tsutsugamushi. Mol Microbiol, 105 (3), pp. 440-452. | Citations: 3 (Scopus) | Show Abstract | Read more

Bacterial cell walls are composed of the large cross-linked macromolecule peptidoglycan, which maintains cell shape and is responsible for resisting osmotic stresses. This is a highly conserved structure and the target of numerous antibiotics. Obligate intracellular bacteria are an unusual group of organisms that have evolved to replicate exclusively within the cytoplasm or vacuole of a eukaryotic cell. They tend to have reduced amounts of peptidoglycan, likely due to the fact that their growth and division takes place within an osmotically protected environment, and also due to a drive to reduce activation of the host immune response. Of the two major groups of obligate intracellular bacteria, the cell wall has been much more extensively studied in the Chlamydiales than the Rickettsiales. Here, we present the first detailed analysis of the cell envelope of an important but neglected member of the Rickettsiales, Orientia tsutsugamushi. This bacterium was previously reported to completely lack peptidoglycan, but here we present evidence supporting the existence of a peptidoglycan-like structure in Orientia, as well as an outer membrane containing a network of cross-linked proteins, which together confer cell envelope stability. We find striking similarities to the unrelated Chlamydiales, suggesting convergent adaptation to an obligate intracellular lifestyle.

Paton C, Karopka T. 2017. The Role of Free/Libre and Open Source Software in Learning Health Systems. Yearb Med Inform, 26 (1), pp. 53-58. | Show Abstract | Read more

Objective: To give an overview of the role of Free/Libre and Open Source Software (FLOSS) in the context of secondary use of patient data to enable Learning Health Systems (LHSs). Methods: We conducted an environmental scan of the academic and grey literature utilising the MedFLOSS database of open source systems in healthcare to inform a discussion of the role of open source in developing LHSs that reuse patient data for research and quality improvement. Results: A wide range of FLOSS is identified that contributes to the information technology (IT) infrastructure of LHSs including operating systems, databases, frameworks, interoperability software, and mobile and web apps. The recent literature around the development and use of key clinical data management tools is also reviewed. Conclusions: FLOSS already plays a critical role in modern health IT infrastructure for the collection, storage, and analysis of patient data. The nature of FLOSS systems to be collaborative, modular, and modifiable may make open source approaches appropriate for building the digital infrastructure for a LHS.

Gilbert SC, Warimwe GM. 2017. Rapid development of vaccines against emerging pathogens: The replication-deficient simian adenovirus platform technology. Vaccine, 35 (35 Pt A), pp. 4461-4464. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Despite the fact that there had been multiple small outbreaks of Ebola Virus Disease, when a large outbreak occurred in 2014 there were no vaccines or drugs available for use. Clinical development of multiple candidate vaccines was then initiated in parallel with attempts to contain the outbreak but only one vaccine was eventually tested in a phase III trial. In order to be better prepared for future outbreaks of known human pathogens, platform technologies to accelerate vaccine development should be employed, allowing vaccine developers to take advantage of detailed knowledge of the vaccine platform and facilitating rapid progress to clinical trials and eventually to vaccine stockpiles. This review gives an example of one such vaccine platform, replication-deficient simian adenoviruses, and describes progress in human and livestock vaccine development for three outbreak pathogens, Ebola virus, Rift Valley Fever Virus and Middle East Respiratory Syndrome Coronavirus.

Tran Vu Thieu N, Trinh Van T, Tran Tuan A, Klemm EJ, Nguyen Ngoc Minh C, Voong Vinh P, Pham Thanh D, Ho Ngoc Dan T, Pham Duc T, Langat P et al. 2017. An evaluation of purified Salmonella Typhi protein antigens for the serological diagnosis of acute typhoid fever. J Infect, 75 (2), pp. 104-114. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: The diagnosis of typhoid fever is a challenge. Aiming to develop a typhoid diagnostic we measured antibody responses against Salmonella Typhi (S. Typhi) protein antigens and the Vi polysaccharide in a cohort of Bangladeshi febrile patients. METHODS: IgM against 12 purified antigens and the Vi polysaccharide was measured by ELISA in plasma from patients with confirmed typhoid fever (n = 32), other confirmed infections (n = 17), and healthy controls (n = 40). ELISAs with the most specific antigens were performed on plasma from 243 patients with undiagnosed febrile disease. RESULTS: IgM against the S. Typhi protein antigens correlated with each other (rho > 0.8), but not against Vi (rho < 0.6). Typhoid patients exhibited higher IgM against 11/12 protein antigens and Vi than healthy controls and those with other infections. Vi, PilL, and CdtB exhibited the greatest sensitivity and specificity. Specificity and sensitivity was improved when Vi was combined with a protein antigen, generating sensitivities and specificities of 0.80 and >0.85, respectively. Applying a dynamic cut-off to patients with undiagnosed febrile disease suggested that 34-58% had an IgM response indicative of typhoid. CONCLUSIONS: We evaluated the diagnostic potential of several S. Typhi antigens; our assays give good sensitivity and specificity, but require further assessment in differing patient populations.

Wirjanata G, Handayuni I, Prayoga P, Leonardo L, Apriyanti D, Trianty L, Wandosa R, Gobay B, Kenangalem E, Poespoprodjo JR et al. 2017. Plasmodium falciparum and Plasmodium vivax Demonstrate Contrasting Chloroquine Resistance Reversal Phenotypes. Antimicrob Agents Chemother, 61 (8), pp. e00355-17-e00355-17. | Show Abstract | Read more

High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.

Garcia-Knight MA, Nduati E, Hassan AS, Nkumama I, Etyang TJ, Hajj NJ, Gambo F, Odera D, Berkley JA, Rowland-Jones SL, Urban B. 2017. Cytomegalovirus viraemia is associated with poor growth and T-cell activation with an increased burden in HIV-exposed uninfected infants. AIDS, 31 (13), pp. 1809-1818. | Show Abstract | Read more

OBJECTIVE: Factors associated with poor health in HIV-exposed-uninfected (HEU) infants are poorly defined. We describe the prevalence and correlates of cytomegalovirus (CMV) viraemia in HEU and HIV-unexposed-uninfected (HUU) infants, and quantify associations with anthropometric, haematological, and immunological outcomes. DESIGN: Cross-sectional, including HEU and HUU infants from rural coastal Kenya. METHODS: Infants aged 2-8 months were studied. The primary outcome was CMV viraemia and viral load, determined by quantitative PCR. Correlates were tested by logistic and linear regression; coefficients were used to describe associations between CMV viraemia and clinical/immunological parameters. RESULTS: In total, 42 of 65 (64.6%) infants had CMV viraemia [median viral load, 3.0 (interquartile ranges: 2.7-3.5) log10 IU/ml]. Compared to community controls, HEU infants had six-fold increased odds of being viraemic (adjusted odds ratio 5.95 [95% confidence interval: 1.82-19.36], P = 0.003). Age, but not HEU/HUU status, was a strong correlate of CMV viral load (coefficient = -0.15, P = 0.009). CMV viral load associated negatively with weight-for-age (WAZ) Z-score (coefficient =  -1.06, P = 0.008) and head circumference-for-age Z-score (coefficient =  -1.47, P = 0.012) and positively with CD8 T-cell coexpression of CD38/human leucocyte antigen DR (coefficient = 15.05, P = 0.003). CONCLUSION: The odds of having CMV viraemia was six-fold greater in HEU than HUU infants when adjusted for age. CMV viral load was associated with adverse growth and heightened CD8 T-cell immune activation. Longitudinal assessments of the clinical effects of primary CMV infection and associated immunomodulation in early life in HEU and HUU populations are warranted.

Yeap AD, Woods K, Dance DAB, Pichon B, Rattanavong S, Davong V, Phetsouvanh R, Newton PN, Shetty N, Kearns AM. 2017. Molecular Epidemiology of Staphylococcus aureus Skin and Soft Tissue Infections in the Lao People's Democratic Republic. Am J Trop Med Hyg, 97 (2), pp. 423-428. | Show Abstract | Read more

This is the first report of the molecular epidemiology of Staphylococcus aureus from skin and soft tissue infections (SSTI) in Laos. We selected a random sample of 96 S. aureus SSTI isolates received by the Microbiology Laboratory, Mahosot Hospital, Vientiane, between July 2012 and June 2014, including representation from seven referral hospitals. Isolates underwent susceptibility testing by Clinical and Laboratory Standards Institute methods, spa typing and DNA microarray analysis, with whole genome sequencing for rare lineages. Median patient age was 19.5 years (interquartile range 2-48.5 years); 52% (50) were female. Forty-three spa types, representing 17 lineages, were identified. Fifty-eight percent (56) of all isolates encoded Panton-Valentine leukocidin (PVL), representing six lineages: half of these patients had abscesses and three had positive blood cultures. The dominant lineage was CC121 (39; 41%); all but one isolate encoded PVL and 49% (19) were from children under five. Staphyococcus argenteus was identified in six (6%) patients; mostly adults > 50 years and with diabetes. Six isolates (6%) belonged to rare lineage ST2885; two possibly indicate cross-infection in a neonatal unit. One isolate from a previously undescribed lineage, ST1541, was identified. Antibiotic resistance was uncommon except for penicillin (93; 97%) and tetracycline (48; 50%). Seven (7%) isolates were methicillin-resistant S. aureus (MRSA), belonging to ST239-MRSA-III, CC59-MRSA-V(T) Taiwan Clone, ST2250-MRSA-IV, ST2885-MRSA-V and CC398-MRSA-V. Globally widespread CC5 and CC30 were absent. There are parallels in S. aureus molecular epidemiology between Laos and neighboring countries and these data highlight the prominence of PVL and suggest infiltration of MRSA clones of epidemic potential from surrounding countries.

Moore CE, Parry CM. 2017. Antimicrobial susceptibility of uropathogens isolated from Cambodian children. Paediatr Int Child Health, 37 (3), pp. 233. | Citations: 1 (Scopus) | Read more

Kajeechiwa L, Thwin MM, Nosten S, Tun SW, Parker D, von Seidlein L, Tangseefa D, Nosten F, Cheah PY. 2017. Community engagement for the rapid elimination of malaria: the case of Kayin State, Myanmar. Wellcome Open Res, 2 pp. 59. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND:  Currently, malaria elimination efforts are ongoing in several locations across Southeast Asia,  including in Kayin State (also known as Karen State), Myanmar . This paper describes the community engagement efforts for a pilot malaria elimination project, the challenges encountered and lessons learnt. METHODS:  Between May 2013 and June 2015, a study on targeted malaria elimination (TME) that included mass drug administration was conducted in four villages (TPN, TOT, KNH, and HKT) of Kayin State. Community engagement efforts included workshops, meetings and house-to-house visits with community members.  Exhibitions related to malaria and fun activities were organized for children. In addition, we provided primary care, small individual incentives and village-level incentives. This paper is based on our analysis of data extracted from meeting minutes, field notes, feedback sessions among staff and with community members as well as our own reflections. RESULTS:  Average participation across three rounds of MDA were 84.4%, 57.4%, 88.6% and 59.3% for TPN, TOT, KNH and HKT, respectively. Community engagement was fraught with practical challenges such as seasonal tasks of the villagers. There were challenges in explaining difficult concepts like drug resistance and submicroscopic infection. Another was understanding and navigating the politics of these villages, which are located in politically contested areas.  Managing expectations of villagers was difficult as they assumed that the community team must know everything related to health. CONCLUSIONS:  In the TME project, many different community engagement strategies were employed. We encountered many challenges which included logistical, scientific and political difficulties.  An approach that is tailored to the local population is key.

de Jong HK, Garcia-Laorden MI, Hoogendijk AJ, Parry CM, Maude RR, Dondorp AM, Faiz MA, van der Poll T, Wiersinga WJ. 2017. Expression of intra- and extracellular granzymes in patients with typhoid fever. PLoS Negl Trop Dis, 11 (7), pp. e0005823. | Show Abstract | Read more

BACKGROUND: Typhoid fever, caused by the intracellular pathogen Salmonella (S.) enterica serovar Typhi, remains a major cause of morbidity and mortality worldwide. Granzymes are serine proteases promoting cytotoxic lymphocytes mediated eradication of intracellular pathogens via the induction of cell death and which can also play a role in inflammation. We aimed to characterize the expression of extracellular and intracellular granzymes in patients with typhoid fever and whether the extracellular levels of granzyme correlated with IFN-γ release. METHODS AND PRINCIPAL FINDINGS: We analyzed soluble protein levels of extracellular granzyme A and B in healthy volunteers and patients with confirmed S. Typhi infection on admission and day of discharge, and investigated whether this correlated with interferon (IFN)-γ release, a cytokine significantly expressed in typhoid fever. The intracellular expression of granzyme A, B and K in subsets of lymphocytic cells was determined using flow cytometry. Patients demonstrated a marked increase of extracellular granzyme A and B in acute phase plasma and a correlation of both granzymes with IFN-γ release. In patients, lower plasma levels of granzyme B, but not granzyme A, were found at day of discharge compared to admission, indicating an association of granzyme B with stage of disease. Peripheral blood mononuclear cells of typhoid fever patients had a higher percentage of lymphocytic cells expressing intracellular granzyme A and granzyme B, but not granzyme K, compared to controls. CONCLUSION: The marked increase observed in extra- and intracellular levels of granzyme expression in patients with typhoid fever, and the correlation with stage of disease, suggests a role for granzymes in the host response to this disease.

Lees JA, Croucher NJ, Goldblatt D, Nosten F, Parkhill J, Turner C, Turner P, Bentley SD. 2017. Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration. Elife, 6 | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Streptococcus pneumoniae is a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, but variability in its duration is currently only understood at the serotype level. Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data, and combined these results with whole genome sequence data. We estimated that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas the host traits considered here (age and previous carriage) accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype (17%), drug-resistance (9%) and other significant locus effects (7%). A pan-genome-wide association study identified prophage sequences as being associated with decreased carriage duration independent of serotype, potentially by disruption of the competence mechanism. These findings support theoretical models of pneumococcal competition and antibiotic resistance.

Phyo AP, von Seidlein L. 2017. Challenges to replace ACT as first-line drug. Malar J, 16 (1), pp. 296. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

The spread of artemisinin and partner drug resistance through Asia requires changes in first-line therapy. The traditional modus has been the replacement of one first-line anti-malarial regimen with another. The number of anti-malarial drug candidates currently in development may have given false confidence in the expectation that resistance to artemisinin-based combination therapy (ACT) can be solved with a switch to the next anti-malarial drug regimen. A number of promising anti-malarial drug regimens did not succeed in becoming first-line drugs due to safety concerns or rapid development of resistance. Currently promising candidates for inclusion in first-line regimens, such as KAE 609, KAF 156, OZ 439, and OZ 277, have already triggered safety concerns or fears that point mutations could render the drugs inefficacious. An additional challenge for a new first-line drug is finding an appropriate partner drug. There is hope that none of the above-mentioned concerns will be substantiated in larger, upcoming trials. Meanwhile, combining already licensed anti-malarials may be a promising stop-gap measure. Practitioners in Vietnam have empirically started to add mefloquine to the current dihydroartemisinin-piperaquine. Practitioners in Africa could do worse than empirically combine already licensed co-artemether and amodiaquine when treatment with ACT no longer clears Plasmodium falciparum. Both combinations are currently undergoing trials.

Woodrow CJ, Fanello C. 2017. Pfhrp2 Deletions in the Democratic Republic of Congo: Evidence of Absence, or Absence of Evidence? J Infect Dis, 216 (4), pp. 504-506. | Citations: 1 (Scopus) | Read more

Henson SP, Boinett CJ, Ellington MJ, Kagia N, Mwarumba S, Nyongesa S, Mturi N, Kariuki S, Scott JAG, Thomson NR, Morpeth SC. 2017. Molecular epidemiology of Klebsiella pneumoniae invasive infections over a decade at Kilifi County Hospital in Kenya. Int J Med Microbiol, 307 (7), pp. 422-429. | Show Abstract | Read more

Multidrug resistant (MDR) Klebsiella pneumoniae is a common cause of nosocomial infections worldwide. Recent years have seen an explosion of resistance to extended-spectrum β-lactamases (ESBLs) and emergence of carbapenem resistance. Here, we examine 198 invasive K. pneumoniae isolates collected from over a decade in Kilifi County Hospital (KCH) in Kenya. We observe a significant increase in MDR K. pneumoniae isolates, particularly to third generation cephalosporins conferred by ESBLs. Using whole-genome sequences, we describe the population structure and the distribution of antimicrobial resistance genes within it. More than half of the isolates examined in this study were ESBL-positive, encoding CTX-M-15, SHV-2, SHV-12 and SHV-27, and 79% were MDR conferring resistance to at least three antimicrobial classes. Although no isolates in our dataset were found to be resistant to carbapenems we did find a plasmid with the genetic architecture of a known New Delhi metallo-β-lactamase-1 (NDM)-carrying plasmid in 25 isolates. In the absence of carbapenem use in KCH and because of the instability of the NDM-1 gene in the plasmid, the NDM-1 gene has been lost in these isolates. Our data suggests that isolates that encode NDM-1 could be present in the population; should carbapenems be introduced as treatment in public hospitals in Kenya, resistance is likely to ensue rapidly.

Peters-Sengers H, Heemskerk MBA, Geskus RB, Kers J, Homan van der Heide JJ, Berger SP, Bemelman FJ. 2017. Validation of the Prognostic Kidney Donor Risk Index (KDRI) Scoring System of Deceased Donors for Renal Transplantation in the Netherlands Transplantation, 102 (1), pp. 1-1. | Citations: 1 (Scopus) | Show Abstract | Read more

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Background The prognostic Kidney Donor Risk Index (KDRI) - developed and internally validated in the United States - is a widely used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the United States. Methods We aimed to externally validate the KDRI donor-only and KDRI full as proposed by Rao et al (2009). KDRI donor-only consist of 10 donor factors, and KDRI full with an additional 4 transplant factors. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. Results The median Dutch KDRI was 1.21 and comparable with the year 2012 in the United States (median of 1.24). The calibration-slope was 0.98 and 0.96 for the KDRI full and KDRI donor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell C) of the KDRI full and the KDRI donor-only at 5 years was 0.63 (95% confidence interval [CI], 0.62-0.64), and 0.62 (95% CI, 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (P = 0.002), weight (P = 0.017), and cold ischemia time (P < 0.001). Adding the use of inotropic drugs before donation (P = 0.040) and the interact ion between circulatory-death donor kidneys and prolonged cold ischemic time ( > 24 hours vs 12 hours; P = 0.059) could improve predictive ability. Conclusions The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRI may contribute to a standardized policy meeting the growing demand of donor kidneys in the Eurotransplant region.

Nhat NTD, Todd S, de Bruin E, Thao TTN, Vy NHT, Quan TM, Vinh DN, van Beek J, Anh PH, Lam HM et al. 2017. Structure of general-population antibody titer distributions to influenza A virus. Sci Rep, 7 (1), pp. 6060. | Show Abstract | Read more

Seroepidemiological studies aim to understand population-level exposure and immunity to infectious diseases. Their results are normally presented as binary outcomes describing the presence or absence of pathogen-specific antibody, despite the fact that many assays measure continuous quantities. A population's natural distribution of antibody titers to an endemic infectious disease may include information on multiple serological states - naiveté, recent infection, non-recent infection, childhood infection - depending on the disease in question and the acquisition and waning patterns of immunity. In this study, we investigate 20,152 general-population serum samples from southern Vietnam collected between 2009 and 2013 from which we report antibody titers to the influenza virus HA1 protein using a continuous titer measurement from a protein microarray assay. We describe the distributions of antibody titers to subtypes 2009 H1N1 and H3N2. Using a model selection approach to fit mixture distributions, we show that 2009 H1N1 antibody titers fall into four titer subgroups and that H3N2 titers fall into three subgroups. For H1N1, our interpretation is that the two highest-titer subgroups correspond to recent and historical infection, which is consistent with 2009 pandemic attack rates. Similar interpretations are available for H3N2, but right-censoring of titers makes these interpretations difficult to validate.

Watson CH, Baker S, Lau CL, Rawalai K, Taufa M, Coriakula J, Thieu NTV, Van TT, Ngoc DTT, Hens N et al. 2017. A cross-sectional seroepidemiological survey of typhoid fever in Fiji. PLoS Negl Trop Dis, 11 (7), pp. e0005786. | Citations: 2 (Scopus) | Show Abstract | Read more

Fiji, an upper-middle income state in the Pacific Ocean, has experienced an increase in confirmed case notifications of enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi). To characterize the epidemiology of typhoid exposure, we conducted a cross-sectional sero-epidemiological survey measuring IgG against the Vi antigen of S. Typhi to estimate the effect of age, ethnicity, and other variables on seroprevalence. Epidemiologically relevant cut-off titres were established using a mixed model analysis of data from recovering culture-confirmed typhoid cases. We enrolled and assayed plasma of 1787 participants for anti-Vi IgG; 1,531 of these were resident in mainland areas that had not been previously vaccinated against S. Typhi (seropositivity 32.3% (95%CI 28.2 to 36.3%)), 256 were resident on Taveuni island, which had been previously vaccinated (seropositivity 71.5% (95%CI 62.1 to 80.9%)). The seroprevalence on the Fijian mainland is one to two orders of magnitude higher than expected from confirmed case surveillance incidence, suggesting substantial subclinical or otherwise unreported typhoid. We found no significant differences in seropositivity prevalences by ethnicity, which is in contrast to disease surveillance data in which the indigenous iTaukei Fijian population are disproportionately affected. Using multivariable logistic regression, seropositivity was associated with increased age (odds ratio 1.3 (95% CI 1.2 to 1.4) per 10 years), the presence of a pit latrine (OR 1.6, 95%CI 1.1 to 2.3) as opposed to a septic tank or piped sewer, and residence in settlements rather than residential housing or villages (OR 1.6, 95% CI 1.0 to 2.7). Increasing seropositivity with age is suggestive of low-level endemic transmission in Fiji. Improved sanitation where pit latrines are used and addressing potential transmission routes in settlements may reduce exposure to S. Typhi. Widespread unreported infection suggests there may be a role for typhoid vaccination in Fiji, in addition to public health management of cases and outbreaks.

Seale AC, Obiero CW, Jones KD, Barsosio HC, Thitiri J, Ngari M, Morpeth S, Mohammed S, Fegan G, Mturi N, Berkley JA. 2017. Should First-line Empiric Treatment Strategies for Neonates Cover Coagulase-negative Staphylococcal Infections in Kenya? Pediatr Infect Dis J, 36 (11), pp. 1073-1078. | Show Abstract | Read more

BACKGROUND: Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. While coagulase-negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-Staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. METHODS: We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998-2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard World Health Organization guidelines. RESULTS: CoNS was isolated from blood culture in 995 of 9552 (10%) neonates. Case fatality among neonates with CoNS isolated from blood did not differ from other neonatal admissions (P = 0.2), and duration of admission was not prolonged [odds ratio (OR) = 0.9 (0.7-1.0), P = 0.040]. Neonates with CoNS were more likely to have convulsions [OR = 1.4 (1.0-1.8), P = 0.031] but less likely to have impaired consciousness or severe indrawing [OR = 0.8 (0.7-0.9), P = 0.025; OR = 0.9 (0.7-1.0), P = 0.065]. CONCLUSIONS: CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard World Health Organization guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for CoNS infections in neonates in this setting.

Sadiq MB, Tharaphan P, Chotivanich K, Tarning J, Anal AK. 2017. In vitro antioxidant and antimalarial activities of leaves, pods and bark extracts of Acacia nilotica (L.) Del. BMC Complement Altern Med, 17 (1), pp. 372. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The emergence of drug resistant malaria is threatening our ability to treat and control malaria in the Southeast Asian region. There is an urgent need to develop novel and chemically diverse antimalarial drugs. This study aimed at evaluating the antimalarial and antioxidant potentials of Acacia nilotica plant extracts. METHODS: The antioxidant activities of leaves, pods and bark extracts were determined by standard antioxidant assays; reducing power capacity, % lipid peroxidation inhibition and ferric reducing antioxidant power assay. The antimalarial activities of plant extracts against Plasmodium falciparum parasites were determined by the 48 h schizont maturation inhibition assay. Further confirmation of schizonticide activity of extracts was made by extending the incubation period up to 96 h after removing the plant extract residues from parasites culture. Inhibition assays were analyzed by dose-response modelling. RESULTS: In all antioxidant assays, leaves of A. nilotica showed higher antioxidant activity than pods and bark. Antimalarial IC50 values of leaves, pods and bark extracts were 1.29, 4.16 and 4.28 μg/ml respectively, in the 48 h maturation assay. The IC50 values determined for leaves, pods and bark extracts were 3.72, 5.41 and 5.32 μg/ml respectively, after 96 h of incubation. All extracts inhibited the development of mature schizont, indicating schizonticide activity against P. falciparum. CONCLUSION: A. nilotica extracts showed promising antimalarial and antioxidant effects. However, further investigation is needed to isolate and identify the active components responsible for the antimalarial and antioxidant effects.

White NJ. 2017. Identifying Malaria Hot Spots. J Infect Dis, 216 (9), pp. 1051-1052. | Read more

Thapa SS, Basnyat B. 2017. Chronic Diarrhea in a Traveler: Cyclosporiasis. Am J Med, 130 (12), pp. e535-e536. | Read more

Vanaerschot M, Lucantoni L, Li T, Combrinck JM, Ruecker A, Kumar TRS, Rubiano K, Ferreira PE, Siciliano G, Gulati S et al. 2017. Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. Nat Microbiol, 2 (10), pp. 1403-1414. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

Haniffa R, Pubudu De Silva A, Weerathunga P, Mukaka M, Athapattu P, Munasinghe S, Mahesh B, Mahipala P, De Silva T, Abayadeera A et al. 2017. Applicability of the APACHE II model to a lower middle income country. J Crit Care, 42 pp. 178-183. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

PURPOSE: To determine the utility of APACHE II in a low-and middle-income (LMIC) setting and the implications of missing data. MATERIALS AND METHODS: Patients meeting APACHE II inclusion criteria admitted to 18 ICUs in Sri Lanka over three consecutive months had data necessary for the calculation of APACHE II, probabilities prospectively extracted from case notes. APACHE II physiology score (APS), probabilities, Standardised (ICU) Mortality Ratio (SMR), discrimination (AUROC), and calibration (C-statistic) were calculated, both by imputing missing measurements with normal values and by Multiple Imputation using Chained Equations (MICE). RESULTS: From a total of 995 patients admitted during the study period, 736 had APACHE II probabilities calculated. Data availability for APS calculation ranged from 70.6% to 88.4% for bedside observations and 18.7% to 63.4% for invasive measurements. SMR (95% CI) was 1.27 (1.17, 1.40) and 0.46 (0.44, 0.49), AUROC (95% CI) was 0.70 (0.65, 0.76) and 0.74 (0.68, 0.80), and C-statistic was 68.8 and 156.6 for normal value imputation and MICE, respectively. CONCLUSIONS: An incomplete dataset confounds interpretation of prognostic model performance in LMICs, wherein imputation using normal values is not a suitable strategy. Improving data availability, researching imputation methods and developing setting-adapted and simpler prognostic models are warranted.

Nabwera HM, Jepkosgei J, Muraya KW, Hassan AS, Molyneux CS, Ali R, Prentice AM, Berkley JA, Mwangome MK. 2017. What influences feeding decisions for HIV-exposed infants in rural Kenya? International Breastfeeding Journal, 12 (1), | Read more

Dat VQ, Vu HN, Nguyen The H, Nguyen HT, Hoang LB, Vu Tien Viet D, Bui CL, Van Nguyen K, Nguyen TV, Trinh DT et al. 2017. Bacterial bloodstream infections in a tertiary infectious diseases hospital in Northern Vietnam: aetiology, drug resistance, and treatment outcome. BMC Infect Dis, 17 (1), pp. 493. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Bloodstream infections (BSIs) are associated with high morbidity and mortality worldwide. However their aetiology, antimicrobial susceptibilities and associated outcomes differ between developed and developing countries. Systematic data from Vietnam are scarce. Here we present aetiologic data on BSI in adults admitted to a large tertiary referral hospital for infectious diseases in Hanoi, Vietnam. METHODS: A retrospective study was conducted at the National Hospital for Tropical Diseases between January 2011 and December 2013. Cases of BSI were determined from records in the microbiology department. Case records were obtained where possible and clinical findings, treatment and outcome were recorded. BSI were classified as community acquired if the blood sample was drawn ≤48 h after hospitalization or hospital acquired if >48 h. RESULTS: A total of 738 patients with BSI were included for microbiological analysis. The predominant pathogens were: Klebsiella pneumoniae (17.5%), Escherichia coli (17.3%), Staphylococcus aureus (14.9%), Stenotrophomonas maltophilia (9.6%) and Streptococcus suis (7.6%). The overall proportion of extended spectrum beta-lactamase (ESBL) production among Enterobacteriaceae was 25.1% (67/267 isolates) and of methicillin-resistance in S. aureus (MRSA) 37% (40/108). Clinical data was retrieved for 477 (64.6%) patients; median age was 48 years (IQR 36-60) with 27.7% female. The overall case fatality rate was 28.9% and the highest case fatality was associated with Enterobacteriaceae BSI (34.7%) which accounted for 61.6% of all BSI fatalities. CONCLUSIONS: Enterobacteriaceae (predominantly K. pneumoniae and E. coli) are the most common cause of both community and hospital acquired bloodstream infections in a tertiary referral clinic in northern Vietnam.

Chotsiri P, Wattanakul T, Hoglund RM, Hanboonkunupakarn B, Pukrittayakamee S, Blessborn D, Jittamala P, White NJ, Day NPJ, Tarning J. 2017. Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin-piperaquine in healthy volunteers. Br J Clin Pharmacol, 83 (12), pp. 2752-2766. | Show Abstract | Read more

AIMS: The aims of the present study were to evaluate the pharmacokinetic properties of dihydroartemisinin (DHA) and piperaquine, potential drug-drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers. METHODS: The population pharmacokinetic properties of DHA and piperaquine were assessed in 16 healthy Thai adults using an open-label, randomized, crossover study. Drug concentration-time data and electrocardiographic measurements were evaluated with nonlinear mixed-effects modelling. RESULTS: The developed models described DHA and piperaquine population pharmacokinetics accurately. Concomitant treatment with primaquine did not affect the pharmacokinetic properties of DHA or piperaquine. A linear pharmacokinetic-pharmacodynamic model described satisfactorily the relationship between the individually corrected QT intervals and piperaquine concentrations; the population mean QT interval increased by 4.17 ms per 100 ng ml-1 increase in piperaquine plasma concentration. Simulations from the final model showed that monthly and bimonthly mass drug administration in healthy subjects would result in median maximum QT interval prolongations of 18.9 ms and 16.8 ms, respectively, and would be very unlikely to result in prolongation of more than 50 ms. A single low dose of primaquine can be added safely to the existing DHA-piperaquine treatment in areas of multiresistant Plasmodium falciparum malaria. CONCLUSIONS: Pharmacokinetic-pharmacodynamic modelling and simulation in healthy adult volunteers suggested that therapeutic doses of DHA-piperaquine in the prevention or treatment of P. falciparum malaria are unlikely to be associated with dangerous QT prolongation.

Yacoub S, Trung TH, Lam PK, Thien VHN, Hai DHT, Phan TQ, Nguyet OPK, Quyen NTH, Simmons CP, Broyd C et al. 2017. Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress. PLoS Negl Trop Dis, 11 (7), pp. e0005740. | Show Abstract | Read more

BACKGROUND: Dengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac function and intravascular volume parameters plus lactate levels, with the outcomes of recurrent shock and respiratory distress in severe dengue. METHODS/PRINCIPLE FINDINGS: We performed a prospective observational study in Paediatric and adult ICU, at the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam. Patients with dengue were enrolled within 12 hours of admission to paediatric or adult ICU. A haemodynamic assessment and portable echocardiograms were carried out daily for 5 days from enrolment and all interventions recorded. 102 patients were enrolled; 22 patients did not develop DSS, 48 had a single episode of shock and 32 had recurrent shock. Patients with recurrent shock had a higher enrolment pulse than those with 1 episode or no shock (median: 114 vs. 100 vs. 100 b/min, P = 0.002), significantly lower Stroke Volume Index (SVI), (median: 21.6 vs. 22.8 vs. 26.8mls/m2, P<0.001) and higher lactate levels (4.2 vs. 2.9 vs. 2.2 mmol/l, P = 0.001). Higher SVI and worse left ventricular function (higher Left Myocardial Performance Index) on study days 3-5 was associated with the secondary endpoint of respiratory distress. There was an association between the total IV fluid administered during the ICU admission and respiratory distress (OR: 1.03, 95% CI 1.01-1.06, P = 0.001). Admission lactate levels predicted patients who subsequently developed recurrent shock (P = 0.004), and correlated positively with the total IV fluid volume received (rho: 0.323, P = 0.001) and also with admission ALT (rho: 0.764, P<0.001) and AST (rho: 0.773, P<0.001). CONCLUSIONS/SIGNIFICANCE: Echo-derived intravascular volume assessment and venous lactate levels can help identify dengue patients at high risk of recurrent shock and respiratory distress in ICU. These findings may serve to, not only assist in the management of DSS patients, but also these haemodynamic endpoints could be used in future dengue fluid intervention trials.

Htun MW, Mon NCN, Aye KM, Hlaing CM, Kyaw MP, Handayuni I, Trimarsanto H, Bustos D, Ringwald P, Price RN et al. 2017. Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow. Malar J, 16 (1), pp. 281. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax malaria remains a major public health burden in Myanmar. Resistance to chloroquine (CQ), the first-line treatment for P. vivax, has been reported in the country and has potential to undermine local control efforts. METHODS: Patients over 6 years of age with uncomplicated P. vivax mono-infection were enrolled into clinical efficacy studies in Myawaddy in 2014 and Kawthoung in 2012. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. Pvmdr1 copy number (CN) and microsatellite diversity were assessed on samples from the patients enrolled in the clinical study and additional cross-sectional surveys undertaken in Myawaddy and Shwegyin in 2012. RESULTS: A total of 85 patients were enrolled in the CQ clinical studies, 25 in Myawaddy and 60 in Kawthoung. One patient in Myawaddy (1.2%) had an early treatment failure and two patients (2.3%) in Kawthoung presented with late treatment failures on day 28. The day 28 efficacy was 92.0% (95% CI 71.6-97.9) in Myawaddy and 98.3% (95% CI 88.7-99.8) in Kawthoung. By day 2, 92.2% (23/25) in Myawaddy and 85.0% (51/60) in Kawthoung were aparasitaemic. Genotyping and pvmdr1 CN assessment was undertaken on 43, 52 and 46 clinical isolates from Myawaddy, Kawthoung and Shwegyin respectively. Pvmdr1 amplification was observed in 3.2% (1/31) of isolates in Myawaddy, 0% (0/49) in Kawthoung and 2.5% (1/40) in Shwegyin. Diversity was high in all sites (H E 0.855-0.876), with low inter-population differentiation (F ST 0.016-0.026, P < 0.05). CONCLUSIONS: Treatment failures after chloroquine were observed following chloroquine monotherapy, with pvmdr1 amplification present in both Myawaddy and Shwegyin. The results emphasize the importance of ongoing P. vivax drug resistance surveillance in Myanmar, particularly given the potential connectivity between parasite population at different sites.

Kobylinski KC, Ubalee R, Ponlawat A, Nitatsukprasert C, Phasomkulsolsil S, Wattanakul T, Tarning J, Na-Bangchang K, McCardle PW, Davidson SA, Richardson JH. 2017. Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles. Malar J, 16 (1), pp. 280. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Novel vector control methods that can directly target outdoor malaria transmission are urgently needed in the Greater Mekong Subregion (GMS) to accelerate malaria elimination and artemisinin resistance containment efforts. Ivermectin mass drug administration (MDA) to humans has been shown to effectively kill wild Anopheles and suppress malaria transmission in West Africa. Preliminary laboratory investigations were performed to determine ivermectin susceptibility and sporontocidal effect in GMS Anopheles malaria vectors coupled with pharmacokinetic models of ivermectin at escalating doses. METHODS: A population-based pharmacokinetic model of ivermectin was developed using pre-existing data from a clinical trial conducted in Thai volunteers at the 200 µg/kg dose. To assess ivermectin susceptibility, various concentrations of ivermectin compound were mixed in human blood meals and blood-fed to Anopheles dirus, Anopheles minimus, Anopheles sawadwongporni, and Anopheles campestris. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with probit analyses was used to calculate concentrations of ivermectin that killed 50% (LC50) of mosquitoes for each species. Blood samples were collected from Plasmodium vivax positive patients and offered to mosquitoes with or without ivermectin at the ivermectin LC25 or LC5 for An. dirus and An. minimus. RESULTS: The GMS Anopheles displayed a range of susceptibility to ivermectin with species listed from most to least susceptible being An. minimus (LC50 = 16.3 ng/ml) > An. campestris (LC50 = 26.4 ng/ml) = An. sawadwongporni (LC50 = 26.9 ng/ml) > An. dirus (LC50 = 55.6 ng/ml). Mosquito survivorship results, the pharmacokinetic model, and extensive safety data indicated that ivermectin 400 µg/kg is the ideal minimal dose for MDA in the GMS for malaria parasite transmission control. Ivermectin compound was sporontocidal to P. vivax in both An. dirus and An. minimus at the LC25 and LC5 concentrations. CONCLUSIONS: Ivermectin is lethal to dominant GMS Anopheles malaria vectors and inhibits sporogony of P. vivax at safe human relevant concentrations. The data suggest that ivermectin MDA has potential in the GMS as a vector and transmission blocking control tool to aid malaria elimination efforts.

Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, Polack FP, Balsells E, Acacio S, Aguayo C et al. 2017. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet, 390 (10098), pp. 946-958. | Citations: 18 (Scopus) | Show Abstract | Read more

BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. METHODS: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. FINDINGS: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. INTERPRETATION: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. FUNDING: The Bill & Melinda Gates Foundation.

Mataradchakul T, Uthaipibull C, Nosten F, Vega-Rodriguez J, Jacobs-Lorena M, Lek-Uthai U. 2017. Plasmodium vivax rhomboid-like protease 1 gene diversity in Thailand. Exp Parasitol, 181 pp. 1-6. | Show Abstract | Read more

BACKGROUND: Plasmodium vivax infection remains a major public health problem, especially along the Thailand border regions. We examined the genetic diversity of this parasite by analyzing single-nucleotide polymorphisms (SNPs) of the P. vivax rhomboid-like protease 1 gene (Pvrom1) in parasites collected from western (Tak province, Thai-Myanmar border) and eastern (Chanthaburi province, Thai-Cambodia border) regions. METHODS: Data were collected by a cross-sectional survey, consisting of 47 and 45 P. vivax-infected filter paper-spotted blood samples from the western and eastern regions of Thailand, respectively during September 2013 to May 2014. Extracted DNA was examined for presence of P. vivax using Plasmodium species-specific nested PCR. Pvrom1 gene was PCR amplified, sequenced and the SNP diversity was analyzed using F-STAT, DnaSP, MEGA and LIAN programs. RESULTS: Comparison of sequences of the 92 Pvrom1 831-base open reading frames with that of a reference sequence (GenBank acc. no. XM001615211) revealed 17 samples with a total of 8 polymorphic sites, consisting of singleton (exon 3, nt 645) and parsimony informative (exon 1, nt 22 and 39; exon 3, nt 336, 537 and 656; and exon 4, nt 719 and 748) sites, which resulted in six different deduced Pvrom1 variants. Non-synonymous to synonymous substitutions ratio estimated by the DnaSP program was 1.65 indicating positive selection, but the Z-tests of selection showed no significant deviations from neutrality for Pvrom1 samples from western region of Thailand. In addition McDonald Kreitman test (MK) showed not significant, and Fst values are not different between the two regions and the regions combined. Interestingly, only Pvrom1 exon 2 was the most conserved sequences among the four exons. CONCLUSIONS: The relatively high degree of Pvrom1 polymorphism suggests that the protein is important for parasite survival in face of changes in both insect vector and human populations. These polymorphisms could serve as a sensitive marker for studying plasmodial genetic diversity. The significance of Pvrom1 conserved exon 2 sequence remains to be investigated.

Moradigaravand D, Jamrozy D, Mostowy R, Anderson A, Nickerson EK, Thaipadungpanit J, Wuthiekanun V, Limmathurotsakul D, Tandhavanant S, Wikraiphat C et al. 2017. Evolution of the Staphylococcus argenteus ST2250 Clone in Northeastern Thailand Is Linked with the Acquisition of Livestock-Associated Staphylococcal Genes. MBio, 8 (4), pp. e00802-17-e00802-17. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Staphylococcus argenteus is a newly named species previously described as a divergent lineage of Staphylococcus aureus that has recently been shown to have a global distribution. Despite growing evidence of the clinical importance of this species, knowledge about its population epidemiology and genomic architecture is limited. We used whole-genome sequencing to evaluate and compare S. aureus (n = 251) and S. argenteus (n = 68) isolates from adults with staphylococcal sepsis at several hospitals in northeastern Thailand between 2006 and 2013. The majority (82%) of the S. argenteus isolates were of multilocus sequence type 2250 (ST2250). S. aureus was more diverse, although 43% of the isolates belonged to ST121. Bayesian analysis suggested an S. argenteus ST2250 substitution rate of 4.66 (95% confidence interval [CI], 3.12 to 6.38) mutations per genome per year, which was comparable to the S. aureus ST121 substitution rate of 4.07 (95% CI, 2.61 to 5.55). S. argenteus ST2250 emerged in Thailand an estimated 15 years ago, which contrasts with the S. aureus ST1, ST88, and ST121 clades that emerged around 100 to 150 years ago. Comparison of S. argenteus ST2250 genomes from Thailand and a global collection indicated a single introduction into Thailand, followed by transmission to local and more distant countries in Southeast Asia and further afield. S. argenteus and S. aureus shared around half of their core gene repertoire, indicating a high level of divergence and providing strong support for their classification as separate species. Several gene clusters were present in ST2250 isolates but absent from the other S. argenteus and S. aureus study isolates. These included multiple exotoxins and antibiotic resistance genes that have been linked previously with livestock-associated S. aureus, consistent with a livestock reservoir for S. argenteus These genes appeared to be associated with plasmids and mobile genetic elements and may have contributed to the biological success of ST2250.IMPORTANCE In this study, we used whole-genome sequencing to understand the genome evolution and population structure of a systematic collection of ST2250 S. argenteus isolates. A newly identified ancestral species of S. aureus, S. argenteus has become increasingly known as a clinically important species that has been reported recently across various countries. Our results indicate that S. argenteus has spread at a relatively rapid pace over the past 2 decades across northeastern Thailand and acquired multiple exotoxin and antibiotic resistance genes that have been linked previously with livestock-associated S. aureus Our findings highlight the clinical importance and potential pathogenicity of S. argenteus as a recently emerging pathogen.

Njunge JM, Oyaro IN, Kibinge NK, Rono MK, Kariuki SM, Newton CR, Berkley JA, Gitau EN. 2017. Cerebrospinal fluid markers to distinguish bacterial meningitis from cerebral malaria in children. Wellcome Open Res, 2 pp. 47. | Show Abstract | Read more

Background. Few hospitals in high malaria endemic countries in Africa have the diagnostic capacity for clinically distinguishing acute bacterial meningitis (ABM) from cerebral malaria (CM). As a result, empirical use of antibiotics is necessary. A biochemical marker of ABM would facilitate precise clinical diagnosis and management of these infections and enable rational use of antibiotics. Methods. We used label-free protein quantification by mass spectrometry to identify cerebrospinal fluid (CSF) markers that distinguish ABM (n=37) from CM (n=22) in Kenyan children. Fold change (FC) and false discovery rates (FDR) were used to identify differentially expressed proteins. Subsequently, potential biomarkers were assessed for their ability to discriminate between ABM and CM using receiver operating characteristic (ROC) curves. Results. The host CSF proteome response to ABM ( Haemophilusinfluenza and Streptococcuspneumoniae) is significantly different to CM. Fifty two proteins were differentially expressed (FDR<0.01, Log FC≥2), of which 83% (43/52) were upregulated in ABM compared to CM. Myeloperoxidase and lactotransferrin were present in 37 (100%) and 36 (97%) of ABM cases, respectively, but absent in CM (n=22). Area under the ROC curve (AUC), sensitivity, and specificity were assessed for myeloperoxidase (1, 1, and 1; 95% CI, 1-1) and lactotransferrin (0.98, 0.97, and 1; 95% CI, 0.96-1). Conclusion. Myeloperoxidase and lactotransferrin have a high potential to distinguish ABM from CM and thereby improve clinical management. Their validation requires a larger cohort of samples that includes other bacterial aetiologies of ABM.

Darton TC, Meiring JE, Tonks S, Khan MA, Khanam F, Shakya M, Thindwa D, Baker S, Basnyat B, Clemens JD et al. 2017. The STRATAA study protocol: a programme to assess the burden of enteric fever in Bangladesh, Malawi and Nepal using prospective population census, passive surveillance, serological studies and healthcare utilisation surveys. BMJ Open, 7 (6), pp. e016283. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Invasive infections caused bySalmonella entericaserovar Typhi and Paratyphi A are estimated to account for 12-27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidalSalmonellaeinfections is hindered by lack of population-based studies and adequate laboratory diagnostics.The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidalSalmonellaeinfections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history ofSalmonellatransmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies. METHODS/DESIGN: Using census-defined denominator populations of ≥100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidalSalmonellae(seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers. ETHICS AND DISSEMINATION: This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN 12131979. ETHICS REFERENCES: Oxford (Oxford Tropical Research Ethics Committee 39-15).Bangladesh (icddr,b Institutional Review Board PR-15119).Malawi (National Health Sciences Research Committee 15/5/1599).Nepal (Nepal Health Research Council 306/2015).

Gilson L, Barasa E, Nxumalo N, Cleary S, Goudge J, Molyneux S, Tsofa B, Lehmann U. 2017. Everyday resilience in district health systems: emerging insights from the front lines in Kenya and South Africa. BMJ Glob Health, 2 (2), pp. e000224. | Show Abstract | Read more

Recent global crises have brought into sharp relief the absolute necessity of resilient health systems that can recognise and react to societal crises. While such crises focus the global mind, the real work lies, however, in being resilient in the face of routine, multiple challenges. But what are these challenges and what is the work of nurturing everyday resilience in health systems? This paper considers these questions, drawing on long-term, primarily qualitative research conducted in three different district health system settings in Kenya and South Africa, and adopting principles from case study research methodology and meta-synthesis in its analytic approach. The paper presents evidence of the instability and daily disruptions managed at the front lines of the district health system. These include patient complaints, unpredictable staff, compliance demands, organisational instability linked to decentralisation processes and frequently changing, and sometimes unclear, policy imperatives. The paper also identifies managerial responses to these challenges and assesses whether or not they indicate everyday resilience, using two conceptual lenses. From this analysis, we suggest that such resilience seems to arise from the leadership offered by multiple managers, through a combination of strategies that become embedded in relationships and managerial routines, drawing on wider organisational capacities and resources. While stable governance structures and adequate resources do influence everyday resilience, they are not enough to sustain it. Instead, it appears important to nurture the power of leaders across every system to reframe challenges, strengthen their routine practices in ways that encourage mindful staff engagement, and develop social networks within and outside organisations. Further research can build on these insights to deepen understanding.

Heemskerk AD, Nguyen MTH, Dang HTM, Vinh Nguyen CV, Nguyen LH, Do TDA, Nguyen TTT, Wolbers M, Day J, Le TTP et al. 2017. Clinical Outcomes of Patients With Drug-Resistant Tuberculous Meningitis Treated With an Intensified Antituberculosis Regimen. Clin Infect Dis, 65 (1), pp. 20-28. | Show Abstract | Read more

Background: Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment. Methods: We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression. Results: Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15-.76], P = .01) in INH-R TBM. Conclusions: Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored. Clinical Trials Registration: ISRCTN61649292.

van Enter BJD, Lau Y-L, Ling CL, Watthanaworawit W, Sukthana Y, Lee W-C, Nosten F, McGready R. 2017. Seroprevalence ofToxoplasma gondiiInfection in Refugee and Migrant Pregnant Women along the Thailand-Myanmar Border. Am J Trop Med Hyg, 97 (1), pp. 232-235. | Show Abstract | Read more

Toxoplasma gondii primary infection in pregnancy is associated with poor obstetric outcomes. This study aimed to determine the seroprevalence ofToxoplasmainfection in pregnant migrant and refugee women from Myanmar attending antenatal care in Thailand. A random selection of 199 residual blood samples from first antenatal screen in 2014-2015 was tested forToxoplasmaIgG and IgM antibodies. Seroprevalence ofToxoplasmainfection was 31.7% (95% confidence interval = 25.6-38.4). Avidity testing in the three positive IgM cases indicated all were past infections. Multiparity (≥ 3 children) was significantly associated with higherToxoplasmaseropositivity rates. Seroprevalence ofT. gondiiinfection in this pregnant population is similar to the only other report from Myanmar, where multiparity was also identified as a significant association.Toxoplasmainfection is important in pregnant women. Nevertheless, in this marginalized population, this infection may be given less priority, due to resource constraints in providing the most basic components of safe motherhood programs.

Lee N, Cao B, Ke C, Lu H, Hu Y, Tam CHT, Ma RCW, Guan D, Zhu Z, Li H et al. 2017. IFITM3, TLR3, and CD55 Gene SNPs and Cumulative Genetic Risks for Severe Outcomes in Chinese Patients With H7N9/H1N1pdm09 Influenza. J Infect Dis, 216 (1), pp. 97-104. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Background: We examined associations between single-nucleotide polymorphisms (SNPs) of IFITM3, TLR3, and CD55 genes and influenza clinical outcomes in Chinese. Methods: A multicenter study was conducted on 275 adult cases of avian (H7N9) and pandemic (H1N1pdm09) influenza. Host DNA was extracted from diagnostic respiratory samples; IFITM3 rs12252, TLR3 rs5743313, CD55 rs2564978, and TLR4 rs4986790/4986791 were targeted for genotyping (Sanger sequencing). The primary outcome analyzed was death. Results: IFITM3 and TLR3 SNPs were in Hardy-Weinberg equilibrium; their allele frequencies (IFITM3/C-allele 0.56, TLR3/C-allele 0.88) were comparable to 1000 Genomes Han Chinese data. We found over-representation of homozygous IFITM3 CC (54.5% vs 33.2%; P = .02) and TLR3 CC (93.3% vs 76.9%; P = .04) genotypes among fatal cases. Recessive genetic models showed their significant independent associations with higher death risks (adjusted hazard ratio [aHR] 2.78, 95% confidence interval [CI] 1.29-6.02, and aHR 4.85, 95% CI 1.11-21.06, respectively). Cumulative effects were found (aHR 3.53, 95% CI 1.64-7.59 per risk genotype; aHR 9.99, 95% CI 1.27-78.59 with both). Results were consistent for each influenza subtype and other severity indicators. The CD55 TT genotype was linked to severity. TLR4 was nonpolymorphic. Conclusions: Host genetic factors may influence clinical outcomes of avian and pandemic influenza infections. Such findings have important implications on disease burden and patient care in at-risk populations.

Peacock TP, Benton DJ, James J, Sadeyen J-R, Chang P, Sealy JE, Bryant JE, Martin SR, Shelton H, Barclay WS, Iqbal M. 2017. Immune Escape Variants of H9N2 Influenza Viruses Containing Deletions at the Hemagglutinin Receptor Binding Site Retain Fitness In Vivo and Display Enhanced Zoonotic Characteristics. J Virol, 91 (14), pp. e00218-17-e00218-17. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

H9N2 avian influenza viruses are enzootic in poultry across Asia and North Africa, where they pose a threat to human health as both zoonotic agents and potential pandemic candidates. Poultry vaccination against H9N2 viruses has been employed in many regions; however, vaccine effectiveness is frequently compromised due to antigenic drift arising from amino acid substitutions in the major influenza virus antigen hemagglutinin (HA). Using selection with HA-specific monoclonal antibodies, we previously identified H9N2 antibody escape mutants that contained deletions of amino acids in the 220 loop of the HA receptor binding sites (RBSs). Here we analyzed the impact of these deletions on virus zoonotic infection characteristics and fitness. We demonstrated that mutant viruses with RBS deletions are able to escape polyclonal antiserum binding and are able to infect and be transmitted between chickens. We showed that the deletion mutants have increased binding to human-like receptors and greater replication in primary human airway cells; however, the mutant HAs also displayed reduced pH and thermal stability. In summary, we infer that variant influenza viruses with deletions in the 220 loop could arise in the field due to immune selection pressure; however, due to reduced HA stability, we conclude that these viruses are unlikely to be transmitted from human to human by the airborne route, a prerequisite for pandemic emergence. Our findings underscore the complex interplay between antigenic drift and viral fitness for avian influenza viruses as well as the challenges of predicting which viral variants may pose the greatest threats for zoonotic and pandemic emergence.IMPORTANCE Avian influenza viruses, such as H9N2, cause disease in poultry as well as occasionally infecting humans and are therefore considered viruses with pandemic potential. Many countries have introduced vaccination of poultry to try to control the disease burden; however, influenza viruses are able to rapidly evolve to escape immune pressure in a process known as "antigenic drift." Previously, we experimentally generated antigenic-drift variants in the laboratory, and here, we test our "drifted" viruses to assess their zoonotic infection characteristics and transmissibility in chickens. We found that the drifted viruses were able to infect and be transmitted between chickens and showed increased binding to human-like receptors. However, the drift mutant viruses displayed reduced stability, and we predict that they are unlikely to be transmitted from human to human and cause an influenza pandemic. These results demonstrate the complex relationship between antigenic drift and the potential of avian influenza viruses to infect humans.

van der Pluijm RW, Watson J, Woodrow CJ. 2017. Antimalarial Resistance Unlikely To Explain U.K. Artemether-Lumefantrine Failures. Antimicrob Agents Chemother, 61 (7), pp. e00721-17-e00721-17. | Citations: 1 (Web of Science Lite) | Read more

Thi SS, Parker DM, Swe LL, Pukrittayakamee S, Ling CL, Amornpaisarnloet K, Vincenti-Delmas M, Nosten FH. 2017. Migration histories of multidrug-resistant tuberculosis patients from the Thailand-Myanmar border, 2012-2014. Int J Tuberc Lung Dis, 21 (7), pp. 753-758. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing public health threat in South-East Asia. TB is typically a disease of poverty and can be spread by infectious humans who migrate from one region to another. DESIGN: We interviewed 20 MDR-TB patients on the Thailand-Myanmar border with regard to their migration histories. Migration origins and destinations were mapped. RESULTS: All but one participant had a history of migration, and maps of migration ranges revealed wide geographic dispersal. Most described living and work conditions that could contribute to the spread of drug-resistant TB, including numerous contacts and crowded living quarters. CONCLUSION: Our results show that at least some migrant workers in the region carry MDR-TB, and indicate that this subgroup of the population is important with regard to the transmission of MDR-TB throughout the region. Migrants in this region come into contact with high numbers of people and may be able to spread the disease across wide geographic ranges. Access to diagnosis and treatment and socio-economic development are at least as important as any TB control measures, meaning that innovative and bold approaches that extend across international borders are needed to address these problems.

Hoogland J, Boel JA, de Bie RMA, Geskus RB, Schmand BA, Dalrymple-Alford JC, Marras C, Adler CH, Goldman JG, Tröster AI et al. 2017. Mild cognitive impairment as a risk factor for Parkinson's disease dementia Movement Disorders, 32 (7), pp. 1056-1065. | Citations: 4 (Scopus) | Show Abstract | Read more

© 2017 International Parkinson and Movement Disorder Society Background: The International Parkinson and Movement Disorder Society criteria for mild cognitive impairment in PD were recently formulated. Objectives: The aim of this international study was to evaluate the predictive validity of the comprehensive (level II) version of these criteria by assessment of their contribution to the hazard of PD dementia. Methods: Individual patient data were selected from four separate studies on cognition in PD that provided information on demographics, motor examination, depression, neuropsychological examination suitable for application of level II criteria, and longitudinal follow-up for conversion to dementia. Survival analysis evaluated the predictive value of level II criteria for cognitive decline toward dementia as expressed by the relative hazard of dementia. Results: A total of 467 patients were included. The analyses showed a clear contribution of impairment according to level II mild cognitive impairment criteria, age, and severity of PD motor symptoms to the hazard of dementia. There was a trend of increasing hazard of dementia with declining neuropsychological performance. Conclusions: This is the first large international study evaluating the predictive validity of level II mild cognitive impairment criteria for PD. The results showed a clear and unique contribution of classification according to level II criteria to the hazard of PD dementia. This finding supports their predictive validity and shows that they contribute important new information on the hazard of dementia, beyond known demographic and PD-specific factors of influence. © 2017 International Parkinson and Movement Disorder Society.

Ndour PA, Larréché S, Mouri O, Argy N, Gay F, Roussel C, Jauréguiberry S, Perillaud C, Langui D, Biligui S et al. 2017. Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis. Sci Transl Med, 9 (397), pp. eaaf9377-eaaf9377. | Show Abstract | Read more

Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia-called post-artesunate delayed hemolysis (PADH)-for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimized membrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells from artesunate-treated malaria patients. HRP2 was deposited at the membrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution of whole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89% sensitivity and 73% specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria.

Quyen NTH, Kien DTH, Rabaa M, Tuan NM, Vi TT, Van Tan L, Hung NT, Tuan HM, Van Tram T, Le Da Ha N et al. 2017. Chikungunya and Zika Virus Cases Detected against a Backdrop of Endemic Dengue Transmission in Vietnam. Am J Trop Med Hyg, 97 (1), pp. 146-150. | Citations: 1 (Scopus) | Show Abstract | Read more

Between 2010 and 2014, four chikungunya and two Zika virus infections were identified among 8,105 febrile children in southern Vietnam. Zika viruses were linked to French Polynesian strains, chikungunya to Cambodian strains. Against a backdrop of endemic dengue transmission, chikungunya and Zika present an additional arboviral disease burden in Vietnam.

Sengyee S, Saiprom N, Paksanont S, Limmathurotsakul D, Wuthiekanun V, Chantratita N. 2017. Susceptibility of Clinical Isolates of Burkholderia pseudomallei to a Lipid A Biosynthesis Inhibitor. Am J Trop Med Hyg, 97 (1), pp. 62-67. | Show Abstract | Read more

Burkholderia pseudomallei is the causative agent of melioidosis, a serious infection associated with high mortality and relapse. Current antimicrobial therapy using ceftazidime (CAZ) is often ineffective. Inhibitors of LpxC, the enzyme responsible for lipid A biosynthesis, have potential antimicrobial activity against several Gram-negative bacteria in vivo, but their activity against B. pseudomallei is unclear. Herein, we investigated the susceptibility of B. pseudomallei clinical isolates to LpxC-4, an LpxC inhibitor, and LpxC-4 in combination with CAZ. Time-kill assays for bactericidal activity were conducted for B. pseudomallei K96243, revealing growth inhibition and bactericidal effect at LpxC-4 concentrations of 2 μg/mL and 4 μg/mL, respectively. No significant synergistic effect was observed with the combination of LpxC-4 and CAZ. LpxC-4 susceptibility was tested on three groups of clinical isolates:1) CAZ- and trimethoprim-sulfamethoxazole (SXT)-susceptible (N = 71), 2) CAZ-resistant (N = 14), and 3) SXT-resistant (N = 23) isolates, by broth microdilution. The minimum concentration of LpxC-4 required to inhibit the growth of 90% of organisms was 2 μg/mL for all isolates. The median minimum inhibitory concentration of both the CAZ/SXT-susceptible and CAZ-resistant groups was 1 μg/mL (interquartile range [IQR] = 1-2 μg/mL), compared with 2 μg/mL (IQR = 2-4 μg/mL) for the SXT-resistant group. Cell morphology was observed after drug exposure by immunofluorescent staining, and a change from rod-shaped to cell wall-defective spherical cells was observed in surviving bacteria. LpxC-4 is a potent bactericidal agent against B. pseudomallei and warrants further testing as a new antibiotic to treat melioidosis.

Paredes R, Tzou PL, van Zyl G, Barrow G, Camacho R, Carmona S, Grant PM, Gupta RK, Hamers RL, Harrigan PR et al. 2017. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation. PLoS One, 12 (7), pp. e0181357. | Show Abstract | Read more

INTRODUCTION: HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. METHODS: An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs). RESULTS: There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required. CONCLUSIONS: The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

Molloy SF, Chiller T, Greene GS, Burry J, Govender NP, Kanyama C, Mfinanga S, Lesikari S, Mapoure YN, Kouanfack C et al. 2017. Cryptococcal meningitis: A neglected NTD? PLoS Negl Trop Dis, 11 (6), pp. e0005575. | Read more

Campbell JI, Lan NPH, Phuong PM, Chau LB, Trung Pham Duc, Guzmán-Verri C, Ruiz-Villalobos N, Minh TPT, Muñoz Álvaro PM, Moreno E et al. 2017. Human Brucella melitensis infections in southern Vietnam. Clin Microbiol Infect, 23 (11), pp. 788-790. | Read more

Yacoub S, Lam PK, Huynh TT, Nguyen Ho HH, Dong Thi HT, Van NT, Lien LT, Ha QNT, Le DHT, Mongkolspaya J et al. 2017. Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study. Clin Infect Dis, 65 (9), pp. 1453-1461. | Show Abstract | Read more

Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P < .001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P = .012). RHI correlated negatively with arginase-1 and positively with l-arginine (P = .001). Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.

Teparrukkul P, Kongkasame W, Chitsaeng S, Wongsuwan G, Wuthiekanun V, Peacock SJ, Limmathurotsakul D. 2017. Gastrointestinal tract involvement in melioidosis. Trans R Soc Trop Med Hyg, 111 (4), pp. 185-187. | Show Abstract | Read more

Background: Little is known about the involvement of the human gut in carriage and disease associated with Burkholderia pseudomallei, the cause of melioidosis. Methods: A hospital-based study was conducted in Northeast Thailand to culture stools or rectal swabs from patients with melioidosis, stools from controls with non-infectious diseases, and gastric biopsies from patients undergoing routine endoscopic investigation. Results and Conclusion: B. pseudomallei was isolated from 9/83 (11%) stools and 9/58 (16%) rectal swabs from 141 patients with melioidosis. All stools from 244 control patients and 799 gastric biopsies from 395 patients with no evidence of melioidosis were culture negative for B. pseudomallei. It is not uncommon for melioidosis patients to shed B. pseudomallei in stool. Colonization of the gut of individuals without signs and symptoms of melioidosis may be rare.

Amirian P, van Loggerenberg F, Lang T, Thomas A, Peeling R, Basiri A, Goodman SN. 2017. Using big data analytics to extract disease surveillance information from point of care diagnostic machines PERVASIVE AND MOBILE COMPUTING, 42 pp. 470-486. | Show Abstract | Read more

© 2017 Elsevier B.V. This paper explains a novel approach for knowledge discovery from data generated by Point of Care (POC) devices. A very important element of this type of knowledge extraction is that the POC generated data would never be identifiable, thereby protecting the rights and the anonymity of the individual, whilst still allowing for vital population-level evidence to be obtained. This paper also reveals a real-world implementation of the novel approach in a big data analytics system. Using Internet of Things (IoT) enabled POC devices and the big data analytics system, the data can be collected, stored, and analyzed in batch and real-time modes to provide a detailed picture of a healthcare system as well to identify high-risk populations and their locations. In addition, the system offers benefits to national health authorities in forms of optimized resource allocation (from allocating consumables to finding the best location for new labs) thus supports efficient and timely decision-making processes.

Sigfrid L, Reusken C, Eckerle I, Nussenblatt V, Lipworth S, Messina J, Kraemer M, Ergonul O, Papa A, Koopmans M, Horby P. 2017. Preparing clinicians for (re-)emerging arbovirus infectious diseases in Europe. Clin Microbiol Infect, | Show Abstract | Read more

BACKGROUND: Arthropod-borne virus (Arbovirus) infections are considered an emerging threat for Europe, with an increase in cases in recent decades. The increase in global travel and trade has contributed to the introduction of vectors and viruses into new geographical areas. Tropical arboviruses such as dengue and chikungunya have re-emerged causing local, sporadic outbreaks ignited by travel-imported cases. The recent Zika virus outbreak in the Americas highlighted a need to strengthen preparedness for (re-)emerging arbovirus infections globally. AIMS: To strengthen preparedness for the early identification of (re-)emerging arbovirus outbreaks in Europe and highlight areas for research. SOURCES: An evidence review of published and grey literature together with consultations with European arbovirus experts. CONTENT: This paper presents an overview of endemic and travel-imported arboviruses of clinical significance in Europe. The overview includes syndromic presentation, risk factors for infection and risk of transmission as well as an update on treatments and vaccinations and surveillance notifications and reporting. The paper also presents predictive modelled risks of further geographical expansion of vectors and viruses. IMPLICATIONS: There are a range of arboviruses of clinical significance to Europe. There has been an increase in notifications of endemic and travel-imported arbovirus cases in recent years and an increased geographical range of vectors and viruses. The heterogeneity in surveillance reporting indicates a risk for the early identification of (re-)emerging outbreaks. The data presented show a need to strengthen preparedness for (re-)emerging arbovirus infections and a need for research into neglected arboviruses, risks of non-vector transmission and effective therapeutics and vaccinations.

Moore KA, Simpson JA, Wiladphaingern J, Min AM, Pimanpanarak M, Paw MK, Raksuansak J, Pukrittayakamee S, Fowkes FJI, White NJ et al. 2017. Influence of the number and timing of malaria episodes during pregnancy on prematurity and small-for-gestational-age in an area of low transmission. BMC Med, 15 (1), pp. 117. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Most evidence on the association between malaria in pregnancy and adverse pregnancy outcomes focuses on falciparum malaria detected at birth. We assessed the association between the number and timing of falciparum and vivax malaria episodes during pregnancy on small-for-gestational-age (SGA) and preterm birth. METHODS: We analysed observational data collected from antenatal clinics on the Thailand-Myanmar border (1986-2015). We assessed the effects of the total number of malaria episodes in pregnancy on SGA and the effects of malaria in pregnancy on SGA, very preterm birth, and late preterm birth, by the gestational age at malaria detection and treatment using logistic regression models with time-dependent malaria variables (monthly intervals). World Health Organisation definitions of very preterm birth (≥28 and <32 weeks) and late preterm birth (≥32 and <37 weeks) and international SGA standards were used. RESULTS: Of 50,060 pregnant women followed, 8221 (16%) had malaria during their pregnancy. Of the 50,060 newborns, 10,005 (21%) were SGA, 540 (1%) were very preterm, and 4331 (9%) were late preterm. The rates of falciparum and vivax malaria were highest at 6 and 5 weeks' gestation, respectively. The odds of SGA increased linearly by 1.13-fold (95% confidence interval: 1.09, 1.17) and 1.27-fold (1.21, 1.33) per episode of falciparum and vivax malaria, respectively. Falciparum malaria at any gestation period after 12-16 weeks and vivax malaria after 20-24 weeks were associated with SGA (falciparum odds ratio, OR range: 1.15-1.63 [p range: <0.001-0.094]; vivax OR range: 1.12-1.54 [p range: <0.001-0.138]). Falciparum malaria at any gestation period after 24-28 weeks was associated with either very or late preterm birth (OR range: 1.44-2.53; p range: <0.001-0.001). Vivax malaria at 24-28 weeks was associated with very preterm birth (OR: 1.79 [1.11, 2.90]), and vivax malaria at 28-32 weeks was associated with late preterm birth (OR: 1.23 [1.01, 1.50]). Many of these associations held for asymptomatic malaria. CONCLUSIONS: Protection against malaria should be started as early as possible in pregnancy. Malaria control and elimination efforts in the general population can avert the adverse consequences associated with treated asymptomatic malaria in pregnancy.

Inzaule SC, Hamers RL, Mukui I, Were K, Owiti P, Kwaro D, Rinke de Wit TF, Zeh C. 2017. Emergence of untreatable, multidrug-resistant HIV-1 in patients failing second-line therapy in Kenya AIDS, 31 (10), pp. 1495-1498. | Show Abstract | Read more

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. We performed a countrywide assessment of HIV drug resistance among 123 patients with virological failure on second-line antiretroviral therapy (ART) in Kenya. The percentage of patients harbouring intermediate-to-high-level resistance was 27% for lopinavir-ritonavir, 24% for atazanavir-ritonavir and 7% for darunavir-ritonavir, and 25% had complete loss of activity to all available first and second-line drugs. Overall, one in four patients failing second-line ART have completely exhausted available antiretrovirals in Kenya, highlighting the need for increased access to third-line drugs.

Ongas M, Standing J, Ogutu B, Waichungo J, Berkley JA, Kipper K. 2017. Liquid chromatography–tandem mass spectrometry for the simultaneous quantitation of ceftriaxone, metronidazole and hydroxymetronidazole in plasma from seriously ill, severely malnourished children Wellcome Open Research, 2 pp. 43-43. | Read more

Leffler EM, Band G, Busby GBJ, Kivinen K, Le QS, Clarke GM, Bojang KA, Conway DJ, Jallow M, Sisay-Joof F et al. 2017. Resistance to malaria through structural variation of red blood cell invasion receptors SCIENCE, 356 (6343), | Citations: 2 (Web of Science Lite) | Read more

Le T, Kinh NV, Cuc NTK, Tung NLN, Lam NT, Thuy PTT, Cuong DD, Phuc PTH, Vinh VH, Hanh DTH et al. 2017. A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis. N Engl J Med, 376 (24), pp. 2329-2340. | Citations: 5 (Scopus) | Show Abstract | Read more

BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS: Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

Driscoll AJ, Karron RA, Morpeth SC, Bhat N, Levine OS, Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Howie SRC et al. 2017. Standardization of Laboratory Methods for the PERCH Study. Clin Infect Dis, 64 (suppl_3), pp. S245-S252. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

The Pneumonia Etiology Research for Child Health study was conducted across 7 diverse research sites and relied on standardized clinical and laboratory methods for the accurate and meaningful interpretation of pneumonia etiology data. Blood, respiratory specimens, and urine were collected from children aged 1-59 months hospitalized with severe or very severe pneumonia and community controls of the same age without severe pneumonia and were tested with an extensive array of laboratory diagnostic tests. A standardized testing algorithm and standard operating procedures were applied across all study sites. Site laboratories received uniform training, equipment, and reagents for core testing methods. Standardization was further assured by routine teleconferences, in-person meetings, site monitoring visits, and internal and external quality assurance testing. Targeted confirmatory testing and testing by specialized assays were done at a central reference laboratory.

Day JN, Qihui S, Thanh LT, Trieu PH, Van AD, Thu NH, Chau TTH, Lan NPH, Chau NVV, Ashton PM et al. 2017. Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam. PLoS Negl Trop Dis, 11 (6), pp. e0005628. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher's exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109 cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.

Fancourt N, Deloria Knoll M, Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Howie SRC, Kotloff KL, Levine OS, Madhi SA et al. 2017. Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study. Clin Infect Dis, 64 (suppl_3), pp. S262-S270. | Show Abstract | Read more

Background.: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. Methods.: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. Results.: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. Conclusions.: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.

Crawley J, Prosperi C, Baggett HC, Brooks WA, Deloria Knoll M, Hammitt LL, Howie SRC, Kotloff KL, Levine OS, Madhi SA et al. 2017. Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites. Clin Infect Dis, 64 (suppl_3), pp. S228-S237. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Background.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. Results.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. Conclusions.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Ny NTH, Anh NT, Hang VTT, Nguyet LA, Thanh TT, Ha DQ, Minh NNQ, Ha DLA, McBride A, Tuan HM et al. 2017. Enterovirus D68 in Viet Nam (2009-2015). Wellcome Open Res, 2 pp. 41. | Show Abstract | Read more

BACKGROUND: Since 1962, enterovirus D68 (EV-D68) has been implicated in multiple outbreaks and sporadic cases of respiratory infection worldwide, but especially in the USA and Europe with an increasing frequency between 2010 and 2014. We describe the detection, associated clinical features and molecular characterization of EV-D68 in central and southern Viet Nam between 2009 and 2015. METHODS: Enterovirus/rhinovirus PCR positive respiratory or CSF samples taken from children and adults with respiratory/central nervous system infections in Viet Nam were tested by an EV-D68 specific PCR. The included samples were derived from 3 different observational studies conducted at referral hospitals across central and southern Viet Nam between 2009 and 2015. Whole-genome sequencing was carried out using a MiSeq based approach. Phylogenetic reconstruction and estimation of evolutionary rate and recombination were carried out in BEAST and Recombination Detection Program, respectively. RESULTS: EV-D68 was detected in 21/625 (3.4%) enterovirus/rhinovirus PCR positive respiratory samples but in none of the 15 CSF. All the EV-D68 patients were young children (age range: 11.8 - 24.5 months) and had moderate respiratory infections. Phylogenetic analysis suggested that the Vietnamese sequences clustered with those from Asian countries, of which 9 fell in the B1 clade, and the remaining sequence was identified within the A2 clade. One intra sub-clade recombination event was detected, representing the second reported recombination within EV-D68. The evolutionary rate of EV-D68 was estimated to be 5.12E -3 substitutions/site/year. Phylogenetic analysis indicated that the virus was imported into Viet Nam in 2008. CONCLUSIONS: We have demonstrated for the first time EV-D68 has been circulating at low levels in Viet Nam since 2008, associated with moderate acute respiratory infection in children. EV-D68 in Viet Nam is most closely related to Asian viruses, and clusters separately from recent US and European viruses that were suggested to be associated with acute flaccid paralysis.

Dijkstra M, de Bree GJ, Stolte IG, Davidovich U, Sanders EJ, Prins M, Schim van der Loeff MF. 2017. Development and validation of a risk score to assist screening for acute HIV-1 infection among men who have sex with men. BMC Infect Dis, 17 (1), pp. 425. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Early treatment of acute HIV-1 infection (AHI) is beneficial for patients and could reduce onward transmission. However, guidelines on whom to test for AHI with HIV-1 RNA testing are lacking. METHODS: A risk score for possible AHI based on literature and expert opinion - including symptoms associated with AHI and early HIV-1 - was evaluated using data from the Amsterdam Cohort Studies among men who have sex with men (MSM). Subsequently, we optimized the risk score by constructing two multivariable logistic regression models: one including only symptoms and one combining symptoms with known risk factors for HIV-1 seroconversion, using generalized estimating equations. Several risk scores were generated from these models and the optimal risk score was validated using data from the Multicenter AIDS Cohort Study. RESULTS: Using data from 1562 MSM with 175 HIV-1 seroconversion visits and 17,271 seronegative visits in the Amsterdam Cohort Studies, the optimal risk score included four symptoms (oral thrush, fever, lymphadenopathy, weight loss) and three risk factors (self-reported gonorrhea, receptive condomless anal intercourse, more than five sexual partners, all in the preceding six months) and yielded an AUC of 0.82. Sensitivity was 76.3% and specificity 76.3%. Validation in the Multicenter AIDS Cohort Study resulted in an AUC of 0.78, sensitivity of 56.2% and specificity of 88.8%. CONCLUSIONS: The optimal risk score had good overall performance in the Amsterdam Cohort Studies and performed comparable (but showed lower sensitivity) in the validation study. Screening for AHI with four symptoms and three risk factors would increase the efficiency of AHI testing and potentially enhance early diagnosis and immediate treatment.

Carrique-Mas JJ, Rushton J. 2017. Integrated Interventions to Tackle Antimicrobial Usage in Animal Production Systems: The ViParc Project in Vietnam Frontiers in Microbiology, 8 (JUN), | Show Abstract | Read more

© 2017 Carrique-Mas and Rushton. Antimicrobial usage and antimicrobial resistance (AMR) in animal production is now recognized to be an important contributor to the global problem of AMR. Initiatives to curb indiscriminate antimicrobial use in animal production are currently being discussed in many low- and middle-income countries. Well-designed, scientifically sound interventions aimed to tackle excessive antimicrobial usage should provide scientists and policy makers with evidence of the highest quality to guide changes in policy and to formulate better targeted research initiatives. However, since large-scale interventions are costly, they require careful planning in order not to waste valuable resources. Here, we describe the components of the ViParc project (, one of the first large-scale interventions of its kind to tackle excessive antimicrobial usage in Southeast Asian animal production systems. The project has been formulated as a "randomized before-and-after controlled study" targeting small-scale poultry farms in the Mekong Delta region of Vietnam. It aims to provide farmers with a locally-adapted veterinary support service to help them reduce their reliance on antimicrobials. ViParc has been developed in the backdrop of efforts by the Government of Vietnam to develop a National Action Plan to reduce Antimicrobials in Livestock and Aquaculture. Crucially, the project integrates socio-economic analyses that will provide insights into the drivers of antimicrobial usage, as well as an assessment of the cost-effectiveness of the proposed intervention. Information generated from ViParc should help the Government of Vietnam refine its policies to curb excessive antimicrobial usage in poultry production, while lessons from ViParc will help tackle excessive antimicrobial usage in other productions systems in Vietnam and in the broader Southeast Asian region.

Whitehorn J, Kien DTH, Quyen NTH, Wills B, Van Vinh Chau N, Tam DTH, Tuan NM, Jaenisch T, Hibberd M, Khor CC, Simmons CP. 2017. Genetic variants of MICB and PLCE1 and associations with the laboratory features of dengue. BMC Infect Dis, 17 (1), pp. 412. | Show Abstract | Read more

BACKGROUND: A previous genome-wide association study identified 2 susceptibility loci for severe dengue at MICB rs3132468 and PLCE1 rs3740360 and further work showed these mutations to be also associated with less severe clinical presentations. The aim of this study was to determine if these specific loci were associated with laboratory features of dengue that correlate with clinical severity with the aim of elucidating the functional basis of these genetic variants. METHODS: This was a case-only analysis of laboratory-confirmed dengue patients obtained from 2 prospective cohort studies and 1 randomised clinical trial in Vietnam (Trial registration: ISRCTN ISRCTN03147572. Registered 24th July 2012). 2742 dengue cases were successfully genotyped at MICB rs3132468 and PLCE1 rs3740360. Laboratory variables were compared between genotypes and stratified by DENV serotype. RESULTS: The analysis showed no association between MICB and PLCE1 genotype and early viraemia level, platelet nadir, white cell count nadir, or maximum haematocrit in both overall analysis and in analysis stratified by serotype. DISCUSSION: The lack of an association between genotype and viremia level may reflect the sampling procedures within the included studies. The study findings mean that the functional basis of these mutations remains unclear. TRIAL REGISTRATION: ISRCTN ISRCTN03147572 . Registered 24th July 2012.

Grigg MJ, Cox J, William T, Jelip J, Fornace KM, Brock PM, von Seidlein L, Barber BE, Anstey NM, Yeo TW, Drakeley CJ. 2017. Individual-level factors associated with the risk of acquiring humanPlasmodium knowlesimalaria in Malaysia: a case-control study. Lancet Planet Health, 1 (3), pp. e97-e104. | Show Abstract | Read more

BACKGROUND: The emergence of human malaria due to the monkey parasitePlasmodium knowlesithreatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reportedP knowlesicases, but the role of individual-level factors is unclear. To address this knowledge gap we assessed human and environmental factors associated with zoonotic knowlesi malaria risk. METHODS: We did this population-based case-control study over a 2 year period in the state of Sabah in Malaysia. We enrolled cases with microscopy-positive, PCR-confirmed malaria who presented to two primary referral hospitals serving the adjacent districts of Kudat and Kota Marudu. We randomly selected three malaria-negative community controls per case, who were matched by village within 2 weeks of case detection. We obtained questionnaire data on demographics, behaviour, and residential malaria risk factors, and we also assessed glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. We used conditional logistic regression models to evaluate exposure risk betweenP knowlesicases and controls, and betweenP knowlesiand human-onlyPlasmodiumspp malaria cases. FINDINGS: From Dec 5, 2012, to Jan 30, 2015, we screened 414 patients and subsequently enrolled 229 cases withP knowlesimalaria mono-infection and 91 cases with otherPlasmodiumspp infection. We enrolled 953 matched controls, including 683 matched toP knowlesicases and 270 matched to non-P knowlesicases. Age 15 years or older (adjusted odds ratio [aOR] 4·16, 95% CI 2·09-8·29, p<0·0001), male gender (4·20, 2·54-6·97, p<0·0001), plantation work (3·50, CI, 1·34-9·15, p=0·011), sleeping outside (3·61, 1·48-8·85, p=0·0049), travel (2·48, 1·45-4·23, p=0·0010), being aware of the presence of monkeys in the past 4 weeks (3·35, 1·91-5·88, p<0·0001), and having open eaves or gaps in walls (2·18, 1·33-3·59, p=0·0021) were independently associated with increased risk of symptomaticP knowlesiinfection. Farming occupation (aOR 1·89, 95% CI 1·07-3·35, p=0·028), clearing vegetation (1·89, 1·11-3·22, p=0·020), and having long grass around the house (2·08, 1·25-3·46, p=0·0048) increased risk forP knowlesiinfection but not otherPlasmodiumspp infection. G6PD deficiency seemed to be protective againstP knowlesi(aOR 0·20, 95% CI 0·04-0·96, p=0·045), as did residual insecticide spraying of household walls (0·52, 0·31-0·87, p=0·014), with the presence of young sparse forest (0·35, 0·20-0·63, p=00040) and rice paddy around the house (0·16, 0·03-0·78, 0·023) also associated with decreased risk. INTERPRETATION: Adult men working in agricultural areas were at highest risk of knowlesi malaria, although peri-domestic transmission also occurrs. Human behavioural factors associated withP knowlesitransmission could be targeted in future public health interventions. FUNDING: United Kingdom Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council.

Manivanh L, Pierret A, Rattanavong S, Kounnavongsa O, Buisson Y, Elliott I, Maeght J-L, Xayyathip K, Silisouk J, Vongsouvath M et al. 2017. Burkholderia pseudomallei in a lowland rice paddy: seasonal changes and influence of soil depth and physico-chemical properties. Sci Rep, 7 (1), pp. 3031. | Show Abstract | Read more

Melioidosis, a severe infection with the environmental bacterium Burkholderia pseudomallei, is being recognised increasingly frequently. What determines its uneven distribution within endemic areas is poorly understood. We cultured soil from a rice field in Laos for B. pseudomallei at different depths on 4 occasions over a 13-month period. We also measured physical and chemical parameters in order to identify associated characteristics. Overall, 195 of 653 samples (29.7%) yielded B. pseudomallei. A higher prevalence of B. pseudomallei was found at soil depths greater than the 30 cm currently recommended for B. pseudomallei environmental sampling. B. pseudomallei was associated with a high soil water content and low total nitrogen, carbon and organic matter content. Our results suggested that a sampling grid of 25 five metre square quadrats (i.e. 25 × 25 m) should be sufficient to detect B. pseudomallei at a given location if samples are taken at a soil depth of at least 60 cm. However, culture of B. pseudomallei in environmental samples is difficult and liable to variation. Future studies should both rely on molecular approaches and address the micro-heterogeneity of soil when investigating physico-chemical associations with the presence of B. pseudomallei.

Bancone G, Malleret B, Suwanarusk R, Chowwiwat N, Chu CS, McGready R, Rénia L, Nosten F, Russell B. 2017. Asian G6PD-Mahidol Reticulocytes Sustain Normal Plasmodium Vivax Development. J Infect Dis, 216 (2), pp. 263-266. | Show Abstract | Read more

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder in humans and appears to be protective against falciparum severe malaria. Controversially, it is also thought that Plasmodium vivax has driven the recent selection of G6PD alleles. We use an experimental approach to determine whether G6PD-MahidolG487A variant, a widespread cause of severe G6PD deficiency in Southeast Asia, provides a barrier against vivax malaria. Our results show that the immature reticulocytes (CD71+) targeted by P. vivax invasion are enzymatically normal, even in hemizygous G6PD-Mahidol G487A mutants; thus, allowing the normal growth, development, and high parasite density in severely deficient samples.

Mohanty S, Benjamin LA, Majhi M, Panda P, Kampondeni S, Sahu PK, Mohanty A, Mahanta KC, Pattnaik R, Mohanty RR et al. 2017. Magnetic Resonance Imaging of Cerebral Malaria Patients Reveals Distinct Pathogenetic Processes in Different Parts of the Brain. mSphere, 2 (3), pp. e00193-17-e00193-17. | Citations: 5 (Scopus) | Show Abstract | Read more

The mechanisms underlying the rapidly reversible brain swelling described in patients with cerebral malaria (CM) are unknown. Using a 1.5-Tesla (T) magnetic resonance imaging (MRI) scanner, we undertook an observational study in Rourkela, India, of 11 Indian patients hospitalized with CM and increased brain volume. Among the 11 cases, there were 5 adults and 6 children. All patients had reduced consciousness and various degrees of cortical swelling at baseline. The latter was predominately posterior in distribution. The findings on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps were consistent with vasogenic edema in all cases. Reversibility after 48 to 72 h was observed in >90% of cases. DWI/ADC mismatch suggested the additional presence of cytotoxic edema in the basal nuclei of 5 patients; all of these had perfusion parameters consistent with vascular engorgement and not with ischemic infarcts. Our results suggest that an impairment of the blood-brain barrier is responsible for the brain swelling in CM. In 5 cases, vasogenic edema occurred in conjunction with changes in the basal nuclei consistent with venous congestion, likely to be caused by the sequestration of Plasmodium falciparum-infected erythrocytes. While both mechanisms have been individually postulated to play an important role in the development of CM, this is the first demonstration of their concurrent involvement in different parts of the brain. The clinical and radiological characteristics observed in the majority of our patients are consistent with posterior reversible encephalopathy syndrome (PRES), and we show for the first time a high frequency of PRES in the context of CM. IMPORTANCE The pathophysiology and molecular mechanisms underlying cerebral malaria (CM) are still poorly understood. Recent neuroimaging studies demonstrated that brain swelling is a common feature in CM and a major contributor to death in pediatric patients. Consequently, determining the precise mechanisms responsible for this swelling could open new adjunct therapeutic avenues in CM patients. Using an MRI scanner with a higher resolution than the ones used in previous reports, we identified two distinct origins of brain swelling in both adult and pediatric patients from India, occurring in distinct parts of the brain. Our results support the hypothesis that both endothelial dysfunction and microvascular obstruction by Plasmodium falciparum-infected erythrocytes make independent contributions to the pathogenesis of CM, providing opportunities for novel therapeutic interventions.

Flasche S, Ojal J, Le Polain de Waroux O, Otiende M, O'Brien KL, Kiti M, Nokes DJ, Edmunds WJ, Scott JAG. 2017. Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya. BMC Med, 15 (1), pp. 113. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: The World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low- and middle-income countries, to quantify the optimal breadth of such catch-up campaigns. METHODS: In Kilifi, Kenya, PCV10 was introduced in 2011 using the three-dose Expanded Programme on Immunisation infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data, including nasopharyngeal carriage and invasive pneumococcal disease (IPD), to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting and to estimate the likely impact of alternative campaigns and their dose efficiency. RESULTS: We estimated that, within 10 years of introduction, the catch-up campaign among children <5 years old prevents an additional 65 (48-84) IPD cases across age groups, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121-193) IPD cases and used 1321 (1058-1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection, and hence its dose efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732-1184) doses per IPD case averted. We estimated that a two-dose catch-up among children <1 year old uses an additional 910 (732-1184) doses per additional IPD case averted. Furthermore, by extending a single-dose catch-up campaign to children aged 1 to <2 years and subsequently to those aged 2 to <5 years, the campaign uses an additional 412 (296-606) and 543 (403-763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants. CONCLUSIONS: We find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease.

Kamuya DM, Molyneux CS, Theobald S. 2017. Gendered negotiations for research participation in community-based studies: implications for health research policy and practice. BMJ Glob Health, 2 (2), pp. e000320. | Show Abstract | Read more

There is a growing literature documenting the complex realities of consent processes in the field, and the negotiations and ethical dilemmas involved. Much has also been written about how gender and power shape household decision-making processes. However, these bodies of literature have rarely been brought together to inform research theory and practice in low-income settings. In this paper, qualitative research (observation, focus group discussions and interviews) were used alongside large clinical community-based studies conducted on the Kenyan Coast to explore how gender and power relations within households and communities and between fieldworkers and communities shape consent processes and interactions. This exploration is embedded in relevant literature and the implications for community-based health research policy and practice are considered. Across diverse forms of households, we observed significant consultation on whether or not to participate in research. Although men are typically described as household decision-makers, in practice, decision-making processes are often far more nuanced, with many women using their agency to control, sometimes subtly, the decisions made. Where decisions are made without adequately consulting women, many find strategies to exercise their choice, in ways that safeguard important relationships within households in the longer term. We also found that the gender of field staff who typically conduct research activities in the field, including consent processes, can influence household dynamics and decision-making processes with important implications for the science and ethics of research. It is essential that frontline field staff and their supervisors are aware of the complex and gendered realities of consent processes at household level, and their implications, and that they develop appropriate context-informed approaches that support ethical practice.

Thu AM, Phyo AP, Landier J, Parker DM, Nosten FH. 2017. Combating multidrug-resistant Plasmodium falciparum malaria. FEBS J, 284 (16), pp. 2569-2578. | Citations: 2 (Scopus) | Show Abstract | Read more

Over the past 50 years, Plasmodium falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine and mefloquine. More recently, resistance to the artemisinin derivatives and the resulting failure of artemisinin-based combination therapy (ACT) are threatening all major gains made in malaria control. Each time resistance has developed progressively, with delayed clearance of parasites first emerging only in a few regions, increasing in prevalence and geographic range, and then ultimately resulting in the complete failure of that antimalarial. Drawing from this repeated historical chain of events, this article presents context-specific approaches for combating drug-resistant P. falciparum malaria. The approaches begin with a context of drug-sensitive parasites and focus on the prevention of the emergence of drug resistance. Next, the approaches address a scenario in which resistance has emerged and is increasing in prevalence and geographic extent, with interventions focused on disrupting transmission through vector control, early diagnosis and treatment, and the use of new combination therapies. Elimination is also presented as an approach for addressing the imminent failure of all available antimalarials. The final drug resistance context presented is one in which all available antimalarials have failed; leaving only personal protection and the use of new antimalarials (or new combinations of antimalarials) as a viable strategy for dealing with complete resistance. All effective strategies and contexts require a multipronged, holistic approach.

Boonyuen U, Chamchoy K, Swangsri T, Junkree T, Day NPJ, White NJ, Imwong M. 2017. A trade off between catalytic activity and protein stability determines the clinical manifestations of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Int J Biol Macromol, 104 (Pt A), pp. 145-156. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common polymorphism and enzymopathy in humans, affecting approximately 400 million people worldwide. It is responsible for various clinical manifestations, including favism, hemolytic anemia, chronic non-spherocytic hemolytic anemia, spontaneous abortion, and neonatal hyperbilirubinemia. Understanding the molecular mechanisms underlying the severity of G6PD deficiency is of great importance but that of many G6PD variants are still unknown. In this study, we report the construction, expression, purification, and biochemical characterization in terms of kinetic properties and stability of five clinical G6PD variants-G6PD Bangkok, G6PD Bangkok noi, G6PD Songklanagarind, G6PD Canton+Bangkok noi, and G6PD Union+Viangchan. G6PD Bangkok and G6PD Canton+Bangkok noi showed a complete loss of catalytic activity and moderate reduction in thermal stability when compared with the native G6PD. G6PD Bangkok noi and G6PD Union+Viangchan showed a significant reduction in catalytic efficiency, whereas G6PD Songklanagarind showed a catalytic activity comparable to the wild-type enzyme. The Union+Viangchan mutation showed a remarkable effect on the global stability of the enzyme. In addition, our results indicate that the location of mutations in G6PD variants affects their catalytic activity, stability, and structure. Hence, our results provide a molecular explanation for clinical manifestations observed in individuals with G6PD deficiency.

McGregor K, Myat Min A, Karunkonkowit N, Keereechareon S, Tyrosvoutis ME, Tun NW, Rijken MJ, Hoogenboom G, Boel M, Chotivanich K et al. 2017. Obstetric ultrasound aids prompt referral of gestational trophoblastic disease in marginalized populations on the Thailand-Myanmar border. Glob Health Action, 10 (1), pp. 1296727. | Show Abstract | Read more

BACKGROUND: The use of obstetric ultrasound in the diagnosis of gestational trophoblastic disease (GTD) in high-income settings is well established, leading to prompt management and high survival rates. Evidence from low-income settings suggests ultrasound is essential in identifying complicated pregnancies, but with limited studies reviewing specific conditions including GTD. OBJECTIVE: The aim of this study is to review the role of ultrasound in diagnosis and management of GTD in a marginalized population on the Thailand-Myanmar border. Antenatal ultrasound became available in this rural setting in 2001 and care for women with GTD has been provided by Thailand public hospitals for 20 years. DESIGN: Retrospective record review. RESULTS: The incidence of GTD was 103 of 57,004 pregnancies in Karen and Burmese women on the Thailand-Myanmar border from 1993-2013. This equates to a rate of 1.8 (95% CI 1.5-2.2) per 1000 or 1 in 553 pregnancies. Of the 102 women with known outcomes, one (1.0%) died of haemorrhage at home. The median number of days between first antenatal clinic attendance and referral to hospital was reduced from 20 (IQR 5-35; range 1-155) to 2 (IQR 2-6; range 1-179) days (p = 0.002) after the introduction of ultrasound. The proportion of severe outcomes (death and total abdominal hysterectomy) was 25% (3/12) before ultrasound compared to 8.9% (8/90) with ultrasound (p = 0.119). A recurrence rate of 2.5% (2/80) was observed in the assessable population. The presence of malaria parasites in maternal blood was not associated with GTD. CONCLUSIONS: The rate of GTD in pregnancy in this population is comparable to rates previously reported within South-East Asia. Referral time for uterine evacuation was significantly shorter for those women who had an ultrasound. Ultrasound is an effective method to improve diagnosis of GTD in low-income settings and an effort to increase availability in marginalized populations is required.

Wang X, Jiang H, Wu P, Uyeki TM, Feng L, Lai S, Wang L, Huo X, Xu K, Chen E et al. 2017. Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis, 17 (8), pp. 822-832. | Citations: 21 (Scopus) | Show Abstract | Read more

BACKGROUND: The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016-17 prompted concerns that the epidemiology of the virus might have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016-17 epidemic compared with previous epidemics. METHODS: In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques. FINDINGS: Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory-confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013-14, 219 in 2014-15, 114 in 2015-16, and 447 in 2016-17. The 2016-17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016-17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015-16 and 2016-17 epidemics (63% [72 of 114] and 61% [274 of 447], respectively) were higher than those in the first three epidemics (39% [52 of 134], 55% [169 of 306], and 56% [122 of 219], respectively). The clinical severity of individuals admitted to hospital in the 2016-17 epidemic was similar to that in the previous epidemics. INTERPRETATION: Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus. FUNDING: The National Science Fund for Distinguished Young Scholars.

Haenssgen MJ, Ariana P. 2017. The Social Implications of Technology Diffusion: Uncovering the Unintended Consequences of People's Health-Related Mobile Phone Use in Rural India and China WORLD DEVELOPMENT, 94 pp. 286-304. | Citations: 2 (Scopus) | Show Abstract | Read more

© 2017 The Authors After three decades of mobile phone diffusion, thousands of mobile-phone-based health projects worldwide (“mHealth”), and hundreds of thousands of smartphone health applications, fundamental questions about the effect of phone diffusion on people's healthcare behavior continue to remain unanswered. This study investigated whether, in the absence of specific mHealth interventions, people make different healthcare decisions if they use mobile phones during an illness. Following mainstream narratives, we hypothesized that phone use during an illness (a) increases and (b) accelerates healthcare access. Our study was based on original survey data from 800 respondents in rural Rajasthan (India) and Gansu (China), sampled from the general adult population in 2014 in a three-stage stratified cluster random sampling design. We analyzed single- and multi-level logistic, Poisson, and negative binomial regression models with cluster-robust standard errors. Contrary to other research at the intersection of mobile phones and healthcare, we captured actual health-related mobile phone use during people's illnesses irrespective of whether they own a phone. Our analysis produced the first quantitative micro-evidence that patients’ personal mobile phone use is correlated with their healthcare decisions. Despite a positive association between phone use and healthcare access, health-related phone use was also linked to delayed access to public doctors and nurses. We considered theoretical explanations for the observed patterns by augmenting transaction cost and information deficit arguments with the prevailing health system configuration and with notions of heuristic decision-making during the healthcare-seeking process. Our study was a first step toward understanding the implications of mobile technology diffusion on health behavior in low- and middle-income countries in the absence of specific mHealth interventions. Future research will have to explore the causal relationships underlying these statistical associations. Such a link could potentially mean that development interventions aimed at improving access to healthcare continue to require conventional solutions to sustain healthcare equity.

Niehus R, Picot A, Oliveira NM, Mitri S, Foster KR. 2017. The evolution of siderophore production as a competitive trait. Evolution, 71 (6), pp. 1443-1455. | Citations: 8 (Scopus) | Show Abstract | Read more

Microbes have the potential to be highly cooperative organisms. The archetype of microbial cooperation is often considered to be the secretion of siderophores, molecules scavenging iron, where cooperation is threatened by "cheater" genotypes that use siderophores without making them. Here, we show that this view neglects a key piece of biology: siderophores are imported by specific receptors that constrain their use by competing strains. We study the effect of this specificity in an ecoevolutionary model, in which we vary siderophore sharing among strains, and compare fully shared siderophores with private siderophores. We show that privatizing siderophores fundamentally alters their evolution. Rather than a canonical cooperative good, siderophores become a competitive trait used to pillage iron from other strains. We also study the physiological regulation of siderophores using in silico long-term evolution. Although shared siderophores evolve to be downregulated in the presence of a competitor, as expected for a cooperative trait, privatized siderophores evolve to be upregulated. We evaluate these predictions using published experimental work, which suggests that some siderophores are upregulated in response to competition akin to competitive traits like antibiotics. Although siderophores can act as a cooperative good for single genotypes, we argue that their role in competition is fundamental to understanding their biology.

Thompson CN, Karkey A, Dongol S, Arjyal A, Wolbers M, Darton T, Farrar JJ, Thwaites GE, Dolecek C, Basnyat B, Baker S. 2017. Treatment Response in Enteric Fever in an Era of Increasing Antimicrobial Resistance: An Individual Patient Data Analysis of 2092 Participants Enrolled into 4 Randomized, Controlled Trials in Nepal. Clin Infect Dis, 64 (11), pp. 1522-1531. | Citations: 4 (Scopus) | Show Abstract | Read more

Background.: Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia. Methods.: Individual data from 2092 patients with enteric fever randomized into 4 trials in Kathmandu, Nepal, were pooled. All trials compared gatifloxacin with 1 of the following comparator drugs: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome. Results.: Overall, 855 (41%) patients had either S. Typhi (n = 581, 28%) or S. Paratyphi A (n = 274, 13%) cultured from blood. There were 139 (6.6%) treatment failures with 1 death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found that the minimum inhibitory concentrations (MICs) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005-2014), and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment. Conclusion.: The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones for enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.

Bhandari SS, Koirala P, Lohani S, Phuyal P, Basnyat B. 2017. Breathlessness at High Altitude: First Episode of Bronchoconstriction in an Otherwise Healthy Sojourner. High Alt Med Biol, 18 (2), pp. 179-181. | Show Abstract | Read more

Bhandari, Sanjeeb Sudarshan, Pranawa Koirala, Sadichhya Lohani, Pratibha Phuyal, and Buddha Basnyat. Breathlessness at high altitude: first episode of bronchoconstriction in an otherwise healthy sojourner. High Alt Med Biol.. 18:179-181, 2017-High-altitude illness is a collective term for less severe acute mountain sickness and more severe high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema, which we can experience while traveling to high altitude. These get better when we get down to the lower altitudes. People with many comorbidities also have been traveling to high altitudes from the dawn of civilization. Obstructive airway diseases can be confused with HAPE at high altitude. Asthma is one of those obstructive pulmonary diseases, but it is shown to get better with travel to the altitudes higher than the residing altitude. We present a case of 55-year-old nonsmoker, athletic, female, a lowland resident who developed difficulty breathing for the first time at high altitude. She did not get better with the descent to lower altitude and timely intake of acetazolamide. Her pulmonary function test showed obstructive airway pattern, which got better with salbutamol/ipratropium nebulization and oxygen.

Kayastha GK, Ranjitkar N, Gurung R, Kc RK, Karki S, Shrestha R, Thapa RK, Rajbhandari P, Poudyal B, Acharya P et al. 2017. Treating Philadelphia chromosome/BCR-ABL1 positive patients with Glivec (Imatinib mesylate): 10 years' experience at Patan Hospital, Nepal. Br J Haematol, 177 (6), pp. 991-999. | Show Abstract | Read more

The Glivec International Patient Assistance Programme makes Glivec (Imatinib mesylate) available to Philadelphia chromosome/BCR-ABL1 positive patients with chronic myeloid leukaemia (CML) in Lower and Middle Income Countries (LMIC). We have established a large cohort of 211 CML patients who are eligible for Imatinib, in Kathmandu, Nepal. Thirty-one patients were lost to follow-up. We report on 180 CML patients with a median age of 38 years (range 9-81). Of these 180 patients, 162 underwent cytogenetic testing and 110 were investigated by reverse transcription polymerase chain reaction. One hundred and thirty-nine of the 180 patients (77·2%) had at least one optimal response. Taken together, our cohort has a 95% overall survival rate and 78% of the patients were still taking Glivec at a median time of 48·8 months (range 3-140 months). The number of patients who actually failed therapy, as defined by the LeukaemiaNet 2013 criteria, was 39 (21·7%). While our cohort has some differences with those in North America or Europe, we have shown Glivec is effective in inducing an optimal response in our patients in Nepal and that it is possible to deliver a clinical service for CML patients using tyrosine kinase inhibitors in resource-poor settings.

Kayastha GK, Ranjitkar N, Gurung R, Kc RK, Karki S, Shrestha R, Rajbhandari P, Thapa RK, Poudyal B, Acharya P et al. 2017. The use of Imatinib resistance mutation analysis to direct therapy in Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia patients failing Imatinib treatment, in Patan Hospital, Nepal. Br J Haematol, 177 (6), pp. 1000-1007. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia (CML) can be successfully treated with Glivec (Imatinib), which is available free of cost through the Glivec International Patient Assistance programme (GIPAP) to patients with proven CML without means to pay for the drug. We review the acquired mutations in the tyrosine kinase encoded by the BCR-ABL1 gene underlying Glivec failure or resistance in a cohort of 388 imatinib-treated CML patients (149 Female and 239 male) registered between February 2003 and June 2016 in Nepal. Forty-five patients (11 female 34 male) were studied; 18 different BCR-ABL1 mutations were seen in 33 patients. P-loop mutation, Kinase domain and A-loop mutations were seen in 9, 16 and 4 patients respectively. Other mutations were seen in five patients. A T315I mutation was the most common mutation, followed by F359V and M244V. Sixteen mutations showed intermediate activity to complete resistance to Glivec. Among the 45 patients evaluated for BCR-ABL1 mutations, 4 were lost to follow-up, 14 died and 27 are still alive. Among the surviving patients, 16 are receiving Nilotinib, 5 Dasatinib and 3 Ponatinib, while 3 patients were referred to India, one of who received allogenic bone marrow transplantation. Understanding the spectrum of further acquired mutations in BCR-ABL1 may help to choose more specific targeted tyrosine kinase inhibitors that can be provided by GIPAP.

Verani JR, Baqui AH, Broome CV, Cherian T, Cohen C, Farrar JL, Feikin DR, Groome MJ, Hajjeh RA, Johnson HL et al. 2017. Case-control vaccine effectiveness studies: Data collection, analysis and reporting results. Vaccine, 35 (25), pp. 3303-3308. | Show Abstract | Read more

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a 'real world' context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies.

Leffler EM, Band G, Busby GBJ, Kivinen K, Le QS, Clarke GM, Bojang KA, Conway DJ, Jallow M, Sisay-Joof F et al. 2017. Resistance to malaria through structural variation of red blood cell invasion receptors. Science, 356 (6343), pp. eaam6393-eaam6393. | Citations: 7 (Scopus) | Show Abstract | Read more

The malaria parasitePlasmodium falciparuminvades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genesGYPAandGYPBWe find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss ofGYPBand gain of twoGYPB-Ahybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.

Carrara VI, Stuetz W, Lee SJ, Sriprawat K, Po B, Hanboonkunupakarn B, Nosten FH, McGready R. 2017. Longer exposure to a new refugee food ration is associated with reduced prevalence of small for gestational age: results from 2 cross-sectional surveys on the Thailand-Myanmar border. Am J Clin Nutr, 105 (6), pp. 1382-1390. | Show Abstract | Read more

Background: Despite the high risk of compromised nutrition, evidence of the effect of refugee rations on fetal growth is limited. A new ration containing micronutrient-fortified flour without increased caloric content of the general food basket was introduced to the Maela refugee camp in Thailand, July 2004.Objective: The effect of the length of gestational exposure of the new ration on fetal growth was compared with birth outcomes [small for gestational age (SGA), preterm birth (PTB)].Design: In an observational study in 987 newborns from 1048 prospectively followed antenatal clinic (ANC) attendees enrolled in 2 cross-sectional surveys, exposure was categorized in 2004 according to gestation at the time of commencing the new ration and in 2006 as comprehensive (preconception and pregnancy). In both surveys, the pregnancy-specific ration and vitamin supplements were routine.Results: In 2004, the proportions of SGA decreased with longer exposure to the new ration: no exposure during pregnancy (27.7%; n = 13 of 47) and exposure in the third (27.6%; n = 37 of 134), second (18.6%; n = 35 of 188), and first (19.4%; n = 6 of 31) trimesters, respectively (adjusted P-trend = 0.046). In 2006, the new ration was available to all women and there was no significant additional impact of the pregnancy-specific ration and vitamin supplements. Between 2004 and 2006, SGA decreased from 28.9% (13 of 45) to 17.3% (69 of 398) (adjusted P = 0.050), a reduction of 40.1% (95% CI: 34.7%, 45.9%); there was also a decrease in the percentage of underweight women on admission to the ANC (38.2%; 95% CI: 31.4%, 45.5%). PTB rates were low and not significantly different with exposure to the new ration.Conclusions: In 2004, the earlier in gestation in which the new ration was available the greater the effect on fetal growth as shown by a reduced prevalence of SGA. In 2006, additional benefits to fetal growth from the pregnancy-specific ration and vitamin supplements beyond those of the preconception ration were not observed. Good nutrition in pregnancy remains an important challenge for refugee populations. This trial was registered at as DRKS00007736.

Phillips L, Basnyat B, Chang Y, Swenson ER, Harris NS. 2017. Findings of Cognitive Impairment at High Altitude: Relationships to Acetazolamide Use and Acute Mountain Sickness. High Alt Med Biol, 18 (2), pp. 121-127. | Citations: 1 (Scopus) | Show Abstract | Read more

Phillips, Lara, Buddha Basnyat, Yuchiao Chang, Erik R. Swenson, and N. Stuart Harris. Findings of cognitive impairment at high altitude: relationships to acetazolamide use and acute mountain sickness. High Alt Med Biol. 18:121-127, 2017. OBJECTIVE: Acute mountain sickness (AMS) is defined by patient-reported symptoms using the Lake Louise Score (LLS), which provides limited insight into any possible underlying central nervous system (CNS) dysfunction. Some evidence suggests AMS might coexist with altered neural functioning. Cognitive impairment (CI) may go undetected unless a sensitive test is applied. Our hypothesis was that a standardized test for mild CI would provide an objective measure of CNS dysfunction, which may correlate with the symptoms of AMS and so provide a potential new tool to better characterize altitude-related CNS dysfunction. We compared a cognitive screening tool with the LLS to see if it correlated with CNS dysfunction. METHODS: Adult native English-speaking subjects visiting Himalayan Rescue Association aid stations in Nepal at 3520 m (11,548 ft) and 4550 m (14,927 ft) were recruited. Subjects were administered the LLS and a slightly modified version of the environmental Quick mild cognitive impairment screen (eQmci). Medication use for altitude illness was recorded. Scores were compared using the Spearman's correlation coefficient. Data also included medication use. RESULTS: Seventy-nine subjects were enrolled. A cut-off of three or greater was used for the LLS to diagnose AMS and 67 or less for the eQmci to diagnose CI. There were 22 (28%) subjects who met criteria for AMS and 17 (22%) subjects who met criteria for CI. There was a weak correlation (r2 = 0.06, p = 0.04) between eQmci score and LLS. In matched subjects with identical LLS, recent acetazolamide use was associated with significantly more CI. CONCLUSION: Field assessment of CI using a rapid standardized tool demonstrated that a substantial number of subjects were found to have mild CI following rapid ascent to 3520-4550 m (11,548-14,927 ft). The weak correlation between the LLS and eQmci suggests that AMS does not result in CI. Use of acetazolamide appears to be associated with CI at all levels of AMS severity.

Kanaan NC, Peterson AL, Pun M, Holck PS, Starling J, Basyal B, Freeman TF, Gehner JR, Keyes L, Levin DR et al. 2017. Prophylactic Acetaminophen or Ibuprofen Results in Equivalent Acute Mountain Sickness Incidence at High Altitude: A Prospective Randomized Trial. Wilderness Environ Med, 28 (2), pp. 72-78. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: Recent trials have demonstrated the usefulness of ibuprofen in the prevention of acute mountain sickness (AMS), yet the proposed anti-inflammatory mechanism remains unconfirmed. Acetaminophen and ibuprofen were tested for AMS prevention. We hypothesized that a greater clinical effect would be seen from ibuprofen due to its anti-inflammatory effects compared with acetaminophen's mechanism of possible symptom reduction by predominantly mediating nociception in the brain. METHODS: A double-blind, randomized trial was conducted testing acetaminophen vs ibuprofen for the prevention of AMS. A total of 332 non-Nepali participants were recruited at Pheriche (4371 m) and Dingboche (4410 m) on the Everest Base Camp trek. The participants were randomized to either acetaminophen 1000 mg or ibuprofen 600 mg 3 times a day until they reached Lobuche (4940 m), where they were reassessed. The primary outcome was AMS incidence measured by the Lake Louise Questionnaire score. RESULTS: Data from 225 participants who met inclusion criteria were analyzed. Twenty-five participants (22.1%) in the acetaminophen group and 18 (16.1%) in the ibuprofen group developed AMS (P = .235). The combined AMS incidence was 19.1% (43 participants), 14 percentage points lower than the expected AMS incidence of untreated trekkers in prior studies at this location, suggesting that both interventions reduced the incidence of AMS. CONCLUSIONS: We found little evidence of any difference between acetaminophen and ibuprofen groups in AMS incidence. This suggests that AMS prevention may be multifactorial, affected by anti-inflammatory inhibition of the arachidonic-acid pathway as well as other analgesic mechanisms that mediate nociception. Additional study is needed.

Alharbi NK, Padron-Regalado E, Thompson CP, Kupke A, Wells D, Sloan MA, Grehan K, Temperton N, Lambe T, Warimwe G et al. 2017. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine, 35 (30), pp. 3780-3788. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

The Middle East respiratory syndrome coronavirus (MERS-CoV) has infected more than 1900 humans, since 2012. The syndrome ranges from asymptomatic and mild cases to severe pneumonia and death. The virus is believed to be circulating in dromedary camels without notable symptoms since the 1980s. Therefore, dromedary camels are considered the only animal source of infection. Neither antiviral drugs nor vaccines are approved for veterinary or medical use despite active research on this area. Here, we developed four vaccine candidates against MERS-CoV based on ChAdOx1 and MVA viral vectors, two candidates per vector. All vaccines contained the full-length spike gene of MERS-CoV; ChAdOx1 MERS vaccines were produced with or without the leader sequence of the human tissue plasminogen activator gene (tPA) where MVA MERS vaccines were produced with tPA, but either the mH5 or F11 promoter driving expression of the spike gene. All vaccine candidates were evaluated in a mouse model in prime only or prime-boost regimens. ChAdOx1 MERS with tPA induced higher neutralising antibodies than ChAdOx1 MERS without tPA. A single dose of ChAdOx1 MERS with tPA elicited cellular immune responses as well as neutralising antibodies that were boosted to a significantly higher level by MVA MERS. The humoral immunogenicity of a single dose of ChAdOx1 MERS with tPA was equivalent to two doses of MVA MERS (also with tPA). MVA MERS with mH5 or F11 promoter induced similar antibody levels; however, F11 promoter enhanced the cellular immunogenicity of MVA MERS to significantly higher magnitudes. In conclusion, our study showed that MERS-CoV vaccine candidates could be optimized by utilising different viral vectors, various genetic designs of the vectors, or different regimens to increase immunogenicity. ChAdOx1 and MVA vectored vaccines have been safely evaluated in camels and humans and these MERS vaccine candidates should now be tested in camels and in clinical trials.

Douangngeun B, Theppangna W, Phommachanh P, Chomdara K, Phiphakhavong S, Khounsy S, Mukaka M, Dance DAB, Blacksell SD. 2017. Rabies surveillance in dogs in Lao PDR from 2010-2016. PLoS Negl Trop Dis, 11 (6), pp. e0005609. | Show Abstract | Read more

BACKGROUND: Rabies is a fatal viral disease that continues to threaten both human and animal health in endemic countries. The Lao People's Democratic Republic (Lao PDR) is a rabies-endemic country in which dogs are the main reservoir and continue to present health risks for both human and animals throughout the country. METHODS: Passive, laboratory-based rabies surveillance was performed for suspected cases of dog rabies in Vientiane Capital during 2010-2016 and eight additional provinces between 2015-2016 using the Direct Fluorescent Antibody Test (DFAT). RESULTS: There were 284 rabies positive cases from 415 dog samples submitted for diagnosis. 257 cases were from Vientiane Capital (2010-2016) and the remaining 27 cases were submitted during 2015-2016 from Champassak (16 cases), Vientiane Province (4 cases), Xieng Kuang (3 cases), Luang Prabang (2 cases), Saravan (1 case), Saisomboun (1 case) and Bokeo (1 case). There was a significant increase in rabies cases during the dry season (p = 0.004) (November to April; i.e., <100mm of rainfall per month). No significant differences were noted between age, sex, locality of rabies cases. CONCLUSION: The use of laboratory-based rabies surveillance is a useful method of monitoring rabies in Lao PDR and should be expanded to other provincial centers, particularly where there are active rabies control programs.

Plugge E, Stürup-Toft S, O'Moore ÉJ, Møller L. 2017. WEPHREN: a global prison health research network. Int J Prison Health, 13 (2), pp. 65-67. | Read more

De Silva AP, Sujeewa JA, De Silva N, Rathnayake RMD, Vithanage L, Sigera PC, Munasinghe S, Beane A, Stephens T, Athapattu PL et al. 2017. A Retrospective Study of Physiological Observation-reporting Practices and the Recognition, Response, and Outcomes Following Cardiopulmonary Arrest in a Low-to-middle-income Country. Indian J Crit Care Med, 21 (6), pp. 343-345. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND AND AIMS: In Sri Lanka, as in most low-to-middle-income countries (LMICs), early warning systems (EWSs) are not in use. Understanding observation-reporting practices and response to deterioration is a necessary step in evaluating the feasibility of EWS implementation in a LMIC setting. This study describes the practices of observation reporting and the recognition and response to presumed cardiopulmonary arrest in a LMIC. PATIENTS AND METHODS: This retrospective study was carried out at District General Hospital Monaragala, Sri Lanka. One hundred and fifty adult patients who had cardiac arrests and were reported to a nurse responder were included in the study. RESULTS: Availability of six parameters (excluding mentation) was significantly higher at admission (P < 0.05) than at 24 and 48 h prior to cardiac arrest. Patients had a 49.3% immediate return of spontaneous circulation (ROSC) and 35.3% survival to hospital discharge. Nearly 48.6% of patients who had ROSC did not receive postarrest intensive care. Intubation was performed in 46 (62.2%) patients who went on to have ROSC compared with 28 (36.8%) with no ROSC (P < 0.05). Defibrillation, performed in eight (10.8%) patients who had ROSC and eight (10.5%) in whom did not, was statistically insignificant (P = 0.995). CONCLUSIONS: Observations commonly used to detect deterioration are poorly reported, and reporting practices would need to be improved prior to EWS implementation. These findings reinforce the need for training in acute care and resuscitation skills for health-care teams in LMIC settings as part of a program of improving recognition and response to acute deterioration.

Rutstein SE, Ananworanich J, Fidler S, Johnson C, Sanders EJ, Sued O, Saez-Cirion A, Pilcher CD, Fraser C, Cohen MS et al. 2017. Clinical and public health implications of acute and early HIV detection and treatment: a scoping review. J Int AIDS Soc, 20 (1), pp. 21579. | Citations: 3 (Scopus) | Show Abstract | Read more

INTRODUCTION: The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying and treating persons with AHI. METHODS: We searched PubMed, in addition to hand-review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low- and middle-income countries (LMICs) published in the last fifteen years. RESULTS AND DISCUSSION: Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease-of-use, suitability for application and distribution in LMIC, and throughput for high-volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI - evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point-of-care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre-exposure prophylaxis outcomes by avoiding treatment initiation for HIV-seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting. CONCLUSIONS: There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale-up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point-of-care diagnostics, and efficacious and effective first-line regimens.

Adetifa IMO, Bwanaali T, Wafula J, Mutuku A, Karia B, Makumi A, Mwatsuma P, Bauni E, Hammitt LL, Nokes DJ et al. 2017. Cohort Profile: The Kilifi Vaccine Monitoring Study International Journal of Epidemiology, 46 (3), pp. dyw202-dyw202. | Read more

Musicha P, Feasey NA, Cain AK, Kallonen T, Chaguza C, Peno C, Khonga M, Thompson S, Gray KJ, Mather AE et al. 2017. Genomic landscape of extended-spectrum β-lactamase resistance in Escherichia coli from an urban African setting. J Antimicrob Chemother, 72 (6), pp. 1602-1609. | Show Abstract | Read more

Objectives: Efforts to treat Escherichia coli infections are increasingly being compromised by the rapid, global spread of antimicrobial resistance (AMR). Whilst AMR in E. coli has been extensively investigated in resource-rich settings, in sub-Saharan Africa molecular patterns of AMR are not well described. In this study, we have begun to explore the population structure and molecular determinants of AMR amongst E. coli isolates from Malawi. Methods: Ninety-four E. coli isolates from patients admitted to Queen's Hospital, Malawi, were whole-genome sequenced. The isolates were selected on the basis of diversity of phenotypic resistance profiles and clinical source of isolation (blood, CSF and rectal swab). Sequence data were analysed using comparative genomics and phylogenetics. Results: Our results revealed the presence of five clades, which were strongly associated with E. coli phylogroups A, B1, B2, D and F. We identified 43 multilocus STs, of which ST131 (14.9%) and ST12 (9.6%) were the most common. We identified 25 AMR genes. The most common ESBL gene was bla CTX-M-15 and it was present in all five phylogroups and 11 STs, and most commonly detected in ST391 (4/4 isolates), ST648 (3/3 isolates) and ST131 [3/14 (21.4%) isolates]. Conclusions: This study has revealed a high diversity of lineages associated with AMR, including ESBL and fluoroquinolone resistance, in Malawi. The data highlight the value of longitudinal bacteraemia surveillance coupled with detailed molecular epidemiology in all settings, including low-income settings, in describing the global epidemiology of ESBL resistance.

Brady OJ, Slater HC, Pemberton-Ross P, Wenger E, Maude RJ, Ghani AC, Penny MA, Gerardin J, White LJ, Chitnis N et al. 2017. Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study. Lancet Glob Health, 5 (7), pp. e680-e687. | Citations: 5 (Scopus) | Show Abstract | Read more

BACKGROUND: Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission. METHODS: We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration. FINDINGS: The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest. INTERPRETATION: Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect. FUNDING: Bill & Melinda Gates Foundation.

ACTwatch Group, Newton PN, Hanson K, Goodman C. 2017. Do anti-malarials in Africa meet quality standards? The market penetration of non quality-assured artemisinin combination therapy in eight African countries. Malar J, 16 (1), pp. 204. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Quality of artemisinin-based combination therapy (ACT) is important for ensuring malaria parasite clearance and protecting the efficacy of artemisinin-based therapies. The extent to which non quality-assured ACT (non-QAACT), or those not granted global regulatory approval, are available and used to treat malaria in endemic countries is poorly documented. This paper uses national and sub-national medicine outlet surveys conducted in eight study countries (Benin, Kinshasa and Kantanga [Democratic Republic of the Congo, DRC], Kenya, Madagascar, Nigeria, Tanzania, Uganda and Zambia) between 2009 and 2015 to describe the non-QAACT market and to document trends in availability and distribution of non-QAACT in the public and private sector. RESULTS: In 2014/15, non-QAACT were most commonly available in Kinshasa (83%), followed by Katanga (53%), Nigeria (48%), Kenya (42%), and Uganda (33%). Non-QAACT accounted for 20% of the market share in the private sector in Kenya, followed by Benin and Uganda (19%), Nigeria (12%) and Zambia (8%); this figure was 27% in Katanga and 40% in Kinshasa. Public sector non-QAACT availability and distribution was much lower, with the exception of Zambia (availability, 85%; market share, 32%). Diverse generics and formulations were available, but non-QAACT were most commonly artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHA PPQ), in tablet formulation, imported, and distributed in urban areas at either pharmacies or drug stores. The number of unique manufacturers supplying non-QAACT to each country ranged from 9 in Uganda to 92 in Nigeria. CONCLUSIONS: Addressing the availability and distribution of non-QAACT will require effective private sector engagement and evidence-based strategies to address provider and consumer demand for these products. Given the variation in non-QAACT markets observed across the eight study countries, active efforts to limit registration, importation and distribution of non-QAACT must be tailored to the country context, and will involve addressing complex and challenging aspects of medicine registration, private sector pharmaceutical regulation, local manufacturing and drug importation. These efforts may be critical not only to patient health and safety, but also to effective malaria control and protection of artemisinin drug efficacy in the face of spreading resistance.

Devine A, Parmiter M, Chu CS, Bancone G, Nosten F, Price RN, Lubell Y, Yeung S. 2017. Using G6PD tests to enable the safe treatment of Plasmodium vivax infections with primaquine on the Thailand-Myanmar border: A cost-effectiveness analysis. PLoS Negl Trop Dis, 11 (5), pp. e0005602. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND: Primaquine is the only licensed antimalarial for the radical cure of Plasmodium vivax infections. Many countries, however, do not administer primaquine due to fear of hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In other settings, primaquine is given without G6PD testing, putting patients at risk of hemolysis. New rapid diagnostic tests (RDTs) offer the opportunity to screen for G6PD deficiency prior to treatment with primaquine. Here we assessed the cost-effectiveness of using G6PD RDTs on the Thailand-Myanmar border and provide the model as an online tool for use in other settings. METHODS/PRINCIPAL FINDINGS: Decision tree models for the management of P. vivax malaria evaluated the costs and disability-adjusted life-years (DALYs) associated with recurrences and primaquine-induced hemolysis from a health care provider perspective. Screening with G6PD RDTs before primaquine use was compared to (1) giving chloroquine alone and (2) giving primaquine without screening. Data were taken from a recent study on the impact of primaquine on P. vivax recurrences and a literature review. Compared to the use of chloroquine alone, the screening strategy had similar costs while averting 0.026 and 0.024 DALYs per primary infection in males and females respectively. Compared to primaquine administered without screening, the screening strategy provided modest cost savings while averting 0.011 and 0.004 DALYs in males and females respectively. The probabilistic sensitivity analyses resulted in a greater than 75% certainty that the screening strategy was cost-effective at a willingness to pay threshold of US$500, which is well below the common benchmark of per capita gross domestic product for Myanmar. CONCLUSIONS/SIGNIFICANCE: In this setting G6PD RDTs could avert DALYs by reducing recurrences and reducing hemolytic risk in G6PD deficient patients at low costs or cost savings. The model results are limited by the paucity of data available in the literature for some parameter values, including the mortality rates for both primaquine-induced hemolysis and P. vivax. The online model provides an opportunity to use different parameter estimates to examine the validity of these findings in other settings.

O'Neill PM, Amewu RK, Charman SA, Sabbani S, Gnädig NF, Straimer J, Fidock DA, Shore ER, Roberts NL, Wong MH-L et al. 2017. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat Commun, 8 pp. 15159. | Citations: 5 (Scopus) | Show Abstract | Read more

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.

Dembele L, Ang X, Chavchich M, Bonamy GMC, Selva JJ, Lim MY-X, Bodenreider C, Yeung BKS, Nosten F, Russell BM et al. 2017. The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites. Sci Rep, 7 (1), pp. 2325. | Show Abstract | Read more

Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the in vitro drug sensitivity profile of normally-developing P. falciparum ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings; a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of P. falciparum ART-resistant strains expressing mutant K13.

Tun STT, Lubell Y, Dondorp AM, Fieldman T, Tun KM, Celhay O, Chan XH, Saralamba S, White LJ. 2017. Identifying artemisinin resistance from parasite clearance half-life data with a simple Shiny web application. PLoS One, 12 (5), pp. e0177840. | Show Abstract | Read more

The emergence of artemisinin-resistant Plasmodium falciparum malaria is a major threat to malaria elimination. New tools for supporting the surveillance of artemisinin resistance are critical for current and future malaria control and elimination strategies. We have developed an open-access, user-friendly, web-based tool to analyse parasite clearance half-life data of P. falciparum infected patients after treatment with artemisinin derivatives, so that resistance to artemisinin can be identified. The tool can be accessed at

Kevin Baird J. 2017. Malaria control by commodities without practical malariology. BMC Public Health, 17 (1), pp. 590. | Show Abstract | Read more

Malaria remains a serious clinical and public health problem, the object of an ongoing technological and humanitarian struggle to abate the very substantial harm done. The manner by which humanity approached malaria control changed abruptly and profoundly after 1945 with the advent of the insecticide DDT. Malariologists in the first half of the twentieth century conceived precise modifications to natural or man-made environments aimed at making those less hospitable to specific anopheline mosquito vector species. This practical malariology achieved very significant reductions in burdens of morbidity and mortality, but the revolutionary insecticide eliminated the need for its specialized knowledge and diverse practices. By 1970 mosquito resistance to DDT and perceived environmental concerns precipitated the collapse of what had been a vigorous global campaign to eradicate malaria. Humanity did not then revitalize practical malariology but turned to another commodity as the foundation of control strategy, the war-spurred suite of synthetic antimalarial drugs developed in the 1940s and 1950s. When those drugs became lost to parasite resistance in the latter twentieth century, malaria resurged globally. Since 2005, tens of billions of dollars mobilized new commodities to control malaria: point-of-care diagnostics, effective artemisinin-based treatments, and longer-lasting insecticide treated bed nets. The know-how of practical malariology is not part of that ongoing commodities-based strategy. This article examines contemporary malaria control in the broad strokes of a strategy mitigating the consequences of infection contrasted to that of the abandoned practical malariology strategy of prevention. The inherent risks and limitations of over-reliance upon commodities in striving to control malaria may prompt consideration of a strategic posture inclusive of the proven methods of practical malariology.

Pell C, Tripura R, Nguon C, Cheah P, Davoeung C, Heng C, Dara L, Sareth M, Dondorp A, von Seidlein L, Peto TJ. 2017. Mass anti-malarial administration in western Cambodia: a qualitative study of factors affecting coverage. Malar J, 16 (1), pp. 206. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia. METHODS: Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities. Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo. RESULTS: Malaria was an important health concern and villagers reported a demand for malaria treatment. This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria. Participants generally understood the overall study aim and were familiar with study activities. Comprehension of the study rationale was however limited. After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as "side effects" contributed to a decrease of coverage in round two. Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings. This contributed to a subsequent increase in coverage. CONCLUSION: Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement. Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare.

De Silva AP, Harischandra PL, Beane A, Rathnayaka S, Pimburage R, Wijesiriwardana W, Gamage D, Jayasinghe D, Sigera C, Gunasekara A et al. 2017. A data platform to improve rabies prevention, Sri Lanka. Bull World Health Organ, 95 (9), pp. 646-651. | Show Abstract | Read more

PROBLEM: In Sri Lanka, rabies prevention initiatives are hindered by fragmented and delayed information-sharing that limits clinicians' ability to follow patients and impedes public health surveillance. APPROACH: In a project led by the health ministry, we adapted existing technologies to create an electronic platform for rabies surveillance. Information is entered by trained clinical staff, and both aggregate and individual patient data are visualized in real time. An automated short message system (SMS) alerts patients for vaccination follow-up appointments and informs public health inspectors about incidents of animal bites. LOCAL SETTING: The platform was rolled out in June 2016 in four districts of Sri Lanka, linking six rabies clinics, three laboratories and the public health inspectorate. RELEVANT CHANGES: Over a 9-month period, 12 121 animal bites were reported to clinics and entered in the registry. Via secure portals, clinicians and public health teams accessed live information on treatment and outcomes of patients started on post-exposure prophylaxis (9507) or receiving deferred treatment (2614). Laboratories rapidly communicated the results of rabies virus tests on dead mammals (328/907 positive). In two pilot districts SMS reminders were sent to 1376 (71.2%) of 1933 patients whose contact details were available. Daily SMS reports alerted 17 public health inspectors to bite incidents in their area for investigation. LESSONS LEARNT: Existing technologies in low-resource countries can be harnessed to improve public health surveillance. Investment is needed in platform development and training and support for front-line staff. Greater public engagement is needed to improve completeness of surveillance and treatment.

Offeddu V, Olotu A, Osier F, Marsh K, Matuschewski K, Thathy V. 2017. High Sporozoite Antibody Titers in Conjunction with Microscopically Detectable Blood Infection Display Signatures of Protection from Clinical Malaria. Front Immunol, 8 (MAY), pp. 488. | Show Abstract | Read more

Immunoepidemiological studies typically reveal slow, age-dependent acquisition of immune responses againstPlasmodium falciparumsporozoites. Naturally acquired immunity against preerythrocytic stages is considered inadequate to confer protection against clinical malaria. To explore previously unrecognized antisporozoite responses, we measured serum levels of naturally acquired antibodies to wholePlasmodium falciparumsporozoites (Pfspz) and the immunodominant (NANP)5repeats of the major sporozoite surface protein, circumsporozoite protein, in a well-characterized Kenyan cohort. Sera were sampled at the start of the malaria transmission season, and all subjects were prospectively monitored for uncomplicated clinical malaria in the ensuing 6 months. We used Kaplan-Meier analysis and multivariable regression to investigate the association of antisporozoite immunity with incidence of clinical malaria. Although naturally acquired humoral responses againstPfspz and (NANP)5were strongly correlated (p < 0.0001), 37% ofPfspz responders did not recognize (NANP)5. The prevalence and magnitude of antisporozoite responses increased with age, although some highPfspz responders were identified among children. Survival analysis revealed a reduced risk of and increased time to first or only episode of clinical malaria amongPfspz or (NANP)5responders carrying microscopically detectablePlasmodium falciparum(Pf) parasitemia at the start of the transmission season (p < 0.03). Our Cox regression interaction models indicated a potentially protective interaction between high anti-Pfspz (p = 0.002) or anti-(NANP)5(p = 0.001) antibody levels and microscopically detectablePfparasitemia on the risk of subsequent clinical malaria. Our findings indicate that robust antisporozoite immune responses can be naturally acquired already at an early age. A potentially protective role of high levels of anti-Pfspz antibodies against clinical episodes of uncomplicated malaria was detected, suggesting that antibody-mediated preerythrocytic immunity might indeed contribute to protection in nature.

Miguel-Blanco C, Molina I, Bardera AI, Díaz B, de Las Heras L, Lozano S, González C, Rodrigues J, Delves MJ, Ruecker A et al. 2017. Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen. Nat Commun, 8 pp. 15160. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.

Kombo B, Sariola S, Gichuru E, Molyneux S, Sanders EJ, van der Elst E. 2017. "Facing Our Fears": Using facilitated film viewings to engage communities in HIV research involving MSM in Kenya. Cogent Med, 4 (1), pp. 1330728. | Show Abstract | Read more

Kenya is a generally homophobic country where homosexuality is criminalised and people who engage in same sex sexuality face stigma and discrimination. In 2013, we developed a 16 min documentary entitled "Facing Our Fears" that aimed at sharing information on how and why men who have sex with men (MSM) are involved in on-going KEMRI HIV prevention research, and associated community engagement. To consider the film's usefulness as a communication tool, and its perceived security risks in case the film was publicly released, we conducted nine facilitated viewings with 122 individuals representing seven different stakeholder groups. The documentary was seen as a strong visual communication tool with potential to reduce stigma related to homosexuality, and facilitated film viewings were identified as platforms with potential to support open dialogue about HIV research involving MSM. Despite the potential, there were concerns over possible risks to LGBT communities and those working with them following public release. We opted-giving emphasis to the "do no harm" principle-to use the film only in facilitated settings where audience knowledge and attitudes can be carefully considered and discussed. The results highlight the importance of carefully assessing the range of possible impacts when using visuals in community engagement.

Manzoni G, Marinach C, Topçu S, Briquet S, Grand M, Tolle M, Gransagne M, Lescar J, Andolina C, Franetich J-F et al. 2017. Plasmodium P36 determines host cell receptor usage during sporozoite invasion. Elife, 6 | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

Plasmodium sporozoites, the mosquito-transmitted forms of the malaria parasite, first infect the liver for an initial round of replication before the emergence of pathogenic blood stages. Sporozoites represent attractive targets for antimalarial preventive strategies, yet the mechanisms of parasite entry into hepatocytes remain poorly understood. Here we show that the two main species causing malaria in humans, Plasmodium falciparum and Plasmodium vivax, rely on two distinct host cell surface proteins, CD81 and the Scavenger Receptor BI (SR-BI), respectively, to infect hepatocytes. By contrast, CD81 and SR-BI fulfil redundant functions during infection by the rodent parasite P. berghei. Genetic analysis of sporozoite factors reveals the 6-cysteine domain protein P36 as a major parasite determinant of host cell receptor usage. Our data provide molecular insights into the invasion pathways used by different malaria parasites to infect hepatocytes, and establish a functional link between a sporozoite putative ligand and host cell receptors.

Abreha T, Hwang J, Thriemer K, Tadesse Y, Girma S, Melaku Z, Assef A, Kassa M, Chatfield MD, Landman KZ et al. 2017. Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial. PLoS Med, 14 (5), pp. e1002299. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Recent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia. METHODS AND FINDINGS: Patients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42. The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%-10.4%) after CQ treatment and 0% (95% CI 0%-4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%-20.6%) following AL alone and 2.3% (95% CI 0.6%-9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%-28.0%) after CQ, 1.2% (95% CI 0.2%-8.0%) after CQ+PQ, 29.9% (95% CI 21.6%-40.5%) after AL, and 5.9% (95% CI 2.4%-13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0-3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9-9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6-11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms. The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia. CONCLUSIONS: Despite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y. TRIAL REGISTRATION: NCT01680406.

Salam AP, Rojek A, Dunning J, Horby PW. 2017. Clinical Trials of Therapeutics for the Prevention of Congenital Zika Virus Disease: Challenges and Potential Solutions. Ann Intern Med, 166 (10), pp. 725-732. | Citations: 2 (Scopus) | Show Abstract | Read more

Zika virus (ZIKV) infection in pregnancy is associated with adverse fetal outcomes, such as microcephaly and other congenital malformations. No therapeutic options are available to pregnant women with ZIKV infection to prevent these effects. Drug trials in pregnancy raise several scientific, ethical, and logistic challenges, which are compounded further in ZIKV because of limited knowledge of the disease pathophysiology and a product development pipeline in its infancy. We evaluate the major challenges in choosing therapeutics to prevent congenital ZIKV disease and conducting clinical trials of these treatments, with a focus on preventing congenital central nervous system malformations. These challenges must be characterized and planned for now so that clinical trials can progress expediently and effectively in the future.

Neumayr A, Paris DH, Genton B, Hatz C. 2017. Artemether-Lumefantrine Treatment Failure in Nonimmune European Travelers With Plasmodium falciparum Malaria: Do We Need to Reconsider Dosing in Patients From Nonendemic Regions? Clin Infect Dis, 64 (10), pp. 1466-1467. | Read more

Haenssgen MJ, Ariana P. 2017. The place of technology in the Capability Approach Oxford Development Studies, pp. 1-15. | Citations: 1 (Scopus) | Show Abstract | Read more

© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group Increasing scholarly attention has focussed on how to integrate technology within the Capability Approach (CA), yet without a consistent solution. Some describe technology as a special kind of capability input, but others consider the concept of technology to be fundamentally different from that of an ordinary input. We aim to contribute to the theoretical development of the CA by offering a consistent justification for the explicit inclusion of technology in this framework. We propose that technical objects have a ‘generative’ and a ‘transformative’ dimension through which they enable capabilities directly and affect other inputs in the attainment of valued capabilities. The objects acquire the transformative dimension from the broader technological context, which we propose as a new class of conversion factors. Using the example of mobile phones and their role in healthcare access, we demonstrate that our proposal helps to frame the analysis of the development impact of technology.

Mukherjee A, Bopp S, Magistrado P, Wong W, Daniels R, Demas A, Schaffner S, Amaratunga C, Lim P, Dhorda M et al. 2017. Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia. Malar J, 16 (1), pp. 195. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin-piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. METHODS: Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA0-3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. RESULTS: Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA0-3h = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. CONCLUSIONS: This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine resistance and development of strategies to prevent or overcome anti-malarial resistance.

Pava Z, Noviyanti R, Handayuni I, Trimarsanto H, Trianty L, Burdam FH, Kenangalem E, Utami RAS, Tirta YK, Coutrier F et al. 2017. Genetic micro-epidemiology of malaria in Papua Indonesia: Extensive P. vivax diversity and a distinct subpopulation of asymptomatic P. falciparum infections. PLoS One, 12 (5), pp. e0177445. | Citations: 3 (Scopus) | Show Abstract | Read more

BACKGROUND: Genetic analyses of Plasmodium have potential to inform on transmission dynamics, but few studies have evaluated this on a local spatial scale. We used microsatellite genotyping to characterise the micro-epidemiology of P. vivax and P. falciparum diversity to inform malaria control strategies in Timika, Papua Indonesia. METHODS: Genotyping was undertaken on 713 sympatric P. falciparum and P. vivax isolates from a cross-sectional household survey and clinical studies conducted in Timika. Standard population genetic measures were applied, and the data was compared to published data from Kalimantan, Bangka, Sumba and West Timor. RESULTS: Higher diversity (HE = 0.847 vs 0.625; p = 0.017) and polyclonality (46.2% vs 16.5%, p<0.001) were observed in P. vivax versus P. falciparum. Distinct P. falciparum substructure was observed, with two subpopulations, K1 and K2. K1 was comprised solely of asymptomatic infections and displayed greater relatedness to isolates from Sumba than to K2, possibly reflecting imported infections. CONCLUSIONS: The results demonstrate the greater refractoriness of P. vivax versus P. falciparum to control measures, and risk of distinct parasite subpopulations persisting in the community undetected by passive surveillance. These findings highlight the need for complimentary new surveillance strategies to identify transmission patterns that cannot be detected with traditional malariometric methods.

Beane A, Padeniya A, De Silva AP, Stephens T, De Alwis S, Mahipala PG, Sigera PC, Munasinghe S, Weeratunga P, Ranasinghe D et al. 2017. Closing the theory to practice gap for newly qualified doctors: evaluation of a peer-delivered practical skills training course for newly qualified doctors in preparation for clinical practice. Postgrad Med J, 93 (1104), pp. 592-596. | Show Abstract | Read more

PURPOSE: The Good Intern Programme (GIP) in Sri Lanka has been implemented to bridge the 'theory to practice gap' of doctors preparing for their internship. This paper evaluates the impact of a 2-day peer-delivered Acute Care Skills Training (ACST) course as part of the GIP. STUDY DESIGN: The ACST course was developed by an interprofessional faculty, including newly graduated doctors awaiting internship (pre-intern), focusing on the recognition and management of common medical and surgical emergencies. Course delivery was entirely by pre-intern doctors to their peers. Knowledge was evaluated by a pre- and post-course multiple choice test. Participants' confidence (post-course) and 12 acute care skills (pre- and post-course) were assessed using Likert scale-based questions. A subset of participants provided feedback on the peer learning experience. RESULTS: Seventeen courses were delivered by a faculty consisting of eight peer trainers over 4 months, training 320 participants. The mean (SD) multiple choice questionnaire score was 71.03 (13.19) pre-course compared with 77.98 (7.7) post-course (p<0.05). Increased overall confidence in managing ward emergencies was reported by 97.2% (n=283) of respondents. Participants rated their post-course skills to be significantly higher (p<0.05) than pre-course in all 12 assessed skills. Extended feedback on the peer learning experience was overwhelmingly positive and 96.5% would recommend the course to a colleague. CONCLUSIONS: A peer-delivered ACST course was extremely well received and can improve newly qualified medical graduates' knowledge, skills and confidence in managing medical and surgical emergencies. This peer-based model may have utility beyond pre-interns and beyond Sri Lanka.

Tuti T, Nzinga J, Njoroge M, Brown B, Peek N, English M, Paton C, van der Veer SN. 2017. A systematic review of electronic audit and feedback: intervention effectiveness and use of behaviour change theory. Implement Sci, 12 (1), pp. 61. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Audit and feedback is a common intervention for supporting clinical behaviour change. Increasingly, health data are available in electronic format. Yet, little is known regarding if and how electronic audit and feedback (e-A&F) improves quality of care in practice. OBJECTIVE: The study aimed to assess the effectiveness of e-A&F interventions in a primary care and hospital context and to identify theoretical mechanisms of behaviour change underlying these interventions. METHODS: In August 2016, we searched five electronic databases, including MEDLINE and EMBASE via Ovid, and the Cochrane Central Register of Controlled Trials for published randomised controlled trials. We included studies that evaluated e-A&F interventions, defined as a summary of clinical performance delivered through an interactive computer interface to healthcare providers. Data on feedback characteristics, underlying theoretical domains, effect size and risk of bias were extracted by two independent review authors, who determined the domains within the Theoretical Domains Framework (TDF). We performed a meta-analysis of e-A&F effectiveness, and a narrative analysis of the nature and patterns of TDF domains and potential links with the intervention effect. RESULTS: We included seven studies comprising of 81,700 patients being cared for by 329 healthcare professionals/primary care facilities. Given the extremely high heterogeneity of the e-A&F interventions and five studies having a medium or high risk of bias, the average effect was deemed unreliable. Only two studies explicitly used theory to guide intervention design. The most frequent theoretical domains targeted by the e-A&F interventions included 'knowledge', 'social influences', 'goals' and 'behaviour regulation', with each intervention targeting a combination of at least three. None of the interventions addressed the domains 'social/professional role and identity' or 'emotion'. Analyses identified the number of different domains coded in control arm to have the biggest role in heterogeneity in e-A&F effect size. CONCLUSIONS: Given the high heterogeneity of identified studies, the effects of e-A&F were found to be highly variable. Additionally, e-A&F interventions tend to implicitly target only a fraction of known theoretical domains, even after omitting domains presumed not to be linked to e-A&F. Also, little evaluation of comparative effectiveness across trial arms was conducted. Future research should seek to further unpack the theoretical domains essential for effective e-A&F in order to better support strategic individual and team goals.

van Nuil JI, Kestelyn E, Umutoni G, Mwambarangwe L, Umulisa MM, van de Wijgert J, Ravinetto R. 2017. Informed consent, community engagement, and study participation at a research site in Kigali, Rwanda. Dev World Bioeth, | Show Abstract | Read more

People enroll in medical research for many reasons ranging from decisions regarding their own or family members' health situation to broader considerations including access to health and financial resources. In socially vulnerable communities the choice to participate is often based on a risk-benefit assessment that goes beyond the medical aspects of the research, and considers the benefits received. In this qualitative study, we examined the motivations of Rwandan women to participate in a non-commercial collaborative research study examining the safety, acceptability, and adherence of a contraceptive vaginal ring in Rwanda juxtaposed with the perceptions of the research within the community. 351 women attended the screening visit, four were excluded because they were not able to complete the assessment of understanding. The remaining participants' ages ranged from 17 to 38 and 80% had primary level of education or below. 120 were enrolled. Findings highlighted motivations for joining the study that were relayed both formally by the clinic (e.g. testing and treatment) and informally by the community including the positive aspects of the ring. There were also some negative rumors circulating regarding the research site, likely from excluded participants who faced potential stigma based on that exclusion. It was understood by most participants that they were enrolled in a research study and participants actively sought out enrollment in the research for a variety of reasons. The experiences demonstrate that although inequalities in access to health care may create conflicting situations around the study, it is possible to form partnerships between a research center and participants/their partners, for research about reproductive health.

Gitaka J, Ogwang C, Ngari M, Akoo P, Olotu A, Kerubo C, Fegan G, Njuguna P, Nyakaya G, Otieno T et al. 2017. Clinical laboratory reference values amongst children aged 4 weeks to 17 months in Kilifi, Kenya: A cross sectional observational study. PLoS One, 12 (5), pp. e0177382. | Show Abstract | Read more

Reference intervals for clinical laboratory parameters are important for assessing eligibility, toxicity grading and management of adverse events in clinical trials. Nonetheless, haematological and biochemical parameters used for clinical trials in sub-Saharan Africa are typically derived from industrialized countries, or from WHO references that are not region-specific. We set out to establish community reference values for haematological and biochemical parameters amongst children aged 4 weeks to 17 months in Kilifi, Kenya. We conducted a cross sectional study nested within phase II and III trials of RTS, S malaria vaccine candidate. We analysed 10 haematological and 2 biochemical parameters from 1,070 and 423 community children without illness prior to experimental vaccine administration. Statistical analysis followed Clinical and Laboratory Standards Institute EP28-A3c guidelines. 95% reference ranges and their respective 90% confidence intervals were determined using non-parametric methods. Findings were compared with published ranges from Tanzania, Europe and The United States. We determined the reference ranges within the following age partitions: 4 weeks to <6 months, 6 months to less than <12 months, and 12 months to 17 months for the haematological parameters; and 4 weeks to 17 months for the biochemical parameters. There were no gender differences for all haematological and biochemical parameters in all age groups. Hb, MCV and platelets 95% reference ranges in infants largely overlapped with those from United States or Europe, except for the lower limit for Hb, Hct and platelets (lower); and upper limit for platelets (higher) and haematocrit(lower). Community norms for common haematological and biochemical parameters differ from developed countries. This reaffirms the need in clinical trials for locally derived reference values to detect deviation from what is usual in typical children in low and middle income countries.

Birger RB, Le T, Kouyos RD, Grenfell BT, Hallett TB. 2017. The impact of HCV therapy in a high HIV-HCV prevalence population: A modeling study on people who inject drugs in Ho Chi Minh City, Vietnam. PLoS One, 12 (5), pp. e0177195. | Show Abstract | Read more

BACKGROUND: Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection is a major global health problem especially among people who inject drugs (PWID), with significant clinical implications. Mathematical models have been used to great effect to shape HIV care, but few have been proposed for HIV/HCV. METHODS: We constructed a deterministic compartmental ODE model that incorporated layers for HIV disease progression, HCV disease progression and PWID demography. Antiretroviral therapy (ART) and Methadone Maintenance Therapy (MMT) scale-ups were modeled as from 2016 and projected forward 10 years. HCV treatment roll-out was modeled beginning in 2026, after a variety of MMT scale-up scenarios, and projected forward 10 years. RESULTS: Our results indicate that scale-up of ART has a major impact on HIV though not on HCV burden. MMT scale-up has an impact on incidence of both infections. HCV treatment roll-out has a measurable impact on reductions of deaths, increasing multifold the mortality reductions afforded by just ART/MMT scale-ups. CONCLUSION: HCV treatment roll-out can have major and long-lasting effects on averting PWID deaths on top of those averted by ART/MMT scale-up. Efficient intervention scale-up of HCV alongside HIV interventions is critical in Vietnam.

Macharia PM, Ouma PO, Gogo EG, Snow RW, Noor AM. 2017. Spatial accessibility to basic public health services in South Sudan. Geospat Health, 12 (1), pp. 510. | Citations: 1 (Scopus) | Show Abstract | Read more

At independence in 2011, South Sudan's health sector was almost non-existent. The first national health strategic plan aimed to achieve an integrated health facility network that would mean that 70% of the population were within 5 km of a health service provider. Publically available data on functioning and closed health facilities, population distribution, road networks, land use and elevation were used to compute the fraction of the population within 1 hour walking distance of the nearest public health facility offering curative services. This metric was summarised for each of the 78 counties in South Sudan and compared with simpler metrics of the proportion of the population within 5 km of a health facility. In 2016, it is estimated that there were 1747 public health facilities, out of which 294 were non-functional in part due to the on-going civil conflict. Access to a service provider was poor with only 25.7% of the population living within one-hour walking time to a facility and 28.6% of the population within 5 km. These metrics, when applied sub-nationally, identified the same high priority, most vulnerable counties. Simple metrics based upon population distribution and location of facilities might be as valuable as more complex models of health access, where attribute data on travel routes are imperfect or incomplete and sparse. Disparities exist in South Sudan among counties and those with the poorest health access should be targeted for priority expansion of clinical services.

Moore KA, Fowkes FJI, Wiladphaingern J, Wai NS, Paw MK, Pimanpanarak M, Carrara VI, Raksuansak J, Simpson JA, White NJ et al. 2017. Mediation of the effect of malaria in pregnancy on stillbirth and neonatal death in an area of low transmission: observational data analysis. BMC Med, 15 (1), pp. 98. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million stillbirths and neonatal deaths that occur annually. The contribution of malaria in pregnancy in areas of low transmission has not been quantified, and the roles of maternal anaemia, small-for-gestational-age status, and preterm birth in mediating the effect of malaria in pregnancy on stillbirth and neonatal death are poorly elucidated. METHODS: We analysed observational data routinely collected at antenatal clinics on the Thai-Myanmar border (1986-2015). We used Cox regression and sequential mediation analysis to determine the effect of falciparum and vivax malaria in pregnancy on antepartum (death in utero) and intrapartum (death during labour) stillbirth and neonatal mortality as well as mediation through maternal anaemia, preterm birth, and small-for-gestational-age status. RESULTS: Of 61,836 women, 9350 (15%) had malaria in pregnancy, and 526 (0.8%) had stillbirths. In a sub-set of 9090 live born singletons followed from birth there were 153 (1.7%) neonatal deaths. The hazard of antepartum stillbirth increased 2.24-fold [95% confidence interval: 1.47, 3.41] following falciparum malaria (42% mediated through small-for-gestational-age status and anaemia), driven by symptomatic falciparum malaria (hazard ratio, HR: 2.99 [1.83, 4.89]) rather than asymptomatic falciparum malaria (HR: 1.35 [0.61, 2.96]). The hazard of antepartum stillbirth increased 2.21-fold [1.12, 4.33] following symptomatic vivax malaria (24% mediated through small-for-gestational-age status and anaemia) but not asymptomatic vivax malaria (HR: 0.54 [0.20, 1.45]). There was no association between falciparum or vivax malaria in pregnancy and intrapartum stillbirth (falciparum HR: 1.03 [0.58, 1.83]; vivax HR: 1.18 [0.66, 2.11]). Falciparum and vivax malaria in pregnancy increased the hazard of neonatal death 2.55-fold [1.54, 4.22] and 1.98-fold [1.10, 3.57], respectively (40% and 50%, respectively, mediated through small-for-gestational-age status and preterm birth). CONCLUSIONS: Prevention of malaria in pregnancy, new and existing interventions to prevent small-for-gestational-age status and maternal anaemia, and improved capacity for managing preterm and small-for-gestational-age newborns will reduce the number of malaria-associated stillbirths and neonatal deaths in malaria-endemic areas.

Näsström E, Parry CM, Vu Thieu NT, Maude RR, de Jong HK, Fukushima M, Rzhepishevska O, Marks F, Panzner U, Im J et al. 2017. Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa. Elife, 6 | Show Abstract | Read more

Salmonella Typhi is the causative agent of typhoid. Typhoid is diagnosed by blood culture, a method that lacks sensitivity, portability and speed. We have previously shown that specific metabolomic profiles can be detected in the blood of typhoid patients from Nepal (Näsström et al., 2014). Here, we performed mass spectrometry on plasma from Bangladeshi and Senegalese patients with culture confirmed typhoid fever, clinically suspected typhoid, and other febrile diseases including malaria. After applying supervised pattern recognition modelling, we could significantly distinguish metabolite profiles in plasma from the culture confirmed typhoid patients. After comparing the direction of change and degree of multivariate significance, we identified 24 metabolites that were consistently up- or down regulated in a further Bangladeshi/Senegalese validation cohort, and the Nepali cohort from our previous work. We have identified and validated a metabolite panel that can distinguish typhoid from other febrile diseases, providing a new approach for typhoid diagnostics.

Saad NJ, Bowles CC, Grenfell BT, Basnyat B, Arjyal A, Dongol S, Karkey A, Baker S, Pitzer VE. 2017. The impact of migration and antimicrobial resistance on the transmission dynamics of typhoid fever in Kathmandu, Nepal: A mathematical modelling study. PLoS Negl Trop Dis, 11 (5), pp. e0005547. | Show Abstract | Read more

BACKGROUND: A substantial proportion of the global burden of typhoid fever occurs in South Asia. Kathmandu, Nepal experienced a substantial increase in the number of typhoid fever cases (caused by Salmonella Typhi) between 2000 and 2003, which subsequently declined but to a higher endemic level than in 2000. This epidemic of S. Typhi coincided with an increase in organisms with reduced susceptibility against fluoroquinolones, the emergence of S. Typhi H58, and an increase in the migratory population in Kathmandu. METHODS: We devised a mathematical model to investigate the potential epidemic drivers of typhoid in Kathmandu and fit this model to weekly data of S. Typhi cases between April 1997 and June 2011 and the age distribution of S. Typhi cases. We used this model to determine if the typhoid epidemic in Kathmandu was driven by heightened migration, the emergence of organisms with reduced susceptibility against fluoroquinolones or a combination of these factors. RESULTS: Models allowing for the migration of susceptible individuals into Kathmandu alone or in combination with the emergence of S. Typhi with reduced susceptibility against fluoroquinolones provided a good fit for the data. The emergence of organisms with reduced susceptibility against fluoroquinolones organisms alone, either through an increase in disease duration or increased transmission, did not fully explain the pattern of S. Typhi infections. CONCLUSIONS: Our analysis is consistent with the hypothesis that the increase in typhoid fever in Kathmandu was associated with the migration of susceptible individuals into the city and aided by the emergence of reduced susceptibility against fluoroquinolones. These data support identifying and targeting migrant populations with typhoid immunization programmes to prevent transmission and disease.

Thwaites GE, Day NPJ. 2017. Approach to Fever in the Returning Traveler. N Engl J Med, 376 (18), pp. 1798. | Citations: 2 (Scopus) | Read more

Thwaites GE, Day NPJ. 2017. Approach to Fever in the Returning Traveler REPLY NEW ENGLAND JOURNAL OF MEDICINE, 376 (18), pp. 1798-1798.

Dellicour S, Sevene E, McGready R, Tinto H, Mosha D, Manyando C, Rulisa S, Desai M, Ouma P, Oneko M et al. 2017. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies. PLoS Med, 14 (5), pp. e1002290. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. METHODS AND FINDINGS: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. CONCLUSIONS: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. REVIEW REGISTRATION: PROSPERO CRD42015032371.

Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, Smithuis FM, Hlaing TM, Tun KM, van der Pluijm RW et al. 2017. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis, 17 (5), pp. 491-497. | Citations: 23 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion. METHODS: In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness. FINDINGS: As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014-15, a single long PfKelch13 C580Y haplotype (-50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin. INTERPRETATION: Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective. FUNDING: The Wellcome Trust and the Bill and Melinda Gates Foundation.

Trung NV, Hoi LT, Thuong NTH, Toan TK, Huong TTK, Hoa TM, Fox A, Kinh NV, van Doorn HR, Wertheim HFL et al. 2017. Seroprevalence of Scrub Typhus, Typhus, and Spotted Fever Among Rural and Urban Populations of Northern Vietnam. Am J Trop Med Hyg, 96 (5), pp. 1084-1087. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

AbstractRickettsial infections are recognized as important causes of fever throughout southeast Asia. Herein, we determined the seroprevalence to rickettsioses within rural and urban populations of northern Vietnam. Prevalence of individuals with evidence of prior rickettsial infections (IgG positive) was surprisingly low, with 9.14% (83/908) testing positive to the three major rickettsial serogroups thought to circulate in the region. Prevalence of typhus group rickettsiae (TG)-specific antibodies (6.5%, 58/908) was significantly greater than scrub typhus group orientiae (STG)- or spotted fever group rickettsiae (SFG)-specific antibodies (P < 0.05). The majority of TG seropositives were observed among urban rather than rural residents (P < 0.05). In contrast, overall antibody prevalence to STG and SFG were both very low (1.1%, 10/908 for STG; 1.7%, 15/908 for SFG), with no significant differences between rural and urban residents. These results provide data on baseline population characteristics that may help inform development of Rickettsia serological testing criteria in future clinical studies.

Permala J, Tarning J, Nosten F, White NJ, Karlsson MO, Bergstrand M. 2017. Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine. Antimicrob Agents Chemother, 61 (5), pp. e02491-16-e02491-16. | Show Abstract | Read more

Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

Graustein AD, Horne DJ, Fong JJ, Schwarz F, Mefford HC, Peterson GJ, Wells RD, Musvosvi M, Shey M, Hanekom WA et al. 2017. The SIGLEC14 null allele is associated with Mycobacterium tuberculosis- and BCG-induced clinical and immunologic outcomes. Tuberculosis (Edinb), 104 pp. 38-45. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Humans exposed to Mycobacterium tuberculosis (Mtb) have variable susceptibility to tuberculosis (TB) and its outcomes. Siglec-5 and Siglec-14 are members of the sialic-acid binding lectin family that regulate immune responses to pathogens through inhibitory (Siglec-5) and activating (Siglec-14) domains. The SIGLEC14 coding sequence is deleted in a high proportion of individuals, placing a SIGLEC5-like gene under the expression of the SIGLEC14 promoter (the SIGLEC14 null allele) and causing expression of a Siglec-5 like protein in monocytes and macrophages. We hypothesized that the SIGLEC14 null allele was associated with Mtb replication in monocytes, T-cell responses to the BCG vaccine, and clinical susceptibility to TB. The SIGLEC14 null allele was associated with protection from TB meningitis in Vietnamese adults but not with pediatric TB in South Africa. The null allele was associated with increased IL-2 and IL-17 production following ex-vivo BCG stimulation of blood from 10 week-old South African infants vaccinated with BCG at birth. Mtb replication was increased in THP-1 cells overexpressing either Siglec-5 or Siglec-14 relative to controls. To our knowledge, this is the first study to demonstrate an association between SIGLEC expression and clinical TB, Mtb replication, or BCG-specific T-cell cytokines.

van Kleef E, Kuijper EJ, Bonten MJM, Cooper BS. 2017. Clostridium difficile in England: can we stop washing our hands? Lancet Infect Dis, 17 (5), pp. 478. | Read more

Baird JK. 2017. Rational malaria chemoprophylaxis - The position of primaquine. Travel Med Infect Dis, 17 pp. 3-4. | Citations: 1 (Web of Science Lite) | Read more

McLean ARD, Boel M, McGready R, Ataide R, Drew D, Tsuboi T, Beeson JG, Nosten F, Simpson JA, Fowkes FJI. 2017. Antibody Responses to Plasmodium falciparum and Plasmodium vivax and Prospective Risk of Plasmodium spp. Infection Postpartum. Am J Trop Med Hyg, 96 (5), pp. 1197-1204. | Show Abstract | Read more

AbstractPostpartum women may have an altered susceptibility to Plasmodium falciparum and Plasmodium vivax. The relationship between naturally acquired malarial immunity and susceptibility to malaria postpartum is yet to be determined. IgG levels were measured against P. falciparum and P. vivax antigens from delivery in 201 postpartum and 201 nonpregnant controls over 12 weeks. Associations between time-varying antibody levels and time to first microscopically confirmed species-specific infection were determined by Cox regression. Associations between antibody levels and prospective risk of Plasmodium infection were similar in postpartum and control women. A 2-fold increase in P. falciparum antibody levels was associated with increased prospective risk of P. falciparum infection (hazard ratio [HR] range = 1.37-1.94). Antibody levels against most P. vivax antigens displayed no association with prospective risk of P. vivax infection (HR range = 1.02-1.05) with the exception of PvMSP119 antibodies that were weakly associated with prospective risk of P. vivax infection (HR = 1.14 (95% confidence interval = 1.02, 1.28) per 2-fold increase in levels). Associations between antibody levels and prospective risk of infection attenuated when adjusted for documented retrospective exposure. Serology may be a useful tool to predict and monitor women at increased risk of P. falciparum infection postpartum, particularly in the absence of a detailed history of retrospective infections.

Kinyoki DK, Moloney GM, Uthman OA, Kandala N-B, Odundo EO, Noor AM, Berkley JA. 2017. Conflict in Somalia: impact on child undernutrition BMJ Global Health, 2 (2), pp. e000262-e000262. | Read more

Cerqueira GC, Cheeseman IH, Schaffner SF, Nair S, McDew-White M, Phyo AP, Ashley EA, Melnikov A, Rogov P, Birren BW et al. 2017. Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance. Genome Biol, 18 (1), pp. 78. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001-2014). RESULTS: We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. CONCLUSIONS: This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.

Ruizendaal E, Tahita MC, Geskus RB, Versteeg I, Scott S, d'Alessandro U, Lompo P, Derra K, Traore-Coulibaly M, de Jong MD et al. 2017. Increase in the prevalence of mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates collected from early to late pregnancy in Nanoro, Burkina Faso. Malar J, 16 (1), pp. 179. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Pregnant women are a high-risk group for Plasmodium falciparum infections, which may result in maternal anaemia and low birth weight newborns, among other adverse birth outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy (IPTp-SP) is widely implemented to prevent these negative effects of malaria. However, resistance against SP by P. falciparum may decrease efficacy of IPTp-SP. Combinations of point mutations in the dhps (codons A437, K540) and dhfr genes (codons N51, C59, S108) of P. falciparum are associated with SP resistance. In this study the prevalence of SP resistance mutations was determined among P. falciparum found in pregnant women and the general population (GP) from Nanoro, Burkina Faso and the association of IPTp-SP dosing and other variables with mutations was studied. METHODS: Blood spots on filter papers were collected from pregnant women at their first antenatal care visit (ANC booking) and at delivery, from an ongoing trial and from the GP in a cross-sectional survey. The dhps and dhfr genes were amplified by nested PCR and products were sequenced to identify mutations conferring resistance (ANC booking, n = 400; delivery, n = 223; GP, n = 400). Prevalence was estimated with generalized estimating equations and for multivariate analyses mixed effects logistic regression was used. RESULTS: The prevalence of the triple dhfr mutation was high, and significantly higher in the GP and at delivery than at ANC booking, but it did not affect birth weight. Furthermore, quintuple mutations (triple dhfr and double dhps mutations) were found for the first time in Burkina Faso. IPTp-SP did not significantly affect the occurrence of any of the mutations, but high transmission season was associated with increased mutation prevalence in delivery samples. It is unclear why the prevalence of mutations was higher in the GP than in pregnant women at ANC booking. CONCLUSION: The high number of mutants and the presence of quintuple mutants in Burkina Faso confirm concerns about the efficacy of IPTp-SP in the near future. Other drug combinations to tackle malaria in pregnancy should, therefore, be explored. An increase in mutation prevalence due to IPTp-SP dosing could not be confirmed.

Lam PK, Ngoc TV, Thu Thuy TT, Hong Van NT, Nhu Thuy TT, Hoai Tam DT, Dung NM, Hanh Tien NT, Thanh Kieu NT, Simmons C et al. 2017. The value of daily platelet counts for predicting dengue shock syndrome: Results from a prospective observational study of 2301 Vietnamese children with dengue. PLoS Negl Trop Dis, 11 (4), pp. e0005498. | Show Abstract | Read more

BACKGROUND: Dengue is the most important mosquito-borne viral infection to affect humans. Although it usually manifests as a self-limited febrile illness, complications may occur as the fever subsides. A systemic vascular leak syndrome that sometimes progresses to life-threatening hypovolaemic shock is the most serious complication seen in children, typically accompanied by haemoconcentration and thrombocytopenia. Robust evidence on risk factors, especially features present early in the illness course, for progression to dengue shock syndrome (DSS) is lacking. Moreover, the potential value of incorporating serial haematocrit and platelet measurements in prediction models has never been assessed. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed data from a prospective observational study of Vietnamese children aged 5-15 years admitted with clinically suspected dengue to the Hospital for Tropical Diseases in Ho Chi Minh City between 2001 and 2009. The analysis population comprised all children with laboratory-confirmed dengue enrolled between days 1-4 of illness. Logistic regression was the main statistical model for all univariate and multivariable analyses. The prognostic value of daily haematocrit levels and platelet counts were assessed using graphs and separate regression models fitted on each day of illness. Among the 2301 children included in the analysis, 143 (6%) progressed to DSS. Significant baseline risk factors for DSS included a history of vomiting, higher temperature, a palpable liver, and a lower platelet count. Prediction models that included serial daily platelet counts demonstrated better ability to discriminate patients who developed DSS from others, than models based on enrolment information only. However inclusion of daily haematocrit values did not improve prediction of DSS. CONCLUSIONS/SIGNIFICANCE: Daily monitoring of platelet counts is important to help identify patients at high risk of DSS. Development of dynamic prediction models that incorporate signs, symptoms, and daily laboratory measurements, could improve DSS prediction and thereby reduce the burden on health services in endemic areas.

Plewes K, Kingston HWF, Ghose A, Maude RJ, Herdman MT, Leopold SJ, Ishioka H, Hasan MMU, Haider MS, Alam S et al. 2017. Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study. BMC Infect Dis, 17 (1), pp. 313. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown. METHODS: As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined. RESULTS: AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 μM; 95% CI, 6.2-12.3 μM), F2-isoprostane (56.7 pg/ml; 95% CI, 45.3-71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1-140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 μM; 95% CI, 4.0-6.6 μM; P = 0.018; F2-IsoPs: 27.8 pg/ml; 95% CI, 23.7-32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2-57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2-IsoPs. Plasma F2-IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2-IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2-IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2-IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis. CONCLUSIONS: Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.

Jeong C, Peter BM, Basnyat B, Neupane M, Beall CM, Childs G, Craig SR, Novembre J, Di Rienzo A. 2017. A longitudinal cline characterizes the genetic structure of human populations in the Tibetan plateau. PLoS One, 12 (4), pp. e0175885. | Citations: 2 (Scopus) | Show Abstract | Read more

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their demography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with worldwide genetic variation data. We found a clear signal of genetic stratification across the east-west axis within Tibetan samples. Samples from more eastern locations tend to have higher genetic affinity with lowland East Asians, which can be explained by more gene flow from lowland East Asia onto the plateau. Our findings corroborate a previous report of admixture signals in Tibetans, which were based on a subset of the samples analyzed here, but add evidence for isolation by distance in a broader geospatial context.

Muema DM, Macharia GN, Olusola BA, Hassan AS, Fegan GW, Berkley JA, Urban BC, Nduati EW. 2017. Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children. PLoS One, 12 (4), pp. e0175570. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: HIV causes defects in memory B cells in children, but the mechanisms of those defects have not been fully elucidated. One possible mechanism is the lack of T-cell help to B cells during immune reactions. However, few studies have assessed the effect of HIV on follicular helper T cells (TFH cells) in children. METHODS: In this study, follicular-homing CD4 T cells and memory B cells were assessed in HIV-infected children and compared with children from the community. CXCR5 and CD45RO were used as markers of follicular-homing T cells and memory T cells, respectively. Memory TFH cells were identified as CD3+CD8-CD4+CXCR5+CD45RO+PD1+. Central memory T cells were identified based on CCR7 expression. Relationship between the proportions of follicular-homing CD4 T cells and memory B cells were determined in multivariable regression models. RESULTS: Highly viremic HIV-infected children had lower proportions of memory TFH cells when compared with community control children. In multivariable analyses, high proportions of memory TFH cells were associated with increased percentages of resting memory B cells after adjusting for other covariates. CONCLUSION: The impact of HIV on follicular helper T cells could influence the accumulation of memory B cells in HIV-infected children.

Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP, Abraham TS, Lee MCS, Basak R, Ghidelli-Disse S, Lafuente-Monasterio MJ et al. 2017. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med, 9 (387), pp. eaad9735-eaad9735. | Citations: 6 (Scopus) | Show Abstract | Read more

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.

Dung TTN, Duy PT, Sessions OM, Sangumathi UK, Phat VV, Tam PTT, To NTN, Phuc TM, Hong Chau TT, Chau NNM et al. 2017. A universal genome sequencing method for rotavirus A from human fecal samples which identifies segment reassortment and multi-genotype mixed infection. BMC Genomics, 18 (1), pp. 324. | Show Abstract | Read more

BACKGROUND: Genomic characterization of rotavirus (RoV) has not been adopted at large-scale due to the complexity of obtaining sequences for all 11 segments, particularly when feces are used as starting material. METHODS: To overcome these limitations, we developed a novel RoV capture and genome sequencing method combining commercial enzyme immunoassay plates and a set of routinely used reagents. RESULTS: Our approach had a 100% success rate, producing >90% genome coverage for diverse RoV present in fecal samples (Ct < 30). CONCLUSIONS: This method provides a novel, reproducible and comparatively simple approach for genomic RoV characterization and could be scaled-up for use in global RoV surveillance systems. TRIAL REGISTRATION (PROSPECTIVELY REGISTERED): Current Controlled Trials ISRCTN88101063 . Date of registration: 14/06/2012.

Teparrukkul P, Hantrakun V, Day NPJ, West TE, Limmathurotsakul D. 2017. Management and outcomes of severe dengue patients presenting with sepsis in a tropical country. PLoS One, 12 (4), pp. e0176233. | Show Abstract | Read more

BACKGROUND: Dengue is a common cause of infection in adults in tropical countries. Sepsis is a syndrome of systemic manifestations induced by infection of any organisms; including bacterial, fungal and viral agents. Here, we investigated the diagnosis, management and outcomes of dengue patients presenting with sepsis in a prospective study of community-acquired sepsis in Thailand. METHODS: From June to December 2015, 874 adult patients (age≥18 years) with suspected or documented community-acquired infection, with ≥3 diagnostic criteria for sepsis according to the Surviving Sepsis Campaign 2012, and within 24 hours of admission were evaluated. Serum was stored and later tested for dengue PCR assays. RESULTS: A total of 126 patients had dengue PCR assays positive (2 DENV-1, 12 DENV-2, 24 DENV-3 and 88 DENV-4), and 5 of them (4%) died. We found that attending physicians suspected dengue infection on admission in 84 patients (67%), and recorded dengue infection as the final diagnosis in 96 patients (76%). Four of five fatal cases were diagnosed and treated as septic shock not due to dengue. In multivariable analysis, there was a trend showing that age≥60 years, hypoxemia and misdiagnosis of dengue by attending physicians were associated with 28-day mortality. CONCLUSIONS: A number of adult patients who died of dengue are misdiagnosed as severe sepsis and septic shock. Diagnosis of dengue based on clinical features alone is difficult. Rapid diagnostic tests for dengue may need to be routinely used in adult patients presenting with sepsis and septic shock in tropical countries. This approach could improve diagnosis and management of those patients.

Verani JR, Baqui AH, Broome CV, Cherian T, Cohen C, Farrar JL, Feikin DR, Groome MJ, Hajjeh RA, Johnson HL et al. 2017. Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls. Vaccine, 35 (25), pp. 3295-3302. | Show Abstract | Read more

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential.

Cho JI, Basnyat B, Jeong C, Di Rienzo A, Childs G, Craig SR, Sun J, Beall CM. 2017. Ethnically Tibetan women in Nepal with low hemoglobin concentration have better reproductive outcomes. Evol Med Public Health, 2017 (1), pp. 82-96. | Show Abstract | Read more

Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high altitudes compared with visitors and Andean highlanders. This study hypothesized that natural selection favors an unelevated hemoglobin concentration among Tibetans. It considered nonheritable sociocultural factors affecting reproductive success and tested the hypotheses that a higher percent of oxygen saturation of hemoglobin (indicating less stress) or lower hemoglobin concentration (indicating dampened response) associated with higher lifetime reproductive success. Methodology: We sampled 1006 post-reproductive ethnically Tibetan women residing at 3000-4100 m in Nepal. We collected reproductive histories by interviews in native dialects and noninvasive physiological measurements. Regression analyses selected influential covariates of measures of reproductive success: the numbers of pregnancies, live births and children surviving to age 15. Results: Taking factors such as marriage status, age of first birth and access to health care into account, we found a higher percent of oxygen saturation associated weakly and an unelevated hemoglobin concentration associated strongly with better reproductive success. Women who lost all their pregnancies or all their live births had hemoglobin concentrations significantly higher than the sample mean. Elevated hemoglobin concentration associated with a lower probability a pregnancy progressed to a live birth. Conclusions and implications: These findings are consistent with the hypothesis that unelevated hemoglobin concentration is an adaptation shaped by natural selection resulting in the relatively low hemoglobin concentration of Tibetans compared with visitors and Andean highlanders.

Srisutham S, Saralamba N, Malleret B, Rénia L, Dondorp AM, Imwong M. 2017. Four human Plasmodium species quantification using droplet digital PCR. PLoS One, 12 (4), pp. e0175771. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Droplet digital polymerase chain reaction (ddPCR) is a partial PCR based on water-oil emulsion droplet technology. It is a highly sensitive method for detecting and delineating minor alleles from complex backgrounds and provides absolute quantification of DNA targets. The ddPCR technology has been applied for detection of many pathogens. Here the sensitive assay utilizing ddPCR for detection and quantification of Plasmodium species was investigated. The assay was developed for two levels of detection, genus specific for all Plasmodium species and for specific Plasmodium species detection. The ddPCR assay was developed based on primers and probes specific to the Plasmodium genus 18S rRNA gene. Using ddPCR for ultra-sensitive P. falciparum assessment, the lower level of detection from concentrated DNA obtained from a high volume (1 mL) blood sample was 11 parasites/mL. For species identification, in particular for samples with mixed infections, a duplex reaction was developed for detection and quantification P. falciparum/ P. vivax and P. malariae/ P. ovale. Amplification of each Plasmodium species in the duplex reaction showed equal sensitivity to singleplex single species detection. The duplex ddPCR assay had higher sensitivity to identify minor species in 32 subpatent parasitaemia samples from Cambodia, and performed better than real-time PCR. The ddPCR assay shows high sensitivity to assess very low parasitaemia of all human Plasmodium species. This provides a useful research tool for studying the role of the asymptomatic parasite reservoir for transmission in regions aiming for malaria elimination.

Mwangome M, Ngari M, Fegan G, Mturi N, Shebe M, Bauni E, Berkley JA. 2017. Diagnostic criteria for severe acute malnutrition among infants aged under 6 mo. Am J Clin Nutr, 105 (6), pp. 1415-1423. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

Background: There is an increasing recognition of malnutrition among infants under 6 mo of age (U6M). Current diagnosis criteria use weight-for-lengthzscores (WLZs), but the 2006 WHO standards exclude infants shorter than 45 cm. In older children, midupper arm circumference (MUAC) predicts mortality better than does WLZ. Outcomes may also be influenced by exposure to HIV and size or gestational age at birth. Diagnostic thresholds for WLZ, MUAC, and other indexes have not been fully evaluated against mortality risk among U6M infants.Objective:The aim was to determine the association of anthropometric indexes with risks of inpatient and postdischarge mortality among U6M infants recruited at the time of hospitalization.Design:We analyzed data from a cohort of U6M infants admitted to Kilifi County Hospital (2007-2013), Kenya. The primary outcomes were inpatient death and death during follow-up over 1 y after discharge. We calculated adjusted RRs for inpatient mortality and HRs for postdischarge mortality for different anthropometric measures and thresholds. Discriminatory value was assessed by using receiver operating characteristic curves.Results:A total of 2882 infants were admitted: 140 (4.9%) died in the hospital and 1405 infants were followed up after discharge. Of these, 75 (5.3%) died within 1 y during 1318 child-years of observation. MUAC and weight-for-agezscore (WAZ) predicted inpatient and postdischarge mortality better than did WLZ (P< 0.0001). A single MUAC threshold of <11.0 cm performed similarly to MUAC thresholds that varied with age (allP> 0.05) and performed better than WLZ <-3 for both inpatient and postdischarge mortality (bothP< 0.001). Reported small size at birth did not reduce the risk of death associated with anthropometric indexes.Conclusions:U6M infants at the highest risk of death are best targeted by using MUAC or WAZ. Further research into the effectiveness of potential interventions is required.

Thuong NTT, Heemskerk D, Tram TTB, Thao LTP, Ramakrishnan L, Ha VTN, Bang ND, Chau TTH, Lan NH, Caws M et al. 2017. Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis. J Infect Dis, 215 (7), pp. 1020-1028. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

Background: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results: LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions: LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

Turner C, Pol S, Suon K, Neou L, Day NPJ, Parker M, Kingori P. 2017. Beliefs and practices during pregnancy, post-partum and in the first days of an infant's life in rural Cambodia. BMC Pregnancy Childbirth, 17 (1), pp. 116. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: The aim of this study was to record the beliefs, practices during pregnancy, post-partum and in the first few days of an infant's life, held by a cross section of the community in rural Cambodia to determine beneficial community interventions to improve early neonatal health. METHODS: Qualitative study design with data generated from semi structured interviews (SSI) and focus group discussions (FGD). Data were analysed by thematic content analysis, with an a priori coding structure developed using available relevant literature. Further reading of the transcripts permitted additional coding to be performed in vivo. This study was conducted in two locations, firstly the Angkor Hospital for Children and secondarily in five villages in Sotnikum, Siem Reap Province, Cambodia. RESULTS: A total of 20 participants underwent a SSIs (15 in hospital and five in the community) and six (three in hospital and three in the community; a total of 58 participants) FGDs were conducted. Harmful practices that occurred in the past (for example: discarding colostrum and putting mud on the umbilical stump) were not described as being practiced. Village elders did not enforce traditional views. Parents could describe signs of illness and felt responsible to seek care for their child even if other family members disagreed, however participants were unaware of the signs or danger of neonatal jaundice. Cost of transportation was the major barrier to healthcare that was identified. CONCLUSIONS: In the population examined, traditional practices in late pregnancy and the post-partum period were no longer commonly performed. However, jaundice, a potentially serious neonatal condition, was not recognised. Community neonatal interventions should be tailored to the populations existing practice and knowledge.

van Santen DK, van der Helm JJ, Del Amo J, Meyer L, D'Arminio Monforte A, Price M, Béguelin CA, Zangerle R, Sannes M, Porter K et al. 2017. Lack of decline in hepatitis C virus incidence among HIV-positive men who have sex with men during 1990–2014 Journal of Hepatology, 67 (2), pp. 255-262. | Citations: 1 (Scopus) | Show Abstract | Read more

© 2017 European Association for the Study of the Liver Background & Aims Hepatitis C virus (HCV) incidence among HIV-positive men who have sex with men (MSM) has increased since 2000, although there are regional differences. We aimed to 1) estimate trends in HCV incidence among HIV-positive MSM, 2) assess the association between incidence and geographical region, age and HIV-related measurements and, 3) assess temporal changes from HIV seroconversion to HCV infection. Methods Data was used from MSM with well-estimated dates of HIV seroconversion from the CASCADE Collaboration (1990–2014). Smoothly varying trends in HCV incidence over time were allowed, using restricted cubic splines. The association of calendar year, age, CD4 count (lagged), HIV RNA (lagged), geographical region and HIV infection stage (recent vs. chronic) with HCV incidence were assessed using Poisson regression. Results Of 5,941 MSM, 337 acquired HCV during follow-up. HCV incidence significantly increased from 0.7/1,000 person-years in 1990 to 18/1,000 person-years in 2014. Recent calendar years, younger age, recent HIV infection and higher HIV RNA levels were significantly associated with HCV incidence, while CD4 count was not. Trends differed by geographical region; while incidence appeared to have stabilized in Western Europe and remained stable in Southern Europe, it continued to increase in Northern Europe in recent years. Time from HIV to HCV infection significantly decreased over time (p < 0.001). Conclusions HCV has continued to spread among HIV-positive MSM in recent years, but trends differ by geographical region. Interventions to decrease the risk of HCV acquisition and increase early diagnosis are warranted. Lay summary Hepatitis C virus infection continues to spread among HIV-positive men who have sex with men, especially among younger individuals. However, trends seem to differ by European region in recent years. Furthermore, men who have sex with men with a higher HIV RNA load were more likely to get infected with the hepatitis C virus. During recent HIV infection, MSM appear to be at higher risk of acquiring hepatitis C.

Laxminarayan R, Kakkar M, Horby P, Malavige GN, Basnyat B. 2017. Emerging and re-emerging infectious disease threats in South Asia: status, vulnerability, preparedness, and outlook. BMJ, 357 pp. j1447. | Read more

Berto A, Day J, Van Vinh Chau N, Thwaites GE, My NN, Baker S, Darton TC. 2017. Current challenges and possible solutions to improve access to care and treatment for hepatitis C infection in Vietnam: a systematic review. BMC Infect Dis, 17 (1), pp. 260. | Show Abstract | Read more

BACKGROUND: Hepatitis C infection is a major public health concern in low- and middle-income countries where an estimated 71.1 million individuals are living with chronic infection. The World Health Organization (WHO) has recently released new guidance for hepatitis C virus (HCV) treatment programs, which include improving the access to new direct-acting antiviral agents. In Vietnam, a highly populated middle-income country, the seroprevalence of HCV infection is approximately 4% and multiple genotypes co-circulate in the general population. Here we review what is currently known regarding the epidemiology of HCV in Vietnam and outline options for reducing the significant burden of morbidity and mortality in our setting. METHODS: We performed a systematic review of the currently available literature to evaluate what has been achieved to date with efforts to control HCV infection in Vietnam. RESULTS: This search retrieved few publications specific to Vietnam indicating a significant gap in baseline epidemiological and public health data. Key knowledge gaps identified included an understanding of the prevalence in specific high-risk groups, characterization of circulating HCV genotypes in the population and likely response to treatment, and the extent to which HCV treatment is available, accessed and utilized. CONCLUSIONS: We conclude that there is an urgent need to perform up to date assessments of HCV disease burden in Vietnam, especially in high-risk groups, in whom incidence is high and cross infection with multiple genotypes is likely to be frequent. Coordinating renewed surveillance measures with forthcoming HCV treatment studies should initiate the traction required to achieve the WHO goal of eliminating HCV as a public health threat by 2030, at least in this region.

Rojek AM, Horby PW. 2017. Offering patients more: how the West Africa Ebola outbreak can shape innovation in therapeutic research for emerging and epidemic infections. Philos Trans R Soc Lond B Biol Sci, 372 (1721), pp. 20160294-20160294. | Citations: 1 (Scopus) | Show Abstract | Read more

Although, after an epidemic of over 28 000 cases, there are still no licensed treatments for Ebola virus disease (EVD), significant progress was made during the West Africa outbreak. The pace of pre-clinical development was exceptional and a number of therapeutic clinical trials were conducted in the face of considerable challenges. Given the on-going risk of emerging infectious disease outbreaks in an era of unprecedented population density, international travel and human impact on the environment it is pertinent to focus on improving the research and development landscape for treatments of emerging and epidemic-prone infections. This is especially the case since there are no licensed therapeutics for some of the diseases considered by the World Health Organization as most likely to cause severe outbreaks-including Middle East respiratory syndrome coronavirus, Marburg virus, Crimean Congo haemorrhagic fever and Nipah virus. EVD, therefore, provides a timely exemplar to discuss the barriers, enablers and incentives needed to find effective treatments in advance of health emergencies caused by emerging infectious diseases.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.

Flahault A, Geissbuhler A, Guessous I, Guérin P, Bolon I, Salathé M, Escher G. 2017. Precision global health in the digital age. Swiss Med Wkly, 147 (1314), pp. w14423. | Citations: 2 (Scopus) | Show Abstract | Read more

Precision global health is an approach similar to precision medicine, which facilitates, through innovation and technology, better targeting of public health interventions on a global scale, for the purpose of maximising their effectiveness and relevance. Illustrative examples include: the use of remote sensing data to fight vector-borne diseases; large databases of genomic sequences of foodborne pathogens helping to identify origins of outbreaks; social networks and internet search engines for tracking communicable diseases; cell phone data in humanitarian actions; drones to deliver healthcare services in remote and secluded areas. Open science and data sharing platforms are proposed for fostering international research programmes under fair, ethical and respectful conditions. Innovative education, such as massive open online courses or serious games, can promote wider access to training in public health and improving health literacy. The world is moving towards learning healthcare systems. Professionals are equipped with data collection and decision support devices. They share information, which are complemented by external sources, and analysed in real time using machine learning techniques. They allow for the early detection of anomalies, and eventually guide appropriate public health interventions. This article shows how information-driven approaches, enabled by digital technologies, can help improving global health with greater equity.

Suttisunhakul V, Pumpuang A, Ekchariyawat P, Wuthiekanun V, Elrod MG, Turner P, Currie BJ, Phetsouvanh R, Dance DAB, Limmathurotsakul D et al. 2017. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for the identification of Burkholderia pseudomallei from Asia and Australia and differentiation between Burkholderia species. PLoS One, 12 (4), pp. e0175294. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is increasingly used for rapid bacterial identification. Studies of Burkholderia pseudomallei identification have involved small isolate numbers drawn from a restricted geographic region. There is a need to expand the reference database and evaluate B. pseudomallei from a wider geographic distribution that more fully captures the extensive genetic diversity of this species. Here, we describe the evaluation of over 650 isolates. Main spectral profiles (MSP) for 26 isolates of B. pseudomallei (N = 5) and other Burkholderia species (N = 21) were added to the Biotyper database. MALDI-TOF MS was then performed on 581 B. pseudomallei, 19 B. mallei, 6 B. thailandensis and 23 isolates representing a range of other bacterial species. B. pseudomallei originated from northeast and east Thailand (N = 524), Laos (N = 12), Cambodia (N = 14), Hong Kong (N = 4) and Australia (N = 27). All 581 B. pseudomallei were correctly identified, with 100% sensitivity and specificity. Accurate identification required a minimum inoculum of 5 x 107 CFU/ml, and identification could be performed on spiked blood cultures after 24 hours of incubation. Comparison between a dendrogram constructed from MALDI-TOF MS main spectrum profiles and a phylogenetic tree based on recA gene sequencing demonstrated that MALDI-TOF MS distinguished between B. pseudomallei and B. mallei, while the recA tree did not. MALDI-TOF MS is an accurate method for the identification of B. pseudomallei, and discriminates between this and other related Burkholderia species.

Salerno-Goncalves R, Luo D, Fresnay S, Magder L, Darton TC, Jones C, Waddington CS, Blohmke CJ, Angus B, Levine MM et al. 2017. Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. Front Immunol, 8 (APR), pp. 398. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Gastrointestinal infections by Salmonella enterica serovar Typhi (S. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8+ MAIT cells are activated and have the potential to kill cells exposed to S. Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown. In this study, we characterize the human CD8+ MAIT cell immune response to S. Typhi infection in subjects participating in a challenge clinical trial who received a low- or high dose of wild-type S. Typhi. We define the kinetics of CD8+ MAIT cells as well as their levels of activation, proliferation, exhaustion/apoptosis, and homing potential. Regardless of the dose, in volunteers resistant to infection (NoTD), the levels of CD8+ MAIT cells after S. Typhi challenge fluctuated around their baseline values (day 0). In contrast, volunteers susceptible to the development of typhoid disease (TD) exhibited a sharp decline in circulating MAIT cells during the development of typhoid fever. Interestingly, MAIT cells from low-dose TD volunteers had higher levels of CD38 coexpressing CCR9, CCR6, and Ki67 during the development of typhoid fever than high-dose TD volunteers. No substantial perturbations on the levels of these markers were observed in NoTD volunteers irrespective of the dose. In sum, we describe, for the first time, that exposure to an enteric bacterium, in this case S. Typhi, results in changes in MAIT cell activation, proliferation, and homing characteristics, suggesting that MAIT cells are an important component of the human host response to bacterial infection.

Thriemer K, Ley B, Bobogare A, Dysoley L, Alam MS, Pasaribu AP, Sattabongkot J, Jambert E, Domingo GJ, Commons R et al. 2017. Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group. Malar J, 16 (1), pp. 141. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia-Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by  the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.

Marais BJ, Heemskerk D, Thwaites GE, Tuberculous Meningitis International Research Consortium. 2017. Reply to Dhawan and Sankhyan. Clin Infect Dis, 64 (12), pp. 1805. | Read more

Gathara D, Malla L, Ayieko P, Karuri S, Nyamai R, Irimu G, van Hensbroek MB, Allen E, English M, Clinical Information Network. 2017. Variation in and risk factors for paediatric inpatient all-cause mortality in a low income setting: data from an emerging clinical information network. BMC Pediatr, 17 (1), pp. 99. | Show Abstract | Read more

BACKGROUND: Hospital mortality data can inform planning for health interventions and may help optimize resource allocation if they are reliable and appropriately interpreted. However such data are often not available in low income countries including Kenya. METHODS: Data from the Clinical Information Network covering 12 county hospitals' paediatric admissions aged 2-59 months for the periods September 2013 to March 2015 were used to describe mortality across differing contexts and to explore whether simple clinical characteristics used to classify severity of illness in common treatment guidelines are consistently associated with inpatient mortality. Regression models accounting for hospital identity and malaria prevalence (low or high) were used. Multiple imputation for missing data was based on a missing at random assumption with sensitivity analyses based on pattern mixture missing not at random assumptions. RESULTS: The overall cluster adjusted crude mortality rate across hospitals was 6 · 2% with an almost 5 fold variation across sites (95% CI 4 · 9 to 7 · 8; range 2 · 1% - 11 · 0%). Hospital identity was significantly associated with mortality. Clinical features included in guidelines for common diseases to assess severity of illness were consistently associated with mortality in multivariable analyses (AROC =0 · 86). CONCLUSION: All-cause mortality is highly variable across hospitals and associated with clinical risk factors identified in disease specific guidelines. A panel of these clinical features may provide a basic common data framework as part of improved health information systems to support evaluations of quality and outcomes of care at scale and inform health system strengthening efforts.

Font-Gonzalez A, Feijen ELAM, Geskus RB, Dijkgraaf MGW, van der Pal HJH, Heinen RC, Jaspers MW, van Leeuwen FE, Reitsma JBJ, Caron HN et al. 2017. Risk and associated risk factors of hospitalization for specific health problems over time in childhood cancer survivors: a medical record linkage study Cancer Medicine, 6 (5), pp. 1123-1134. | Show Abstract | Read more

© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Childhood cancer survivors (CCS) experience higher hospitalization rates compared to the general population for neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. We studied trends in hospitalization rates and associated patient and treatment-specific risk factors for diagnosis subgroups among these four diseases. We performed medical record linkage of a ≥5-year CCS cohort with national registers, and obtained a random reference sample matched on age, gender and calendar year per CCS. For each diagnosis subgroup we compared hospitalization rates and trends over time in CCS and the reference population. Further, we analyzed risk factors for hospitalizations within the four CCS diagnosis groups. We used multivariate Poisson regression for all models. We retrieved hospitalization data from 1382 CCS and 26,583 reference persons. CCS had increased hospitalization rates for almost all diagnosis subgroups examined. Hospitalization rates for endocrine/nutritional/metabolic diseases appeared to increase with longer time since primary cancer diagnosis up to 30 years after primary cancer diagnosis. Survivors initially treated with radiotherapy had increased hospitalization rates for neoplasms (P  <  0.001), those initially treated with anthracyclines (2.5 [1.1–5.5]) and radiotherapy to thorax and/or abdomen (9.3 [2.4–36.6] ) had increased hospitalization rates for diseases of the circulatory system, and those initially treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases (6.7 [3.5–12.7]) and diseases of the eye (3.6 [1.5–8.9] ). Our study highlights that long-term health problems resulting in hospitalizations are still clinically relevant later in life of CCS. The identified treatment-related risk factors associated with hospitalizations support targeted follow-up care for these risk groups of CCS.

Ding XC, Ade MP, Baird JK, Cheng Q, Cunningham J, Dhorda M, Drakeley C, Felger I, Gamboa D, Harbers M et al. 2017. Defining the next generation of Plasmodium vivax diagnostic tests for control and elimination: Target product profiles. PLoS Negl Trop Dis, 11 (4), pp. e0005516. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

The global prevalence of malaria has decreased over the past fifteen years, but similar gains have not been realized against Plasmodium vivax because this species is less responsive to conventional malaria control interventions aimed principally at P. falciparum. Approximately half of all malaria cases outside of Africa are caused by P. vivax. This species places dormant forms in human liver that cause repeated clinical attacks without involving another mosquito bite. The diagnosis of acute patent P. vivax malaria relies primarily on light microscopy. Specific rapid diagnostic tests exist but typically perform relatively poorly compared to those for P. falciparum. Better diagnostic tests are needed for P. vivax. To guide their development, FIND, in collaboration with P. vivax experts, identified the specific diagnostic needs associated with this species and defined a series of three distinct target product profiles, each aimed at a particular diagnostic application: (i) point-of-care of acutely ill patients for clinical care purposes; (ii) point-of-care asymptomatic and otherwise sub-patent residents for public health purposes, e.g., mass screen and treat campaigns; and (iii) ultra-sensitive not point-of-care diagnosis for epidemiological research/surveillance purposes. This report presents and discusses the rationale for these P. vivax-specific diagnostic target product profiles. These contribute to the rational development of fit-for-purpose diagnostic tests suitable for the clinical management, control and elimination of P. vivax malaria.

Darton TC, Zhou L, Blohmke CJ, Jones C, Waddington CS, Baker S, Pollard AJ. 2017. Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia. J Infect, 74 (4), pp. 358-366. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Improved diagnostics for typhoid are needed; a typhoid controlled human infection model may accelerate their development and translation. Here, we evaluated a blood culture-PCR assay for detecting infection after controlled human infection with S. Typhi and compared test performance with optimally performed blood cultures. METHODOLOGY/PRINCIPAL FINDINGS: Culture-PCR amplification of blood samples was performed alongside daily blood culture in 41 participants undergoing typhoid challenge. Study endpoints for typhoid diagnosis (TD) were fever and/or bacteraemia. Overall, 24/41 (59%) participants reached TD, of whom 21/24 (86%) had ≥1 positive blood culture (53/674, 7.9% of all cultures) or 18/24 (75%) had ≥1 positive culture-PCR assay result (57/684, 8.3%). A further five non-bacteraemic participants produced culture-PCR amplicons indicating infection; overall sensitivity/specificity of the assay compared to the study endpoints were 70%/65%. We found no significant difference between blood culture and culture-PCR methods in ability to identify cases (12 mismatching pairs, p = 0.77, binomial test). Clinical and stool culture metadata demonstrated that additional culture-PCR amplification positive individuals likely represented true cases missed by blood culture, suggesting the overall attack rate may be 30/41 (73%) rather than 24/41 (59%). Several participants had positive culture-PCR results soon after ingesting challenge providing new evidence for occurrence of an early primary bacteraemia. CONCLUSIONS/SIGNIFICANCE: Overall the culture-PCR assay performed well, identifying extra typhoid cases compared with routine blood culture alone. Despite limitations to widespread field-use, the benefits of increased diagnostic yield, reduced blood volume and faster turn-around-time, suggest that this assay could enhance laboratory typhoid diagnostics in research applications and high-incidence settings.

Thuy-Nhien N, Tuyen NK, Tong NT, Vy NT, Thanh NV, Van HT, Huong-Thu P, Quang HH, Boni MF, Dolecek C et al. 2017. K13 Propeller Mutations in Plasmodium falciparum Populations in Regions of Malaria Endemicity in Vietnam from 2009 to 2016. Antimicrob Agents Chemother, 61 (4), pp. e01578-16-e01578-16. | Citations: 2 (Scopus) | Show Abstract | Read more

The spread of artemisinin-resistantPlasmodium falciparumcompromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT forP. falciparuminfection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060P. falciparumisolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA)in vitroand prolonged parasite clearancein vivoAn analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.

Faiz MA, Ahsan MF, Ghose A, Rahman MR, Amin R, Hossain M, Tareq MNU, Jalil MA, Kuch U, Theakston RDG et al. 2017. Bites by the Monocled Cobra, Naja kaouthia, in Chittagong Division, Bangladesh: Epidemiology, Clinical Features of Envenoming and Management of 70 Identified Cases. Am J Trop Med Hyg, 96 (4), pp. 876-884. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

AbstractWe describe 70 cases of monocled cobra (Naja kaouthia) bite admitted to Chittagong Medical College Hospital, Bangladesh. The biting snakes were identified by examining the dead snake and/or detecting N. kaouthia venom antigens in patients' serum. Bites were most common in the early morning and evening during the monsoon (May-July). Ligatures were routinely applied to the bitten limb before admission. Thirty-seven patients consulted traditional healers, most of whom made incisions around the bite site. Fifty-eight patients experienced severe neurotoxicity and most suffered swelling and pain of the bitten limb. The use of an Indian polyvalent antivenom in patients exhibiting severe neurotoxicity resulted in clinical improvement but most patients experienced moderate-to-severe adverse reactions. Antivenom did not influence local blistering and necrosis appearing in 19 patients; 12 required debridement. Edrophonium significantly improved the ability of patients to open the eyes, endurance of upward gaze, and peak expiratory flow rate suggesting that a longer-acting anticholinesterase drug (neostigmine) could be recommended for first aid. The study suggested that regionally appropriate antivenom should be raised against the venoms of the major envenoming species of Bangladesh and highlighted the need to improve the training of staff of local medical centers and to invest in the basic health infrastructure in rural communities.

Kintz E, Heiss C, Black I, Donohue N, Brown N, Davies MR, Azadi P, Baker S, Kaye PM, van der Woude M. 2017. Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition. Infect Immun, 85 (4), pp. e01021-16-e01021-16. | Citations: 1 (Scopus) | Show Abstract | Read more

Salmonella enterica serovar Typhi is a human-restricted Gram-negative bacterial pathogen responsible for causing an estimated 27 million cases of typhoid fever annually, leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by the activity of glycosyltransferase (gtr) operons acquired by horizontal gene transfer. Here we investigate the role of two gtr operons that we identified in the S Typhi genome. Strains were engineered to express specific gtr operons. Full chemical analysis of the O-antigens of these strains identified gtr-dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered the expression of this glucosylating gtr operon uniform in the population. In contrast, the expression of the acetylating gtrC gene is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism, and thus, this modification may contribute to persistence in a host. In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modifications should be taken into consideration when assessing responses to vaccines, especially O-antigen-based vaccines, and that the Salmonellagtr repertoire may confound the protective efficacy of broad-ranging Salmonella lipopolysaccharide conjugate vaccines.

Göhler A, Trung TT, Hopf V, Kohler C, Hartleib J, Wuthiekanun V, Peacock SJ, Limmathurotsakul D, Tuanyok A, Steinmetz I. 2017. Multitarget Quantitative PCR Improves Detection and Predicts Cultivability of the Pathogen Burkholderia pseudomallei. Appl Environ Microbiol, 83 (8), pp. e03212-16-e03212-16. | Show Abstract | Read more

Burkholderia pseudomallei is present in the environment in many parts of the world and causes the often-fatal disease melioidosis. The sensitive detection and quantification of B. pseudomallei in the environment are a prerequisite for assessing the risk of infection. We recently reported the direct detection of B. pseudomallei in soil samples using a quantitative PCR (qPCR) targeting a single type three secretion system 1 (TTSS1) gene. Here, we extend the qPCR-based analysis of B. pseudomallei in soil by validating novel qPCR gene targets selected from a comparative genomic analysis. Two hundred soil samples from two rice paddies in northeast Thailand were evaluated, of which 47% (94/200) were B. pseudomallei culture positive. The TTSS1 qPCR and two novel qPCR assays that targeted open reading frames (ORFs) BPSS0087 and BPSS0745 exhibited detection rates of 76.5% (153/200), 34.5% (69/200), and 74.5% (150/200), respectively. The combination of TTSS1 and BPSS0745 qPCR increased the detection rate to 90% (180/200). Combining the results of the three qPCR assays and the BPSS1187 nested PCR previously published, all 200 samples were positive by at least one PCR assay. Samples positive by either TTSS1 (n = 153) or BPSS0745 (n = 150) qPCR were more likely to be direct-culture positive, with odds ratios of 4.0 (95% confidence interval [CI], 1.7 to 9.5; P < 0.001) and 9.0 (95% CI, 3.1 to 26.4; P < 0.001), respectively. High B. pseudomallei genome equivalents correlated with high CFU counts by culture. In conclusion, multitarget qPCR improved the B. pseudomallei detection rate in soil samples and predicted culture positivity. This approach has the potential for use as a sensitive environmental screening method for B. pseudomalleiIMPORTANCE The worldwide environmental distribution of the soil bacterium Burkholderia pseudomallei remains to be determined. So far, most environmental studies have relied on culture-based approaches to detect this pathogen. Since current culture methods are laborious, are time consuming, and have limited sensitivity, culture-independent and more sensitive methods are needed. In this study, we show that a B. pseudomallei-specific qPCR approach can detect significantly higher numbers of B. pseudomallei-positive soil samples from areas where it is endemic compared with that from culture. The use of multiple independent B. pseudomallei-specific qPCR targets further increased the detection rate of B. pseudomallei compared with that from single targets. Samples with a high molecular B. pseudomallei load were more likely to be culture positive. We conclude that our quantitative multitarget approach might be useful in defining areas where there is a risk of B. pseudomallei infections in different parts of the world.

Kinyoki DK, Manda SO, Moloney GM, Odundo EO, Berkley JA, Noor AM, Kandala N-B. 2017. Modelling the Ecological Comorbidity of Acute Respiratory Infection, Diarrhoea and Stunting among Children Under the Age of 5 Years in Somalia. Int Stat Rev, 85 (1), pp. 164-176. | Show Abstract | Read more

The aim of this study was to assess spatial co-occurrence of acute respiratory infections (ARI), diarrhoea and stunting among children of the age between 6 and 59 months in Somalia. Data were obtained from routine biannual nutrition surveys conducted by the Food and Agriculture Organization 2007-2010. A Bayesian hierarchical geostatistical shared component model was fitted to the residual spatial components of the three health conditions. Risk maps of the common spatial effects at 1×1 km resolution were derived. The empirical correlations of the enumeration area proportion were 0.37, 0.63 and 0.66 for ARI and stunting, diarrhoea and stunting and ARI and diarrhoea, respectively. Spatially, the posterior residual effects ranged 0.03-20.98, 0.16-6.37 and 0.08-9.66 for shared component between ARI and stunting, diarrhoea and stunting and ARI and diarrhoea, respectively. The analysis showed clearly that the spatial shared component between ARI, diarrhoea and stunting was higher in the southern part of the country. Interventions aimed at controlling and mitigating the adverse effects of these three childhood health conditions should focus on their common putative risk factors, particularly in the South in Somalia.

Phuc BQ, Rasmussen C, Duong TT, Dong LT, Loi MA, Ménard D, Tarning J, Bustos D, Ringwald P, Galappaththy GL, Thieu NQ. 2017. Treatment Failure of Dihydroartemisinin/Piperaquine for Plasmodium falciparum Malaria, Vietnam. Emerg Infect Dis, 23 (4), pp. 715-717. | Citations: 1 (Scopus) | Show Abstract | Read more

We conducted a study in Binh Phuoc, Vietnam, in 2015 on the therapeutic efficacy of dihydroartemisinin/piperaquine for Plasmodium falciparum malaria. A high number of treatment failures (14/40) was found, and piperaquine resistance in Vietnam was confirmed. A change in the malaria treatment policy for Vietnam is in process.

Rocha MV, Françoso KS, Lima LC, Camargo TM, Machado RLD, Costa FTM, Rénia L, Nosten F, Russell B, Rodrigues MM, Soares IS. 2017. Generation, characterization and immunogenicity of a novel chimeric recombinant protein based on Plasmodium vivax AMA-1 and MSP119. Vaccine, 35 (18), pp. 2463-2472. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Plasmodium vivax is the most widely distributed malaria species and the most prevalent species of malaria in America and Asia. Vaccine development against P. vivax is considered a priority in the global program for the eradication of malaria. Earlier studies have characterized the Apical Membrane Antigen 1 (AMA-1) ectodomain and the C-terminal region (19kDa) of the Merozoite Surface Protein 1 (MSP-1) of P. vivax as immunodominant antigens. Based on this characterization, we designed a chimeric recombinant protein containing both merozoite immunodominant domains (PvAMA166-MSP119). The recombinant PvAMA166-MSP119 was successfully expressed in Pichia pastoris and used to immunize two different mouse strains (BALB/c and C57BL/6) in the presence of the Poly (I:C) as an adjuvant. Immunization with the chimeric protein induced high antibody titers against both proteins in both strains of mice as detected by ELISA. Antisera also recognized the native proteins expressed on the merozoites of mature P. vivax schizonts. Moreover, this antigen was able to induce IFN-gamma-secreting cells in C57BL/6 mice. These findings indicate that this novel yeast recombinant protein containing PvAMA166 and PvMSP119 is advantageous, because of improved antibody titers and cellular immune response. Therefore, this formulation should be further developed for pre-clinical trials in non-human primates as a potential candidate for a P. vivax vaccine.

Lubell Y, Althaus T. 2017. Biomarker tests for bacterial infection-a costly wait for the holy grail. Lancet Infect Dis, 17