Tropical Medicine publications 2018

Haniffa R, Beane A, Baker T, Riviello ED, Schell CO, Dondorp AM. 2018. Development and internal validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU). Acta Anaesthesiol Scand, 62 (3), pp. 407-408. | Read more

Quan TM, Phuong HT, Vy NHT, Thanh NTL, Lien NTN, Hong TTK, Dung PN, Chau NVV, Boni MF, Clapham HE. 2018. Evidence of previous but not current transmission of chikungunya virus in southern and central Vietnam: Results from a systematic review and a seroprevalence study in four locations. PLoS Negl Trop Dis, 12 (2), pp. e0006246. | Show Abstract | Read more

BACKGROUND: Arbovirus infections are a serious concern in tropical countries due to their high levels of transmission and morbidity. With the outbreaks of chikungunya (CHIKV) in surrounding regions in recent years and the fact that the environment in Vietnam is suitable for the vectors of CHIKV, the possibility of transmission of CHIKV in Vietnam is of great interest. However, information about CHIKV activity in Vietnam remains limited. METHODOLOGY: In order to address this question, we performed a systematic review of CHIKV in Vietnam and a CHIKV seroprevalence survey. The seroprevalence survey tested for CHIKV IgG in population serum samples from individuals of all ages in 2015 from four locations in Vietnam. PRINCIPAL FINDINGS: The four locations were An Giang province (n = 137), Ho Chi Minh City (n = 136), Dak Lak province (n = 137), and Hue City (n = 136). The findings give us evidence of some CHIKV activity: 73/546 of overall samples were seropositive (13.4%). The age-adjusted seroprevalences were 12.30% (6.58-18.02), 13.42% (7.16-19.68), 7.97% (3.56-12.38), and 3.72% (1.75-5.69) in An Giang province, Ho Chi Minh City, Dak Lak province, and Hue City respectively. However, the age-stratified seroprevalence suggests that the last transmission ended around 30 years ago, consistent with results from the systematic review. We see no evidence for on-going transmission in three of the locations, though with some evidence of recent exposure in Dak Lak, most likely due to transmission in neighbouring countries. Before the 1980s, when transmission was occurring, we estimate on average 2-4% of the population were infected each year in HCMC and An Giang and Hue (though transmision ended earlier in Hue). We estimate lower transmission in Dak Lak, with around 1% of the population infected each year. CONCLUSION: In conclusion, we find evidence of past CHIKV transmission in central and southern Vietnam, but no evidence of recent sustained transmission. When transmission of CHIKV did occur, it appeared to be widespread and affect a geographically diverse population. The estimated susceptibility of the population to chikungunya is continually increasing, therefore the possibility of future CHIKV transmission in Vietnam remains.

Rosala-Hallas A, Bhangu A, Blazeby J, Bowman L, Clarke M, Lang T, Nasser M, Siegfried N, Soares-Weiser K, Sydes MR et al. 2018. Global health trials methodological research agenda: results from a priority setting exercise. Trials, 19 (1), pp. 48. | Show Abstract | Read more

BACKGROUND: Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. METHODS: An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. FINDINGS: Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. CONCLUSION: By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Mfueni E, Devleesschauwer B, Rosas-Aguirre A, Van Malderen C, Brandt PT, Ogutu B, Snow RW, Tshilolo L, Zurovac D, Vanderelst D, Speybroeck N. 2018. True malaria prevalence in children under five: Bayesian estimation using data of malaria household surveys from three sub-Saharan countries. Malar J, 17 (1), pp. 65. | Show Abstract | Read more

BACKGROUND: Malaria is one of the major causes of childhood death in sub-Saharan countries. A reliable estimation of malaria prevalence is important to guide and monitor progress toward control and elimination. The aim of the study was to estimate the true prevalence of malaria in children under five in the Democratic Republic of the Congo, Uganda and Kenya, using a Bayesian modelling framework that combined in a novel way malaria data from national household surveys with external information about the sensitivity and specificity of the malaria diagnostic methods used in those surveys-i.e., rapid diagnostic tests and light microscopy. METHODS: Data were used from the Demographic and Health Surveys (DHS) and Malaria Indicator Surveys (MIS) conducted in the Democratic Republic of the Congo (DHS 2013-2014), Uganda (MIS 2014-2015) and Kenya (MIS 2015), where information on infection status using rapid diagnostic tests and/or light microscopy was available for 13,573 children. True prevalence was estimated using a Bayesian model that accounted for the conditional dependence between the two diagnostic methods, and the uncertainty of their sensitivities and specificities obtained from expert opinion. RESULTS: The estimated true malaria prevalence was 20% (95% uncertainty interval [UI] 17%-23%) in the Democratic Republic of the Congo, 22% (95% UI 9-32%) in Uganda and 1% (95% UI 0-3%) in Kenya. According to the model estimations, rapid diagnostic tests had a satisfactory sensitivity and specificity, and light microscopy had a variable sensitivity, but a satisfactory specificity. Adding reported history of fever in the previous 14 days as a third diagnostic method to the model did not affect model estimates, highlighting the poor performance of this indicator as a malaria diagnostic. CONCLUSIONS: In the absence of a gold standard test, Bayesian models can assist in the optimal estimation of the malaria burden, using individual results from several tests and expert opinion about the performance of those tests.

Price RN, White NJ. 2018. Drugs that reduce transmission of falciparum malaria. Lancet Infect Dis, | Read more

Musoro JZ, Zwinderman AH, Bosman R, Abu-Hanna A, Geskus RB. 2018. Dynamic prediction of mortality among patients in intensive care using the sequential organ failure assessment (SOFA) score: a joint competing risk survival and longitudinal modeling approach Statistica Neerlandica, 72 (1), pp. 34-47. | Show Abstract | Read more

© 2017 The Authors. Statistica Neerlandica © 2017 VVS. In intensive care units (ICUs), besides routinely collected admission data, a daily monitoring of organ dysfunction using scoring systems such as the sequential organ failure assessment (SOFA) score has become practice. Such updated information is valuable in making accurate predictions of patients' survival. Few prediction models that incorporate this updated information have been reported. We used follow-up data of ICU patients who either died or were discharged at the end of hospital stay, without censored cases. We propose a joint model comprising a linear mixed effects submodel for the development of longitudinal SOFA scores and a proportional subdistribution hazards submodel for death as end point with discharge as competing risk. The two parts are linked by shared latent terms. Because there was no censoring, it was straightforward to fit our joint model using available software. We compared predictive values, based on the Brier score and the area under the receiver operating characteristic curve, from our model with those obtained from an earlier modeling approach by Toma et al. [Journal of Biomedical Informatics 40, 649, (2007)] that relied on patterns discovered in the SOFA scores over a given period of time.

Mai NTH, Phu NH, Nghia HDT, Phuong TM, Duc DT, Chau NVV, Wills B, Lim CCT, Thwaites G, Simmons CP, Yacoub S. 2018. Dengue-Associated Posterior Reversible Encephalopathy Syndrome, Vietnam. Emerg Infect Dis, 24 (2), pp. 402-404. | Show Abstract | Read more

Dengue can cause neurologic complications in addition to the more common manifestations of plasma leakage and coagulopathy. Posterior reversible encephalopathy syndrome has rarely been described in dengue, although the pathophysiology of endothelial dysfunction likely underlies both. We describe a case of dengue-associated posterior reversible encephalopathy syndrome and discuss diagnosis and management.

de Alwis R, Watson C, Nikolay B, Lowry JH, Thieu NTV, Van TT, Ngoc DTT, Rawalai K, Taufa M, Coriakula J et al. 2018. Role of environmental factors in shaping spatial distribution of salmonella enterica Serovar Typhi, Fiji Emerging Infectious Diseases, 24 (2), pp. 284-293. | Show Abstract | Read more

© 2018 Centers for Disease Control and Prevention (CDC). All rights Reserved. Fiji recently experienced a sharp increase in reported typhoid fever cases. To investigate geographic distribution and environmental risk factors associated with Salmonella enterica serovar Typhi infection, we conducted a cross-sectional cluster survey with associated serologic testing for Vi capsular antigen-specific antibodies (a marker for exposure to Salmonella Typhi in Fiji in 2013. Hotspots with high seroprevalence of Vi-specific antibodies were identified in northeastern mainland Fiji. Risk for Vi seropositivity increased with increased annual rainfall (odds ratio [OR] 1.26/quintile increase, 95% CI 1.12-1.42), and decreased with increased distance from major rivers and creeks (OR 0.89/km increase, 95% CI 0.80-0.99) and distance to modeled flood-risk areas (OR 0.80/quintile increase, 95% CI 0.69-0.92) after being adjusted for age, typhoid fever vaccination, and home toilet type. Risk for exposure to Salmonella Typhi and its spatial distribution in Fiji are driven by environmental factors. Our findings can directly affect typhoid fever control efforts in Fiji.

Nguyen T-N, von Seidlein L, Nguyen T-V, Truong P-N, Hung SD, Pham H-T, Nguyen T-U, Le TD, Dao VH, Mukaka M et al. 2018. The persistence and oscillations of submicroscopic Plasmodium falciparum and Plasmodium vivax infections over time in Vietnam: an open cohort study. Lancet Infect Dis, | Show Abstract | Read more

BACKGROUND: A substantial proportion of Plasmodium species infections are asymptomatic with densities too low to be detectable with standard diagnostic techniques. The importance of such asymptomatic plasmodium infections in malaria transmission is probably related to their duration and density. To explore the duration of asymptomatic plasmodium infections and changes in parasite densities over time, a cohort of participants who were infected with Plasmodium parasites was observed over a 2-year follow-up period. METHODS: In this open cohort study, inhabitants of four villages in Vietnam were invited to participate in baseline and subsequent 3-monthly surveys up to 24 months, which included the collection of venous blood samples. Samples were batch-screened using ultra-sensitive (u)PCR (lower limit of detection of 22 parasites per mL). Participants found to be infected by uPCR during any of these surveys were invited to join a prospective cohort and provide monthly blood samples. We estimated the persistence of Plasmodium falciparum and Plasmodium vivax infections and changes in parasite densities over a study period of 24 months. FINDINGS: Between Dec 1, 2013, and Jan 8, 2016, 356 villagers participated in between one and 22 surveys. These study participants underwent 4248 uPCR evaluations (11·9 tests per participant). 1874 (32%) of 4248 uPCR tests indicated a plasmodium infection; 679 (36%) of 1874 tests were P falciparum monoinfections, 507 (27%) were P vivax monoinfections, 463 (25%) were co-infections with P falciparum and P vivax, and 225 (12%) were indeterminate species of Plasmodium. The median duration of P falciparum infection was 2 months (IQR 1-3); after accounting for censoring, participants had a 20% chance of having parasitaemia for 4 months or longer. The median duration of P vivax infection was 6 months (3-9), and participants had a 59% chance of having parasitaemia for 4 months or longer. The parasite densities of persistent infections oscillated; following ultralow-density infections, high-density infections developed frequently. INTERPRETATION: Persistent largely asymptomatic P vivax and P falciparum infections are common in this area of low seasonal malaria transmission. Infections with low-density parasitaemias can develop into much higher density infections at a later time, which are likely to sustain malaria endemicity. FUNDING: The Wellcome Trust, Bill & Melinda Gates Foundation.

Wongsuvan G, Wuthiekanun V, Hinjoy S, Day NP, Limmathurotsakul D. 2018. Antibiotic use in poultry: a survey of eight farms in Thailand. Bull World Health Organ, 96 (2), pp. 94-100. | Show Abstract | Read more

Objective: To investigate antibiotic use in poultry farms in Thailand and estimate the total amount of antibiotics used annually in Thai production of chicken meat. Methods: In a single province, we surveyed eight farms in which chickens were raised for meat and interviewed the farms' owners in 2016. The antibiotic use for each chicken was defined as the amount of antibiotic given to the chicken over its entire lifetime divided by the target weight of the chicken at the time of its slaughter. Assuming that the results were nationally representative, we estimated annual antibiotic use on all Thai chickens raised for meat. Findings: No use of antibiotics for growth promotion was reported. Five farms raised 1-kg chickens for company A and reportedly used no antibiotics unless the chickens were sick. The other three farms raised 3-kg chickens for company B and reported routine use of antibiotics for prophylaxis. Per kg final weight, each chicken raised for company B was reportedly routinely given a mean of 101 mg of antibiotics - that is, 33 mg of amoxicillin, 29 mg colistin, 19 mg oxytetracycline, 18 mg doxycycline and 2 mg tilmicosin. The total amount of antibiotic used on all Thai chickens raised for meat in 2016 was estimated to be 161 tonnes. Conclusion: Each year in Thailand, many tonnes of antibiotics are probably routinely used in raising chickens for meat. Labels on retail packs of meat should include data on antibiotic use in the production of the meat.

Amato R, Pearson RD, Almagro-Garcia J, Amaratunga C, Lim P, Suon S, Sreng S, Drury E, Stalker J, Miotto O et al. 2018. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. Lancet Infect Dis, | Show Abstract | Read more

BACKGROUND: Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. METHODS: We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus. FINDINGS: We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia. INTERPRETATION: The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. FUNDING: Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Wiersinga WJ, Virk HS, Torres AG, Currie BJ, Peacock SJ, Dance DAB, Limmathurotsakul D. 2018. Melioidosis. Nat Rev Dis Primers, 4 pp. 17107. | Show Abstract | Read more

Burkholderia pseudomallei is a Gram-negative environmental bacterium and the aetiological agent of melioidosis, a life-threatening infection that is estimated to account for ∼89,000 deaths per year worldwide. Diabetes mellitus is a major risk factor for melioidosis, and the global diabetes pandemic could increase the number of fatalities caused by melioidosis. Melioidosis is endemic across tropical areas, especially in southeast Asia and northern Australia. Disease manifestations can range from acute septicaemia to chronic infection, as the facultative intracellular lifestyle and virulence factors of B. pseudomallei promote survival and persistence of the pathogen within a broad range of cells, and the bacteria can manipulate the host's immune responses and signalling pathways to escape surveillance. The majority of patients present with sepsis, but specific clinical presentations and their severity vary depending on the route of bacterial entry (skin penetration, inhalation or ingestion), host immune function and bacterial strain and load. Diagnosis is based on clinical and epidemiological features as well as bacterial culture. Treatment requires long-term intravenous and oral antibiotic courses. Delays in treatment due to difficulties in clinical recognition and laboratory diagnosis often lead to poor outcomes and mortality can exceed 40% in some regions. Research into B. pseudomallei is increasing, owing to the biothreat potential of this pathogen and increasing awareness of the disease and its burden; however, better diagnostic tests are needed to improve early confirmation of diagnosis, which would enable better therapeutic efficacy and survival.

Salam AP, Horby P. 2018. Isolation of viable Zika virus from spermatozoa. Lancet Infect Dis, 18 (2), pp. 144. | Read more

Stürup-Toft S, O'Moore EJ, Plugge EH. 2018. Looking behind the bars: emerging health issues for people in prison. Br Med Bull, | Show Abstract | Read more

Introduction: There are more than 10 million people imprisoned worldwide. These individuals experience a higher burden of communicable and non-communicable disease, mental health and substance misuse problems than the general population and often come from marginalized and underserved groups in the community. Prisons offer an important opportunity for tackling health problems in a way that can deliver benefits to the individual and to the community. This paper focuses specifically on emerging health issues for prisons across the world. Sources of data: This paper uses sources of international data from published systematic reviews and research studies, the Ministry of Justice for England and Wales, the Prisons and Probations Ombudsmen Review and other United Kingdom government briefing papers. Areas of agreement: Deaths in custody are a key concern for the justice system as well as the health system. Areas of controversy: Suicide is the leading cause of mortality in prisons worldwide but non-communicable diseases, such as cardiovascular disease, are increasing in importance in high-income countries and are now the leading cause of mortality in prisons in England and Wales. Growing points: The prison population is ageing in most high-income countries. Older people in prison typically have multiple and complex medical and social care needs including reduced mobility and personal care needs as well as poor health. Areas timely for developing research: Further research is needed to understand the complex relationship between sentencing patterns, the ageing prison population and deaths in custody; to model its impact on prisons and healthcare provision in the future and to determine effective and cost-effective models of care. Research into the health of prisoners is important in improving the health of prisoners but there is considerable variation in quantity and quality between countries. Recent innovations seek to address this disparity and facilitate the sharing of good practice.

Castonguay-Vanier J, Klitting R, Sengvilaipaseuth O, Piorkowski G, Baronti C, Sibounheuang B, Vongsouvath M, Chanthongthip A, Thongpaseuth S, Mayxay M et al. 2018. Molecular epidemiology of dengue viruses in three provinces of Lao PDR, 2006-2010. PLoS Negl Trop Dis, 12 (1), pp. e0006203. | Show Abstract | Read more

Few data on dengue epidemiology are available for Lao PDR. Here, we provide information on the complexity of dengue epidemiology in the country, demonstrating dynamic circulation that varies over space and time, according to serotype. We recruited 1,912 consenting patients presenting with WHO dengue criteria at Mahosot Hospital, Vientiane (central Laos), between 2006 and 2010. Between 2008 and 2010, 1,413 patients with undifferentiated fever were also recruited at Luang Namtha (LNT) Provincial Hospital (northern Laos) and 555 at Salavan (SV) Provincial Hospital (southern Laos). We report significant variations in Dengue virus (DENV) circulation between the three sites. Peaks of DENV infection were observed in the rainy seasons, although 11% of confirmed cases in the provinces and 4.6% in the capital were detected during the dry and cool seasons (between December and February). Four DENV serotypes were detected among the 867 RT-PCR positive patients: 76.9% DENV-1, 9.6% DENV-2, 7.7% DENV-4 and 5.3% DENV-3. DENV-1 was the predominant serotype throughout the study except in LNT in 2008 and 2009 when it was DENV-2. Before July 2009, DENV-2 was not detected in SV and only rarely detected in Vientiane. DENV-3 and DENV-4 were commonly detected in Vientiane, before 2008 for DENV-4 and after 2009 for DENV-3. The phylogenetic analyses of DENV envelope sequences suggest concurrent multiple introductions of new strains as well as active DENV circulation throughout Laos and with neighboring countries. It is therefore of great importance to develop and strengthen a year-round nation-wide surveillance network in order to collect data that would allow anticipation of public health issues caused by the occurrence of large dengue outbreaks.

Darton TC, Thanh Tuyen H, Chung The H, Newton PN, Dance DAB, Phetsouvanh R, Davong V, Campbell JI, Minh Hoang NV, Thwaites GE et al. 2018. Azithromycin resistance inShigellaspp. in Southeast Asia. Antimicrob Agents Chemother, | Show Abstract | Read more

Infection byShigellaspp. is a common cause of dysentery in Southeast Asia. Antimicrobials are thought to be beneficial for treatment, however antimicrobial resistance inShigellaspp. is becoming widespread. We aimed to assess the frequency and mechanisms associated with decreased susceptibility to azithromycin in Southeast AsianShigellaisolates and use these data to assess appropriate susceptibility breakpoints.Shigellaisolated in Vietnam and Laos were screened for susceptibility against azithromycin (15μg) by disc diffusion and minimum inhibitory concentration (MIC). Phenotypic resistance was confirmed by PCR amplification of macrolide resistance loci. We compared the genetic relationships and plasmid contents of azithromycin resistantS. sonneiusing whole genome sequences. From 475 availableShigellaspp. isolated in Vietnam and Laos between 1994 and 2012, 6/181S. flexneri(3.3%, MIC≥16g/L) and 16/294S. sonnei(5.4%, MIC≥32g/L) were phenotypically resistant to azithromycin. PCR amplification confirmed a resistance mechanism in 22/475 (4.6%) isolates (19mphAand 3ermB). Susceptibility data demonstrated the acceptability ofS. flexneri(MIC≥16g/L, zone≤15mm) andS. sonnei(MIC≥32g/L, zone≤11mm) breakpoints with <3% discrepancy. Phylogenetic analysis demonstrated that decreased susceptibility has arisen sporadically in VietnameseS. sonneion at least seven occasions between 2000 and 2009, but failed to become established. While the proposed susceptibility breakpoints may allow better recognition of resistant isolates, additional studies are required to assess the impact on clinical outcome. The potential emergence of azithromycin resistance highlights the need for alternative management options forShigellainfections in endemic countries.

Cresswell FV, Bangdiwala AS, Meya DB, Bahr NC, Vidal JE, Török ME, Thao LTP, Thwaites GE, Boulware DR. 2018. Absence of Cerebrospinal Fluid Pleocytosis in Tuberculous Meningitis is a Common Occurrence in HIV Co-infection and a Predictor of Poor Outcomes. Int J Infect Dis, | Read more

Peto TJ, Debackere M, Etienne W, Vernaeve L, Tripura R, Falq G, Davoeung C, Nguon C, Rekol H, von Seidlein L et al. 2018. Community participation during two mass anti-malarial administrations in Cambodia: lessons from a joint workshop. Malar J, 17 (1), pp. 53. | Show Abstract | Read more

Two mass drug administrations (MDA) against falciparum malaria were conducted in 2015-16, one as operational research in northern Cambodia, and the other as a clinical trial in western Cambodia. During an April 2017 workshop in Phnom Penh the field teams from Médecins Sans Frontières and the Mahidol-Oxford Tropical Medicine Research Unit discussed lessons for future MDAs.

Näsström E, Jonsson P, Johansson A, Dongol S, Karkey A, Basnyat B, Tran Vu Thieu N, Trinh Van T, Thwaites GE, Antti H, Baker S. 2018. Diagnostic metabolite biomarkers of chronic typhoid carriage. PLoS Negl Trop Dis, 12 (1), pp. e0006215. | Show Abstract | Read more

BACKGROUND: Salmonella Typhi and Salmonella Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic Salmonella carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Detecting chronic carriers is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying Salmonella in their gallbladder. METHODOLOGY/PRINCIPAL FINDINGS: Here we aimed to identify biomarkers of Salmonella carriage using metabolite profiling. We performed metabolite profiling on plasma from Nepali patients undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage (and non-carriage controls) using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. We were able to significantly discriminate Salmonella carriage samples from non-carriage control samples. We were also able to detect differential signatures between S. Typhi and S. Paratyphi A carriers. We additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, we found that Salmonella carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic Salmonella carriers. CONCLUSIONS/SIGNIFICANCE: Our novel approach has highlighted the potential of using metabolomics to search for diagnostic markers of chronic Salmonella carriage. We suggest further epidemiological investigations of these potential biomarkers in alternative endemic enteric fever settings.

Haniffa R, Isaam I, De Silva AP, Dondorp AM, De Keizer NF. 2018. Performance of critical care prognostic scoring systems in low and middle-income countries: a systematic review. Crit Care, 22 (1), pp. 18. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Prognostic models-used in critical care medicine for mortality predictions, for benchmarking and for illness stratification in clinical trials-have been validated predominantly in high-income countries. These results may not be reproducible in low or middle-income countries (LMICs), not only because of different case-mix characteristics but also because of missing predictor variables. The study objective was to systematically review literature on the use of critical care prognostic models in LMICs and assess their ability to discriminate between survivors and non-survivors at hospital discharge of those admitted to intensive care units (ICUs), their calibration, their accuracy, and the manner in which missing values were handled. METHODS: The PubMed database was searched in March 2017 to identify research articles reporting the use and performance of prognostic models in the evaluation of mortality in ICUs in LMICs. Studies carried out in ICUs in high-income countries or paediatric ICUs and studies that evaluated disease-specific scoring systems, were limited to a specific disease or single prognostic factor, were published only as abstracts, editorials, letters and systematic and narrative reviews or were not in English were excluded. RESULTS: Of the 2233 studies retrieved, 473 were searched and 50 articles reporting 119 models were included. Five articles described the development and evaluation of new models, whereas 114 articles externally validated Acute Physiology and Chronic Health Evaluation, the Simplified Acute Physiology Score and Mortality Probability Models or versions thereof. Missing values were only described in 34% of studies; exclusion and or imputation by normal values were used. Discrimination, calibration and accuracy were reported in 94.0%, 72.4% and 25% respectively. Good discrimination and calibration were reported in 88.9% and 58.3% respectively. However, only 10 evaluations that reported excellent discrimination also reported good calibration. Generalisability of the findings was limited by variability of inclusion and exclusion criteria, unavailability of post-ICU outcomes and missing value handling. CONCLUSIONS: Robust interpretations regarding the applicability of prognostic models are currently hampered by poor adherence to reporting guidelines, especially when reporting missing value handling. Performance of mortality risk prediction models in LMIC ICUs is at best moderate, especially with limitations in calibration. This necessitates continued efforts to develop and validate LMIC models with readily available prognostic variables, perhaps aided by medical registries.

Zaka N, Alexander EC, Manikam L, Norman ICF, Akhbari M, Moxon S, Ram PK, Murphy G, English M, Niermeyer S, Pearson L. 2018. Quality improvement initiatives for hospitalised small and sick newborns in low- and middle-income countries: a systematic review. Implement Sci, 13 (1), pp. 20. | Show Abstract | Read more

BACKGROUND: An estimated 2.6 million newborns died in 2016; over 98.5% of deaths occurred in low- and middle-income countries (LMICs). Neonates born preterm and small for gestational age are particularly at risk given the high incidence of infectious complications, cardiopulmonary, and neurodevelopmental disorders in this group. Quality improvement (QI) initiatives can reduce the burden of mortality and morbidity for hospitalised newborns in these settings. We undertook a systematic review to synthesise evidence from LMICs on QI approaches used, outcome measures employed to estimate effects, and the nature of implementation challenges. METHODS: We searched Medline, EMBASE, WHO Global Health Library, Cochrane Library, WHO ICTRP, and ClinicalTrials.gov and scanned the references of identified studies and systematic reviews. Searches covered January 2000 until April 2017. Search terms were "quality improvement", "newborns", "hospitalised", and their derivatives. Studies were excluded if they took place in high-income countries, did not include QI interventions, or did not include small and sick hospitalised newborns. Cochrane Risk of Bias tools were used to quality appraise the studies. RESULTS: From 8110 results, 28 studies were included, covering 23 LMICs and 65,642 participants. Most interventions were meso level (district and clinic level); fewer were micro (patient-provider level) or macro (above district level). In-service training was the most common intervention subtype; service organisation and distribution of referencing materials were also frequently identified. The most commonly assessed outcome was mortality, followed by length of admission, sepsis rates, and infection rates. Key barriers to implementation of quality improvement initiatives included overburdened staff and lack of sufficient equipment. CONCLUSIONS: The frequency of meso level, single centre, and educational interventions suggests that these interventions may be easier for programme planners to implement. The success of some interventions in reducing morbidity and mortality rates suggests that QI approaches have a high potential for benefit to newborns. Going forward, there are opportunities to strengthen the focus of QI initiatives and to develop improved, larger-scale, collaborative research into implementation of quality improvement initiatives for this high-risk group. TRIAL REGISTRATION: PROSPERO CRD42017055459 .

Hantrakun V, Thaipadungpanit J, Rongkard P, Srilohasin P, Amornchai P, Langla S, Mukaka M, Chantratita N, Wuthiekanun V, Dance DAB et al. 2018. Presence of B. thailandensis and B. thailandensis expressing B. pseudomallei-like capsular polysaccharide in Thailand, and their associations with serological response to B. pseudomallei. PLoS Negl Trop Dis, 12 (1), pp. e0006193. | Show Abstract | Read more

BACKGROUND: Burkholderia pseudomallei is an environmental Gram-negative bacillus and the cause of melioidosis. B. thailandensis, some strains of which express a B. pseudomallei-like capsular polysaccharide (BTCV), is also commonly found in the environment in Southeast Asia but is considered non-pathogenic. The aim of the study was to determine the distribution of B. thailandensis and its capsular variant in Thailand and investigate whether its presence is associated with a serological response to B. pseudomallei. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the presence of B. pseudomallei and B. thailandensis in 61 rice fields in Northeast (n = 21), East (n = 19) and Central (n = 21) Thailand. We found BTCV in rice fields in East and Central but not Northeast Thailand. Fourteen fields were culture positive for B. pseudomallei alone, 8 for B. thailandensis alone, 11 for both B. pseudomallei and B. thailandensis, 6 for both B. thailandensis and BTCV, and 5 for B. pseudomallei, B. thailandensis and BTCV. Serological testing using the indirect hemagglutination assay (IHA) of 96 farmers who worked in the study fields demonstrated that farmers who worked in B. pseudomallei-positive fields had higher IHA titers than those who worked in B. pseudomallei-negative fields (median 1:40 [range: <1:10-1:640] vs. <1:10 [range: <1:10-1:320], p = 0.002). In a multivariable ordered logistic regression model, IHA titers were significantly associated with the presence of B. pseudomallei (aOR = 3.7; 95% CI 1.8-7.8, p = 0.001) but were not associated with presence of B. thailandensis (p = 0.32) or BTCV (p = 0.32). One sequence type (696) was identified for the 27 BTCV isolates tested. CONCLUSIONS/SIGNIFICANCE: This is the first report of BTCV in Thailand. The presence of B. pseudomallei and B. thailandensis in the same field was not uncommon. Our findings suggest that IHA positivity of healthy rice farmers in Thailand is associated with the presence of B. pseudomallei in rice fields rather than B. thailandensis or BTCV.

Vercesi V, Pisani L, van Tongeren PSI, Lagrand WK, Leopold SJ, Huson MMA, Henwood PC, Walden A, Smit M, Riviello ED et al. 2018. External confirmation and exploration of the Kigali modification for diagnosing moderate or severe ARDS. Intensive Care Med, pp. 1-2. | Read more

Harvala H, Broberg E, Benschop K, Berginc N, Ladhani S, Susi P, Christiansen C, McKenna J, Allen D, Makiello P et al. 2018. Recommendations for enterovirus diagnostics and characterisation within and beyond Europe. J Clin Virol, 101 pp. 11-17. | Show Abstract | Read more

Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for non-polio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5'noncoding regions (5'NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5'NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden.

Baird JK, Battle KE, Howes RE. 2018. Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms. Malar J, 17 (1), pp. 42. | Show Abstract | Read more

The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species. It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission. The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so-at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations. That problem excludes a large number of people from safe and effective treatment of the latent stage of vivax malaria: the G6PD deficient, pregnant or lactating women, and young infants. These groups were estimated to comprise 14.3% of populations resident in the 95 countries with endemic vivax malaria. Another important obstacle regarding primaquine in the business of killing hypnozoites is its apparent metabolism to an active metabolite exclusively via cytochrome P-450 isozyme 2D6 (CYP2D6). Natural polymorphisms of this allele create genotypes expressing impaired enzymes that occur in over 20% of people living in Southeast Asia, where more than half of P. vivax infections occur globally. Taken together, the estimated frequencies of these primaquine ineligibles due to G6PD toxicity or impaired CYP2D6 activity composed over 35% of the populations at risk of vivax malaria. Much more detailed work is needed to refine these estimates, derive probabilities of error for them, and improve their ethnographic granularity in order to inform control and elimination strategy and tactics.

Haenssgen MJ, Charoenboon N, Khine Zaw Y. 2018. It is time to give social research a voice to tackle antimicrobial resistance? J Antimicrob Chemother, | Read more

Taylor WR, Naw HK, Maitland K, Williams TN, Kapulu M, D'Alessandro U, Berkley JA, Bejon P, Okebe J, Achan J et al. 2018. Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa. BMC Med, 16 (1), pp. 11. | Show Abstract | Read more

BACKGROUND: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. METHODS: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. RESULTS: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. CONCLUSIONS: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Toda M, Zurovac D, Njeru I, Kareko D, Mwau M, Morita K. 2018. Health worker knowledge of Integrated Disease Surveillance and Response standard case definitions: a cross-sectional survey at rural health facilities in Kenya. BMC Public Health, 18 (1), pp. 146. | Show Abstract | Read more

BACKGROUND: The correct knowledge of standard case definition is necessary for frontline health workers to diagnose suspected diseases across Africa. However, surveillance evaluations commonly assume this prerequisite. This study assessed the knowledge of case definitions for health workers and their supervisors for disease surveillance activities in rural Kenya. METHODS: A cross-sectional survey including 131 health workers and their 11 supervisors was undertaken in two counties in Kenya. Descriptive analysis was conducted to classify the correctness of knowledge into four categories for three tracer diseases (dysentery, measles, and dengue). We conducted a univariate and multivariable logistic regression analyses to explore factors influencing knowledge of the case definition for dysentery. RESULTS: Among supervisors, 81.8% knew the correct definition for dysentery, 27.3% for measles, and no correct responses were provided for dengue. Correct knowledge was observed for 50.4% of the health workers for dysentery, only 12.2% for measles, and none for dengue. Of 10 examined factors, the following were significantly associated with health workers' correct knowledge of the case definition for dysentery: health workers' cadre (aOR 2.71; 95% CI 1.20-6.12; p = 0.017), and display of case definition poster (aOR 2.24; 95% CI 1.01-4.98; p = 0.048). Health workers' exposure to the surveillance refresher training, supportive supervision and guidelines were not significantly associated with the knowledge. CONCLUSION: The correct knowledge of standard case definitions was sub-optimal among health workers and their supervisors, which is likely to impact the reliability of routine surveillance reports generated from health facilities.

Phyo AP, Win KK, Thu AM, Swe LL, Htike H, Beau C, Sriprawat K, Winterberg M, Proux S, Imwong M et al. 2018. Poor response to artesunate treatment in two patients with severe malaria on the Thai-Myanmar border. Malar J, 17 (1), pp. 30. | Show Abstract | Read more

BACKGROUND: Malaria has declined dramatically along the Thai-Myanmar border in recent years due to malaria control and elimination programmes. However, at the same time, artemisinin resistance has spread, raising concerns about the efficacy of parenteral artesunate for the treatment of severe malaria. CASE PRESENTATION: In November 2015 and April 2017, two patients were treated for severe malaria with parenteral artesunate. Quinine was added within 24 h due to an initial poor response to treatment. The first patient died within 24 h of starting treatment and the second did not clear his peripheral parasitaemia until 11 days later. Genotyping revealed artemisinin resistance Kelch-13 markers. CONCLUSIONS: Reliable efficacy of artesunate for the treatment of severe malaria may no longer be assured in areas where artemisinin resistance has emerged. Empirical addition of parenteral quinine to artesunate for treatment is recommended as a precautionary measure.

Poespoprodjo JR, Kenangalem E, Wafom J, Chandrawati F, Puspitasari AM, Ley B, Trianti L, Korten Z, Surya A, Syafruddin D et al. 2018. Therapeutic Response to Dihydroartemisinin-Piperaquine for P. falciparum and P. vivax Nine Years after Its Introduction in Southern Papua, Indonesia. Am J Trop Med Hyg, | Show Abstract | Read more

Dihydroartemisinin-piperaquine (DHP) has been the first-line treatment of uncomplicated malaria due to both Plasmodium falciparum and Plasmodium vivax infections in Papua, Indonesia, since March 2006. The efficacy of DHP was reassessed to determine whether there had been any decline following almost a decade of its extensive use. An open-label drug efficacy study of DHP for uncomplicated P. falciparum and P. vivax malaria was carried out between March 2015 and April 2016 in Timika, Papua, Indonesia. Patients with uncomplicated malaria were administered supervised DHP tablets once daily for 3 days. Clinical and laboratory data were collected daily until parasite clearance and then weekly for 6 weeks. Molecular analysis was undertaken for all patients with recurrent parasitemia. A total of 129 study patients were enrolled in the study. At day 42, the polymerase chain reaction-adjusted efficacy was 97.7% (95% confidence intervals [CI]: 87.4-99.9) in the 61 patients with P. falciparum malaria, and 98.2% [95% CI: 90.3-100] in the 56 patients with P. vivax malaria. By day 2, 98% (56/57) of patients with P. falciparum and 96.9% (63/65) of those with P. vivax had cleared their peripheral parasitemia; none of the patients were still parasitaemic on day 3. Molecular analysis of P. falciparum parasites showed that none (0/61) had K13 mutations associated previously with artemisinin resistance or increased copy number of plasmepsin 2-3 (0/61). In the absence of artemisinin resistance, DHP has retained high efficacy for the treatment of uncomplicated malaria despite extensive drug pressure over a 9-year period.

Inzaule SC, Hamers RL, Calis J, Boerma R, Sigaloff K, Zeh C, Mugyenyi P, Akanmu S, Rinke de Wit TF. 2018. When prevention of mother-to-child HIV transmission fails: preventing pretreatment drug resistance in African children. AIDS, 32 (2), pp. 143-147. | Read more

Baniya S, Basnyat B. 2018. Mismanagement of Severe Altitude Illness in a Tertiary Hospital in Nepal: A Cautionary Tale. Wilderness Environ Med, | Read more

Srisutham S, Saralamba N, Sriprawat K, Mayxay M, Smithuis F, Nosten F, Pukrittayakamee S, Day NPJ, Dondorp AM, Imwong M. 2018. Genetic diversity of three surface protein genes in Plasmodium malariae from three Asian countries. Malar J, 17 (1), pp. 24. | Show Abstract | Read more

BACKGROUND: Genetic diversity of the three important antigenic proteins, namely thrombospondin-related anonymous protein (TRAP), apical membrane antigen 1 (AMA1), and 6-cysteine protein (P48/45), all of which are found in various developmental stages of Plasmodium parasites is crucial for targeted vaccine development. While studies related to the genetic diversity of these proteins are available for Plasmodium falciparum and Plasmodium vivax, barely enough information exists regarding Plasmodium malariae. The present study aims to demonstrate the genetic variations existing among these three genes in P. malariae by analysing their diversity at nucleotide and protein levels. METHODS: Three surface protein genes were isolated from 45 samples collected in Thailand (N = 33), Myanmar (N = 8), and Lao PDR (N = 4), using conventional polymerase chain reaction (PCR) assay. Then, the PCR products were sequenced and analysed using BioEdit, MEGA6, and DnaSP programs. RESULTS: The average pairwise nucleotide diversities (π) of P. malariae trap, ama1, and p48/45 were 0.00169, 0.00413, and 0.00029, respectively. The haplotype diversities (Hd) of P. malariae trap, ama1, and p48/45 were 0.919, 0.946, and 0.130, respectively. Most of the nucleotide substitutions were non-synonymous, which indicated that the genetic variations of these genes were maintained by positive diversifying selection, thus, suggesting their role as a potential target of protective immune response. Amino acid substitutions of P. malariae TRAP, AMA1, and P48/45 could be categorized to 17, 20, and 2 unique amino-acid variants, respectively. For further vaccine development, carboxyl terminal of P48/45 would be a good candidate according to conserved amino acid at low genetic diversity (π = 0.2-0.3). CONCLUSIONS: High mutational diversity was observed in P. malariae trap and ama1 as compared to p48/45 in P. malariae samples isolated from Thailand, Myanmar, and Lao PDR. Taken together, these results suggest that P48/45 might be a good vaccine candidate against P. malariae infection because of its sufficiently low genetic diversity and highly conserved amino acids especially on the carboxyl end.

Parati G, Agostoni P, Basnyat B, Bilo G, Brugger H, Coca A, Festi L, Giardini G, Lironcurti A, Luks AM et al. 2018. Clinical recommendations for high altitude exposure of individuals with pre-existing cardiovascular conditions. Eur Heart J, | Read more

Tunpattu S, Newey V, Sigera C, De Silva P, Goonarathna A, Aluthge I, Thambavita P, Perera R, Meegahawatte A, Isaam I et al. 2018. A short, structured skills training course for critical care physiotherapists in a lower-middle income country. Physiother Theory Pract, pp. 1-9. | Show Abstract | Read more

OBJECTIVES: The aim of this article is to describe the delivery and acceptability of a short, structured training course for critical care physiotherapy and its effects on the knowledge and skills of the participants in Sri Lanka, a lower-middle income country. METHODS: The two-day program combining short didactic sessions with small group workshops and skills stations was developed and delivered by local facilitators in partnership with an overseas specialist physiotherapist trainer. The impact was assessed using pre/post-course self-assessment, pre/post-course multiple-choice-question (MCQ) papers, and an end-of-course feedback questionnaire. RESULTS: Fifty-six physiotherapists (26% of critical care physiotherapists in Sri Lanka) participated. Overall confidence in common critical care physiotherapy skills improved from 11.6% to 59.2% in pre/post-training self-assessments, respectively. Post-course MCQ scores (mean score = 63.2) and percentage of passes (87.5%) were higher than pre-course scores (mean score = 36.6; percentage of passes = 12.5%). Overall feedback was very positive as 75% of the participants were highly satisfied with the course's contribution to improved critical care knowledge. CONCLUSIONS: This short, structured, critical care focused physiotherapy training has potential benefit to participating physiotherapists. Further, it provides an evidence that collaborative program can be planned and conducted successfully in a resource poor setting. This sustainable short course model may be adaptable to other resource-limited settings.

Cravo P, Machado RB, Leite JA, Leda T, Suwanarusk R, Bittencourt N, Albrecht L, Judice C, Lopes SCP, Lacerda MVG et al. 2018. In silico epitope mapping and experimental evaluation of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) as a malaria vaccine candidate. Malar J, 17 (1), pp. 20. | Show Abstract | Read more

BACKGROUND: Technical limitations for culturing the human malaria parasite Plasmodium vivax have impaired the discovery of vaccine candidates, challenging the malaria eradication agenda. The immunogenicity of the M2 domain of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) antigen cloned from the Plasmodium yoelii murine parasite, has been previously demonstrated. RESULTS: Detailed epitope mapping of MAEBL through immunoinformatics identified several MHCI, MHCII and B cell epitopes throughout the peptide, with several of these lying in the M2 domain and being conserved between P. vivax, P. yoelii and Plasmodium falciparum, hinting that the M2-MAEBL is pan-reactive. This hypothesis was tested through functional assays, showing that P. yoelii M2-MAEBL antisera are able to recognize and inhibit erythrocyte invasion from both P. falciparum and P. vivax parasites isolated from Thai patients, in ex vivo assays. Moreover, the sequence of the M2-MAEBL is shown to be highly conserved between P. vivax isolates from the Amazon and Thailand, indicating that the MAEBL antigen may constitute a vaccine candidate outwitting strain-specific immunity. CONCLUSIONS: The MAEBL antigen is promising candidate towards the development of a malaria vaccine.

Adhikari B, Phommasone K, Kommarasy P, Soundala X, Souvanthong P, Pongvongsa T, Henriques G, Newton PN, White NJ, Day NPJ et al. 2018. Why do people participate in mass anti-malarial administration? Findings from a qualitative study in Nong District, Savannakhet Province, Lao PDR (Laos). Malar J, 17 (1), pp. 15. | Show Abstract | Read more

BACKGROUND: As a part of targeted malaria elimination (TME) in the Greater Mekong Sub-region (GMS), mass drug administration (MDA) with anti-malarials was conducted in four villages in Nong District, Savannakhet Province, Lao PDR (Laos). A high proportion of the target population participated in the MDA, with over 87% agreeing to take the anti-malarial. Drawing on qualitative data collected alongside the MDA, this article explores the factors that led to this high population coverage. METHODS: Qualitative data collection methods included observations, which were recorded in field notes, focus group discussions (FGDs), and semi-structured interviews (SSIs). Data were collected on local context, MDA-related knowledge, attitudes and perceptions. FGDs and SSIs were audio-recorded, transcribed and translated to English. All transcriptions and field notes underwent qualitative content analysis using QSR NVivo. RESULTS: Respondents recognized malaria as a health concern and described the need for a malaria control program. The risk of malaria including asymptomatic infection was explained in terms of participants' work in forest and fields, and poor hygiene. During the MDA rounds, there was an improvement in knowledge on the concept of asymptomatic malaria, the rationale of MDA and the blood test. In all four villages, poverty affected access to healthcare and the provision of free care by TME was highly appreciated. TME was jointly undertaken by research staff and local volunteers. Authorities were involved in all TME activities. Lao Theung communities were cohesive and community members tended to follow each other's behaviour closely including participation in MDA. Factors such as understanding the concept and rationale of the study, free health care, collaboration with the village volunteers, support from authorities and cohesive communities contributed in building trust and high population coverage in MDA. CONCLUSION: Future malaria control programmes can become successful in achieving the high coverage in MDAs drawing from the success of TME in Laos. A high population coverage in TME was a combination of various factors that included the community engagement to promote the concept and rationale of MDA for asymptomatic malaria in addition to their baseline understanding of malaria as a health concern, provision of free primary health care, partnering of the research with local volunteers and authorities, building social relationship with community members and the cohesive nature of the communities boosted the trust and participation in MDA.

Samanamalee S, Sigera PC, De Silva AP, Thilakasiri K, Rashan A, Wadanambi S, Jayasinghe KSA, Dondorp AM, Haniffa R. 2018. Traumatic brain injury (TBI) outcomes in an LMIC tertiary care centre and performance of trauma scores. BMC Anesthesiol, 18 (1), pp. 4. | Show Abstract | Read more

BACKGROUND: This study evaluates post-ICU outcomes of patients admitted with moderate and severe Traumatic Brain Injury (TBI) in a tertiary neurocritical care unit in an low middle income country and the performance of trauma scores: A Severity Characterization of Trauma, Trauma and Injury Severity Score, Injury Severity Score and Revised Trauma Score in this setting. METHODS: Adult patients directly admitted to the neurosurgical intensive care units of the National Hospital of Sri Lanka between 21st July 2014 and 1st October 2014 with moderate or severe TBI were recruited. A telephone administered questionnaire based on the Glasgow Outcome Scale Extended (GOSE) was used to assess functional outcome of patients at 3 and 6 months after injury. The economic impact of the injury was assessed before injury, and at 3 and 6 months after injury. RESULTS: One hundred and one patients were included in the study. Survival at ICU discharge, 3 and 6 months after injury was 68.3%, 49.5% and 45.5% respectively. Of the survivors at 3 months after injury, 43 (86%) were living at home. Only 19 (38%) patients had a good recovery (as defined by GOSE 7 and 8). Three months and six months after injury, respectively 25 (50%) and 14 (30.4%) patients had become "economically dependent". Selected trauma scores had poor discriminatory ability in predicting mortality. CONCLUSIONS: This observational study of patients sustaining moderate or severe TBI in Sri Lanka (a LMIC) reveals only 46% of patients were alive at 6 months after ICU discharge and only 20% overall attained a good (GOSE 7 or 8) recovery. The social and economic consequences of TBI were long lasting in this setting. Injury Severity Score, Revised Trauma Score, A Severity Characterization of Trauma and Trauma and Injury Severity Score, all performed poorly in predicting mortality in this setting and illustrate the need for setting adapted tools.

Inghammar M, By Y, Farris C, Phe T, Borand L, Kerleguer A, Goyet S, Saphonn V, Phoeung C, Vong S et al. 2018. Serotype Distribution of ClinicalStreptococcus pneumoniaeIsolates before the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in Cambodia. Am J Trop Med Hyg, | Show Abstract | Read more

Childhood vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in Cambodia in January 2015. Baseline data regarding circulating serotypes are scarce. All microbiology laboratories in Cambodia were contacted for identification of stored isolates ofStreptococcus pneumoniaefrom clinical specimens taken before the introduction of PCV13. Available isolates were serotyped using a multiplex polymerase chain reaction method. Among 166 identified isolates available for serotyping from patients with pneumococcal disease, 4% were isolated from upper respiratory samples and 80% were from lower respiratory samples, and 16% were invasive isolates. PCV13 serotypes accounted for 60% (95% confidence interval [CI] 52-67) of all isolates; 56% (95% CI 48-64) of noninvasive and 77% (95% CI 57-89) of invasive isolates. Antibiotic resistance was more common among PCV13 serotypes. This study of clinicalS. pneumoniaeisolates supports the potential for high reduction in pneumococcal disease burden and may serve as baseline data for future monitoring ofS. pneumoniaeserotypes circulation after implementation of PCV13 childhood vaccination in Cambodia.

Nabwera HM, Moore SE, Mwangome MK, Molyneux SC, Darboe MK, Camara-Trawally N, Sonko B, Darboe A, Singhateh S, Fulford AJ, Prentice AM. 2018. The influence of maternal psychosocial circumstances and physical environment on the risk of severe wasting in rural Gambian infants: a mixed methods approach. BMC Public Health, 18 (1), pp. 109. | Show Abstract | Read more

BACKGROUND: Severe wasting affects 16 million under 5's and carries an immediate risk of death. Prevalence remains unacceptably high in sub-Saharan Africa and early infancy is a high-risk period. We aimed to explore risk factors for severe wasting in rural Gambian infants. METHODS: We undertook a case-control study from November 2014 to June 2015, in rural Gambia. Cases had WHO standard weight-for-length z-scores (WLZ) < -3 on at least 1 occasion in infancy. Controls with a WLZ > -3 in the same interval, matched on age, gender, village size and distance from the clinic were selected. Standard questionnaires were used to assess maternal socioeconomic status, water sanitation and hygiene and maternal mental health. Conditional logistic regression using a multivariable model was used to determine the risk factors for severe wasting. Qualitative in depth interviews were conducted with mothers and fathers who were purposively sampled. A thematic framework was used to analyse the in-depth interviews. RESULTS: Two hundred and eighty (77 cases and 203 controls) children were recruited. In-depth interviews were conducted with 16 mothers, 3 fathers and 4 research staff members. The mean age of introduction of complementary feeds was similar between cases and controls (5.2 [SD 1.2] vs 5.1 [SD 1.3] months). Increased odds of severe wasting were associated with increased frequency of complementary feeds (range 1-8) [adjusted OR 2.06 (95%: 1.17-3.62), p = 0.01]. Maternal adherence to the recommended infant care practices was influenced by her social support networks, most importantly her husband, by infant feeding difficulties and maternal psychosocial stressors that include death of a child or spouse, recurrent ill health of child and lack of autonomy in child spacing. CONCLUSION: In rural Gambia, inappropriate infant feeding practices were associated with severe wasting in infants. Additionally, adverse psychosocial circumstances and infant feeding difficulties constrain mothers from practising the recommended child care practices. Interventions that promote maternal resilience through gender empowerment, prioritising maternal psychosocial support and encouraging the involvement of fathers in infant and child care promotion strategies, would help prevent severe wasting in these infants.

Jones C, Talisuna AO, Snow RW, Zurovac D. 2018. "We were being treated like the Queen": understanding trial factors influencing high paediatric malaria treatment adherence in western Kenya. Malar J, 17 (1), pp. 8. | Show Abstract | Read more

BACKGROUND: Adherence to anti-malarial medication is highly variable but frequently suboptimal. Numerous interventions with a variety of methodological approaches have been implemented to address the problem. A recently conducted, randomized, controlled trial in western Kenya evaluated the effects of short message service (SMS) reminders on paediatric adherence to artemether-lumefantrine (AL) and found over 97% adherence rates in both intervention and control arms. The current study was undertaken to explore participants' experiences in the trial and identify the factors contributing to the high adherence rates. METHODS: In July 2016, 5 months after the trial completion, focus group discussions (FGDs) were undertaken with caregivers of children who had been treated in the intervention (n = 2) or control (n = 2) arms and who, post-trial, had received malaria treatment from the same facilities. The FGDs explored similarities and differences in perceptions and experiences of the care they received during and after the trial. RESULTS: Intervention-arm participants reported that SMS messages were effective dosing reminders. Participants from both arms reported that trial instructions to keep empty AL packs for verification during a home visit by a health worker affected their dosing and adherence practices. Differences between trial and post-trial treatment experiences included: administration of the first AL dose by health workers with demonstration of dispersible tablets dilution; advice on what to do if a child vomited; clear instructions on timing of dosing with efforts made to ensure understanding; and, information that dose completion was necessary with explanation provided. Participants reported that after the trial AL was not available at facilities, constraining their ability to adhere to recommended malaria treatment. They emphasized receiving respectful and personal treatment from trial health workers contributing to perceptions of high quality care and enhanced readiness to adhere to dosing instructions. CONCLUSIONS: This study highlights the complex range of factors that influence AL adherence. The results suggest that in addition to standardized definitions and measurement of adherence, and the influence of enrolment procedures, AL adherence trials need to take account of how intervention impact can be influenced by differences in the quality of care received under trial and routine conditions.

Fellmeth G, Plugge EH, Carrara V, Fazel M, Oo MM, Phichitphadungtham Y, Pimanpanarak M, Wai NK, Mu O, Charunwatthana P et al. 2018. Migrant perinatal depression study: a prospective cohort study of perinatal depression on the Thai-Myanmar border. BMJ Open, 8 (1), pp. e017129. | Show Abstract | Read more

PURPOSE: Perinatal depression is a significant contributor to maternal morbidity. Migrant women in resource-poor settings may be at increased risk, yet little research has been conducted in low-income and middle-income settings. This prospective cohort study of migrant women on the Thai-Myanmar border aims to establish prevalence of perinatal depression, identify risk factors for perinatal depression and examine associations with infant outcomes. PARTICIPANTS: Participating women are labour migrants and refugees living on the Thai-Myanmar border. A total of 568 women were recruited in their first trimester of pregnancy and are being followed up to 1-year postpartum. FINDINGS TO DATE: At baseline, women in our study had a median age of 25 years, the predominant ethnicity was Sgaw Karen (48.9%), agriculture was the main employment sector (39.2%) and educational attainment was low with a median of 4 years of education. In the first trimester of pregnancy, a quarter (25.8%; 95% CI 22.3 to 29.5) of all women were depressed as diagnosed by the Structured Clinical Interview for the Diagnosis of DSM-IV Disorders. FUTURE PLANS: Follow-up is ongoing and expected to continue until January 2018. The prevalence of depression at later stages of pregnancy and during the first postpartum year will be identified, and associations between depression status and demographic, social, migration-related, medical, obstetric and infant factors will be quantified. TRIAL REGISTRATION NUMBER: NCT02790905.

Janet S, Carrara VI, Simpson JA, Thin NWW, Say WW, Paw NTM, Chotivanich K, Turner C, Crawley J, McGready R. 2018. Early neonatal mortality and neurological outcomes of neonatal resuscitation in a resource-limited setting on the Thailand-Myanmar border: A descriptive study. PLoS One, 13 (1), pp. e0190419. | Show Abstract | Read more

BACKGROUND: Of the 4 million neonatal deaths worldwide yearly, 98% occur in low and middle-income countries. Effective resuscitation reduces mortality and morbidity but long-term outcomes in resource-limited settings are poorly described. This study reports on newborn neurological outcomes following resuscitation at birth in a resource-limited setting where intensive newborn care including intubation is unavailable. METHODS: Retrospective analysis of births records from 2008 to 2015 at Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border. FINDINGS: From 21,225 newbonrs delivered, 15,073 (71%) met the inclusion criteria (liveborn, singleton, ≥28 weeks' gestation, delivered in SMRU). Neonatal resuscitation was performed in 460 (3%; 422 basic, 38 advanced) cases. Overall early neonatal mortality was 6.6 deaths per 1000 live births (95% CI 5.40-8.06). Newborns receiving basic and advanced resuscitation presented an adjusted rate for death of 1.30 (95%CI 0.66-2.55; p = 0.442), and 6.32 (95%CI 3.01-13.26; p<0.001) respectively, compared to newborns given routine care. Main factors related to increased need for resuscitation were breech delivery, meconium, and fetal distress (p<0.001). Neurodevelopmental follow-up to one year was performed in 1,608 (10.5%) of the 15,073 newborns; median neurodevelopmental scores of non-resuscitated newborns and those receiving basic resuscitation were similar (64 (n = 1565) versus 63 (n = 41); p = 0.732), while advanced resuscitation scores were significantly lower (56 (n = 5); p = 0.017). INTERPRETATIONS: Newborns requiring basic resuscitation at birth have normal neuro-developmental outcomes at one year of age compared to low-risk newborns. Identification of risk factors (e.g., breech delivery) associated with increased need for neonatal resuscitation may facilitate allocation of staff to high-risk deliveries. This work endorses the use of basic resuscitation in low-resource settings, and supports on-going staff training to maintain bag-and-mask ventilation skills.

Okello G, Gerrets R, Zakayo S, Molyneux S, Jones C. 2018. "Every day they keep adding new tools but they don't take any away": Producing indicators for intermittent preventive treatment for malaria in pregnancy (IPTp) from routine data in Kenya. PLoS One, 13 (1), pp. e0189699. | Show Abstract | Read more

BACKGROUND: Intermittent preventive treatment for malaria in pregnancy (IPTp) is part of a multi-pronged strategy aimed at preventing malaria in pregnancy in areas of moderate to high transmission in sub-Saharan Africa. Despite being formally adopted as a malaria prevention policy over a decade ago, IPTp coverage has remained low. Recent demands for action have incorporated calls to strengthen IPTp monitoring and evaluation systems, including the use of routine data, to measure coverage, track implementation and identify roadblocks to improving uptake. Concerns about the quality of malaria indicators reported through routine information systems are well recognized, but there are few data on the realities of IPTp recording practices in frontline facilities or their entry into District Health Information Software (DHIS2). METHODS: Drawing on fieldwork conducted in two malaria endemic sub-counties in Kenya, we explore how local adaptations and innovations employed by health workers and sub-country managers to cope with a range of health system constraints, shape recording practices and in turn, the measurement of IPTp. Data were collected through observations, interviews, and document reviews. Data analysis and interpretation was guided by thematic analysis approach. RESULTS: Measurement of IPTp was undermined by health system constraints such as stock-out of drugs and human resource shortages. Coping strategies adopted by health workers to address these challenges ensured continuity in service delivery and IPTp data generation but had variable consequences on IPTp data quality. Unclear recording and reporting instructions also led to lack of standardization in IPTp data generation. The use of redundant tools created significant data burdens which undermined service delivery in general. CONCLUSIONS: There is need to integrate monthly reporting forms so as to remove redundancies which exacerbates workload for health workers and disrupts service delivery. Similarly, data collection instructions in registers and reporting forms need to be clarified to standardize IPTp data generation across health facilities. There is also need to address broader contextual factors such as stock-out of commodities and human resource shortages which undermine IPTp data generation process.

Hong Chau TT, Minh Chau NN, Hoang Le NT, Chung The H, Voong Vinh P, Nguyen To NT, Ngoc NM, Tuan HM, Chau Ngoc TL, Kolader M-E et al. 2018. A Double-blind, Randomized, Placebo-controlled Trial of Lactobacillus acidophilus for the Treatment of Acute Watery Diarrhea in Vietnamese Children. Pediatr Infect Dis J, 37 (1), pp. 35-42. | Show Abstract | Read more

BACKGROUND: Probiotics are the most frequently prescribed treatment for children hospitalized with diarrhea in Vietnam. We were uncertain of the benefits of probiotics for the treatment of acute watery diarrhea in Vietnamese children. METHODS: We conducted a double-blind, placebo-controlled, randomized trial of children hospitalized with acute watery diarrhea in Vietnam. Children meeting the inclusion criteria (acute watery diarrhea) were randomized to receive either 2 daily oral doses of 2 × 10 CFUs of a local probiotic containing Lactobacillus acidophilus or placebo for 5 days as an adjunct to standard of care. The primary end point was time from the first dose of study medication to the start of the first 24-hour period without diarrhea. Secondary outcomes included the total duration of diarrhea and hospitalization, daily stool frequency, treatment failure, daily fecal concentrations of rotavirus and norovirus, and Lactobacillus colonization. RESULTS: One hundred and fifty children were randomized into each study group. The median time from the first dose of study medication to the start of the first 24-hour diarrhea-free period was 43 hours (interquartile range, 15-66 hours) in the placebo group and 35 hours (interquartile range, 20-68 hours) in the probiotic group (acceleration factor 1.09 [95% confidence interval, 0.78-1.51]; P = 0.62). There was also no evidence that probiotic treatment was efficacious in any of the predefined subgroups nor significantly associated with any secondary end point. CONCLUSIONS: This was a large double-blind, placebo-controlled trial in which the probiotic underwent longitudinal quality control. We found under these conditions that L. acidophilus was not beneficial in treating children with acute watery diarrhea.

Agweyu A, Lilford RJ, English M, Clinical Information Network Author Group. 2018. Appropriateness of clinical severity classification of new WHO childhood pneumonia guidance: a multi-hospital, retrospective, cohort study. Lancet Glob Health, 6 (1), pp. e74-e83. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Management of pneumonia in many low-income and middle-income countries is based on WHO guidelines that classify children according to clinical signs that define thresholds of risk. We aimed to establish whether some children categorised as eligible for outpatient treatment might have a risk of death warranting their treatment in hospital. METHODS: We did a retrospective cohort study of children aged 2-59 months admitted to one of 14 hospitals in Kenya with pneumonia between March 1, 2014, and Feb 29, 2016, before revised WHO pneumonia guidelines were adopted in the country. We modelled associations with inpatient mortality using logistic regression and calculated absolute risks of mortality for presenting clinical features among children who would, as part of revised WHO pneumonia guidelines, be eligible for outpatient treatment (non-severe pneumonia). FINDINGS: We assessed 16 162 children who were admitted to hospital in this period. 832 (5%) of 16 031 children died. Among groups defined according to new WHO guidelines, 321 (3%) of 11 788 patients with non-severe pneumonia died compared with 488 (14%) of 3434 patients with severe pneumonia. Three characteristics were strongly associated with death of children retrospectively classified as having non-severe pneumonia: severe pallor (adjusted risk ratio 5·9, 95% CI 5·1-6·8), mild to moderate pallor (3·4, 3·0-3·8), and weight-for-age Z score (WAZ) less than -3 SD (3·8, 3·4-4·3). Additional factors that were independently associated with death were: WAZ less than -2 to -3 SD, age younger than 12 months, lower chest wall indrawing, respiratory rate of 70 breaths per min or more, female sex, admission to hospital in a malaria endemic region, moderate dehydration, and an axillary temperature of 39°C or more. INTERPRETATION: In settings of high mortality, WAZ less than -3 SD or any degree of pallor among children with non-severe pneumonia was associated with a clinically important risk of death. Our data suggest that admission to hospital should not be denied to children with these signs and we urge clinicians to consider these risk factors in addition to WHO criteria in their decision making. FUNDING: Wellcome Trust.

Carrington LB, Tran BCN, Le NTH, Luong TTH, Nguyen TT, Nguyen PT, Nguyen CVV, Nguyen HTC, Vu TT, Vo LT et al. 2018. Field- and clinically derived estimates of Wolbachia-mediated blocking of dengue virus transmission potential in Aedes aegypti mosquitoes. Proc Natl Acad Sci U S A, 115 (2), pp. 361-366. | Show Abstract | Read more

The wMel strain of Wolbachia can reduce the permissiveness of Aedes aegypti mosquitoes to disseminated arboviral infections. Here, we report that wMel-infected Ae. aegypti (Ho Chi Minh City background), when directly blood-fed on 141 viremic dengue patients, have lower dengue virus (DENV) transmission potential and have a longer extrinsic incubation period than their wild-type counterparts. The wMel-infected mosquitoes that are field-reared have even greater relative resistance to DENV infection when fed on patient-derived viremic blood meals. This is explained by an increased susceptibility of field-reared wild-type mosquitoes to infection than laboratory-reared counterparts. Collectively, these field- and clinically relevant findings support the continued careful field-testing of wMel introgression for the biocontrol of Ae. aegypti-born arboviruses.

Thapa SS, Basnyat B. 2018. Common Bite-Bizarre Rash. Wilderness Environ Med, | Read more

Shrestha P, Shakya M, Caws M, Shrestha S, Karki B, Shrestha S, Karki DB, Maharjan B, Shrestha B, Arjyal A et al. 2018. Tuberculosis in Staff and Students of Patan Hospital. J Nepal Health Res Counc, 15 (3), pp. 268-274. | Show Abstract

BACKGROUND: There is a high risk of occupational exposure to tuberculosis among healthcare workers in endemic countries. Regular screening for tuberculosis among healthcare workers is not carried out in Nepal. Infection control measures are also not routinely implemented. The aim of this study was to determine the prevalence of active tuberculosis among staff/students at Patan Hospital. METHODS: Participants were given a self-administered questionnaire and invited to undergo chest radiography. Cases were scored and reviewed based on predetermined criteria, and presumptive tuberculosis cases were invited to undergo sputum smear and culture. Participants were categorized according to the extent of patient contact and asked about history of tuberculosis medication. RESULTS: Among 560 participants, 76.8% had direct contact with patients. Fifty-eight (10.4%) gave history of cough >2 weeks. Based on symptom history and chest radiography, 20.0% (n=112) cases were reviewed, and 12.5% (n=14) of those reviewed had sputum tested for acid-fast bacilli. One participant had culture-positive tuberculosis. Fifty participants (8.9%) reported tuberculosis in the past, among which 42.0% (n=21) occurred after employment at Patan Hospital and 42.0% before joining Patan Hospital. Security staff, radiology technicians and ward cleaning staff had the highest proportion of cases with a history of tuberculosis.History of tuberculosis medication had no relation with age, sex, education, body mass index and smoking.The incidence rate of tuberculosis at Patan Hospital was 3.6 per 1000 person-years. CONCLUSIONS: Overall incidence of tuberculosis among healthcare workers is noteworthy. However, this study suggests when symptomatic tuberculosis occurs in healthcare worker at Patan Hospital, it is diagnosed and there is not a large pool of undiagnosed tuberculosis.

Haenssgen MJ. 2018. The struggle for digital inclusion: Phones, healthcare, and marginalisation in rural India World Development, 104 pp. 358-374. | Show Abstract | Read more

© 2017 Elsevier Ltd The gains from digital technology diffusion are deemed essential for international development, but they are also distributed unevenly. Does the uneven distribution mean that not everyone benefits from new technologies to the same extent, or do some people experience an absolute disadvantage during this process? I explore this question through the case study of curative healthcare access in the context of rapid mobile phone uptake in rural India, contributing thus to an important yet surprisingly under-researched aspect of the social implications of (mobile) technology diffusion. Inspired by a previous analysis of cross-sectional data from rural India, I hypothesise that health systems increasingly adapt to mobile phone users where phones have diffused widely. This adaptation will leave poor non-adopters worse off than before and increases healthcare inequities. I use a panel of 12,003 rural households with an illness in 2005 and 2012 from the Indian Human Development Survey to test this hypothesis. Based on village-cluster robust fixed-effects linear probability models, I find that (a) mobile phone diffusion is significantly and negatively linked to various forms of rural healthcare access, suggesting that health systems increasingly adapt to phone use and discriminate against non-users; that (b) poor rural households without mobile phones experience more adverse effects compared to more affluent households, which indicates a struggle and competition for healthcare access among marginalised groups; and that (c) no effects emerge for access to public doctors, which implies that some healthcare providers are less responsive to mobile phone use than others. Overall, my findings indicate that the rural Indian healthcare system gradually adapts to increasing mobile phone use at the expense of non-users. I conclude that rapid mobile phone diffusion creates an opportunity to improve people's access to healthcare in rural India, but it also creates new forms of marginalisation among poor rural households.

Devine A, Kenangalem E, Burdam FH, Anstey NM, Poespoprodjo JR, Price RN, Yeung S. 2018. Treatment-Seeking Behavior after the Implementation of a Unified Policy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Malaria in Papua, Indonesia. Am J Trop Med Hyg, 98 (2), pp. 543-550. | Show Abstract | Read more

Artemisinin combination therapy is recommended for the treatment of multidrug resistant Plasmodium falciparum and Plasmodium vivax. In March 2006, antimalarial policy in Indonesia was changed to a unified treatment with dihydroartemisinin-piperaquine for all species of malaria because of the low efficacy of previous drug treatments. In 2013, a randomized cross-sectional household survey in Papua was used to collect data on demographics, parasite positivity, treatment-seeking behavior, diagnosis and treatment of malaria, and household costs. Results were compared with a similar survey undertaken in 2005. A total of 800 households with 4,010 individuals were included in the 2013 survey. The prevalence of malaria parasitemia was 12% (348/2,795). Of the individuals who sought treatment of fever, 67% (66/98) reported attending a public provider at least once compared with 46% (349/764) before policy change (P < 0.001). During the 100 visits to healthcare providers, 95% (95) included a blood test for malaria and 74% (64/86) resulted in the recommended antimalarial for the diagnosed species, the corresponding figures before policy change were 48% (433/894) and 23% (78/336). The proportion of individuals seeking treatment more than once fell from 14% (107/764) before policy change to 2% (2/98) after policy change (P = 0.005). The mean indirect cost per fever episode requiring treatment seeking decreased from US$44.2 in 2005 to US$33.8 in 2013 (P = 0.006). The implementation of a highly effective antimalarial treatment was associated with better adherence of healthcare providers in both the public and private sectors and a reduction in clinical malaria and household costs.

Rono MK, Nyonda MA, Simam JJ, Ngoi JM, Mok S, Kortok MM, Abdullah AS, Elfaki MM, Waitumbi JN, El-Hassan IM et al. 2018. Adaptation of Plasmodium falciparum to its transmission environment. Nat Ecol Evol, 2 (2), pp. 377-387. | Show Abstract | Read more

Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission-intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G-the transcription factor that initiates reproduction-increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1-two histone deacetylases that epigenetically regulate the parasite's replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite's adaptive regulatory architecture has identified new potential molecular targets for malaria control.

Nhung NT, Van NTB, Cuong NV, Duong TTQ, Nhat TT, Hang TTT, Nhi NTH, Kiet BT, Hien VB, Ngoc PT et al. 2018. Antimicrobial residues and resistance against critically important antimicrobials in non-typhoidal Salmonella from meat sold at wet markets and supermarkets in Vietnam. Int J Food Microbiol, 266 pp. 301-309. | Show Abstract | Read more

Excessive antimicrobial usage and deficiencies in hygiene in meat production systems may result in undesirable human health hazards, such as the presence of antimicrobial drug residues and non-typhoidal Salmonella (NTS), including antimicrobial resistant (AMR) NTS. Recently, Vietnam has witnessed the emergence of integrated intensive animal production systems, coexisting with more traditional, locally-sourced wet markets. To date no systematic studies have been carried out to compare health hazards in beef, pork and chicken in different production systems. We aimed to: (1) estimate the prevalence of antimicrobial residues in beef, pork and chicken meat; (2) investigate the prevalence and levels of NTS contamination; and (3) investigate serovar distribution and AMR against critically important antimicrobials by animal species and type of retail (wet market vs. supermarket) in Vietnam. Fresh pork, beef and chicken meat samples (N=357) sourced from wet markets and supermarkets in Ho Chi Minh City (HCMC), Hanoi and Dong Thap were screened for antimicrobial residues by PremiTest, and were further investigated by Charm II. Samples from HCMC (N=113) were cultured using ISO 6579:2002/Amd 1:2007. NTS bacteria were quantified using a minimum probable number (MPN) technique. NTS isolates were assigned to serovar by Multilocus Sequence Typing (MLST), and were investigated for their phenotypic susceptibility against 32 antimicrobials. A total of 26 (7.3%) samples tested positive by PremiTest (9.5% beef, 4.1% pork and 8.4% chicken meat). Sulfonamides, tetracyclines and macrolides were detected by Charm in 3.1%, 2.8% and 2.0% samples, respectively. Overall, meat samples from wet markets had a higher prevalence of residues than those from supermarkets (9.6% vs. 2.6%) (p=0.016). NTS were isolated from 68.4% samples from HCMC. Chicken samples from wet markets had by far the highest NTS counts (median 3.2 logMPN/g). NTS isolates displayed high levels of resistance against quinolones (52.2%) and β-lactams (49.6%), but low levels against 3rd generation cephalosporins (4.4%) and aminoglycosides (0.8%). The highest adjusted prevalence of multidrug resistance (MDR) corresponded to isolates from chicken meat and pork (OR 8.3 and 1.8, respectively) (baseline=beef). S. Kentucky was the most common serovar identified (11 from chicken, 1 from beef) and 91.7% isolates was MDR. 11/12 isolates corresponded to ST198, a worldwide-disseminated multi-resistant NTS clone. We recommend stepping up policy measures to promote responsible antimicrobial use in animal production, as well as awareness about withdrawal periods to limit the hazard of residues in animal products, and improving slaughtering/hygiene procedures to limit cross-contamination with NTS, particularly in poultry wet markets.

Nguon C, Dysoley L, Davoeung C, Sovann Y, Sanann N, Sareth M, Kunthea P, Vuth S, Sovann K, Kol K et al. 2018. Art and theatre for health in rural Cambodia. Glob Bioeth, 29 (1), pp. 16-21. | Show Abstract | Read more

This article describes our experience using art and theatre to engage rural communities in western Cambodia to understand malaria and support malaria control and elimination. The project was a pilot science-arts initiative to supplement existing engagement activities conducted by local authorities. In 2016, the project was conducted in 20 villages, involved 300 community members and was attended by more than 8000 people. Key health messages were to use insecticide-treated bed-nets and repellents, febrile people should attend village malaria workers, and to raise awareness about the risk of forest-acquired malaria. Building on the experience and lessons learnt in the year prior, the 2017 project which was conducted in 15 villages involved 600 community members and attracted more than 12,000 people. In addition to the malaria theme, upon discussion with local health authorities, secondary theme (infant vaccination) was added to the 2017 project. We learnt the following lessons from our experience in Cambodia: involving local people including children from the beginning of the project and throughout the process is important; messages should be kept simple; it is necessary to take into consideration practical issues such as location and timing of the activities; and that the project should offer something unique to communities.

Plewes K, Turner GDH, Dondorp AM. 2018. Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria. Curr Opin Infect Dis, 31 (1), pp. 69-77. | Show Abstract | Read more

PURPOSE OF REVIEW: Cerebral impairment and acute kidney injury (AKI) are independent predictors of mortality in both adults and children with severe falciparum malaria. In this review, we present recent advances in understanding the pathophysiology, clinical features, and management of these complications of severe malaria, and discuss future areas of research. RECENT FINDINGS: Cerebral malaria and AKI are serious and well recognized complications of severe malaria. Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation. Recent MRI studies show significant brain swelling in both adults and children with evidence of posterior reversible encephalopathy syndrome-like syndrome although targeted interventions including mannitol and dexamethasone are not beneficial. Recent work shows association of cell-free hemoglobin oxidation stress involved in the pathophysiology of AKI in both adults and children. Paracetamol protected renal function likely by inhibiting cell-free-mediated oxidative stress. It is unclear if heme-mediated endothelial activation or oxidative stress is involved in cerebral malaria. SUMMARY: The direct causes of cerebral and kidney dysfunction remain incompletely understood. Optimal treatment involves prompt diagnosis and effective antimalarial treatment with artesunate. Renal replacement therapy reduces mortality in AKI but delayed diagnosis is an issue.

Otten C, Brilli M, Vollmer W, Viollier PH, Salje J. 2018. Peptidoglycan in obligate intracellular bacteria. Mol Microbiol, 107 (2), pp. 142-163. | Show Abstract | Read more

Peptidoglycan is the predominant stress-bearing structure in the cell envelope of most bacteria, and also a potent stimulator of the eukaryotic immune system. Obligate intracellular bacteria replicate exclusively within the interior of living cells, an osmotically protected niche. Under these conditions peptidoglycan is not necessarily needed to maintain the integrity of the bacterial cell. Moreover, the presence of peptidoglycan puts bacteria at risk of detection and destruction by host peptidoglycan recognition factors and downstream effectors. This has resulted in a selective pressure and opportunity to reduce the levels of peptidoglycan. In this review we have analysed the occurrence of genes involved in peptidoglycan metabolism across the major obligate intracellular bacterial species. From this comparative analysis, we have identified a group of predicted 'peptidoglycan-intermediate' organisms that includes the Chlamydiae, Orientia tsutsugamushi, Wolbachia and Anaplasma marginale. This grouping is likely to reflect biological differences in their infection cycle compared with peptidoglycan-negative obligate intracellular bacteria such as Ehrlichia and Anaplasma phagocytophilum, as well as obligate intracellular bacteria with classical peptidoglycan such as Coxiella, Buchnera and members of the Rickettsia genus. The signature gene set of the peptidoglycan-intermediate group reveals insights into minimal enzymatic requirements for building a peptidoglycan-like sacculus and/or division septum.

Fox-Lewis S, Pol S, Miliya T, Day NPJ, Turner P, Turner C. 2018. Utilization of a clinical microbiology service at a Cambodian paediatric hospital and its impact on appropriate antimicrobial prescribing. J Antimicrob Chemother, 73 (2), pp. 509-516. | Show Abstract | Read more

Background: Antimicrobial resistance threatens human health worldwide. Antimicrobial misuse is a major driver of resistance. Promoting appropriate antimicrobial use requires an understanding of how clinical microbiology services are utilized, particularly in resource-limited settings. Objectives: To assess the appropriateness of antimicrobial prescribing and the factors affecting utilization of the established clinical microbiology service (CMS). The CMS comprises the microbiology laboratory, clinical microbiologists (infection doctors) and antimicrobial treatment guidelines. Methods: This mixed-methods study was conducted at a non-governmental Cambodian paediatric hospital. Empirical and post-culture antimicrobial prescriptions were reviewed from medical records. The random sample included 10 outpatients per week in 2016 (retrospective) and 20 inpatients per week for 4 weeks in the medical, neonatal and intensive care wards (prospective). Post-culture prescriptions were assessed in patients with positive blood and cerebrospinal fluid cultures from 1 January 2014 to 31 December 2016. Focus group discussions and semi-structured interviews with clinicians explored barriers and facilitators to use of the CMS. Results: Only 31% of outpatients were prescribed empirical antimicrobials. Post-culture prescriptions (394/443, 89%) were more likely to be appropriate than empirical prescriptions (447/535, 84%), based on treatment guidelines, microbiology advice and antimicrobial susceptibility test results (P = 0.015). Being comprehensive, accessible and trusted enabled CMS utilization. Clinical microbiologists provided a crucial human interface between the CMS and physicians. The main barriers were a strong clinical hierarchy and occasional communication difficulties. Conclusions: Antimicrobial prescribing in this hospital was largely appropriate. A culturally appropriate human interface linking the laboratory and physicians is essential in providing effective microbiology services and ensuring appropriate antimicrobial prescribing in resource-limited settings.

Peto TJ, Tripura R, Davoeung C, Nguon C, Nou S, Heng C, Kunthea P, Adhikari B, Lim R, James N et al. 2018. Reflections on a Community Engagement Strategy for Mass Antimalarial Drug Administration in Cambodia. Am J Trop Med Hyg, 98 (1), pp. 100-104. | Show Abstract | Read more

Mass drug administration (MDA) to interrupt malaria transmission requires the participation of entire communities. As part of a clinical trial in western Cambodia, four villages received MDA in 2015-2016. Before approaching study communities, a collaboration was established with the local health authorities, village leaders, and village malaria workers. Formative research guided the development of engagement strategies. In each village, a team of volunteers was formed to explain MDA to their neighbors and provide support during implementation. Public mobilization events featuring drama and music were used to introduce MDA. Villages comprised groups with different levels of understanding and interests; therefore, multiple tailored engagement strategies were required. The main challenges were explaining malaria transmission, managing perceptions of drug side effects, and reaching mobile populations. It was important that local leaders took a central role in community engagement. Coverage during each round of MDA averaged 84%, which met the target for the trial.

Chu TTT, Sinha A, Malleret B, Suwanarusk R, Park JE, Naidu R, Das R, Dutta B, Ong ST, Verma NK et al. 2018. Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol, 180 (1), pp. 118-133. | Show Abstract | Read more

Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi-lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re-arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome-wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub-fractionation into triton-extracted membrane proteins and luminal samples (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin-1/2 and ß-Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)-based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes.

Karkey A, Thwaites GE, Baker S. 2018. The evolution of antimicrobial resistance in Salmonella Typhi. Curr Opin Gastroenterol, 34 (1), pp. 25-30. | Citations: 1 (Scopus) | Show Abstract | Read more

PURPOSE OF REVIEW: Increasing antimicrobial resistance in Salmonella Typhi is a serious public health concern, especially in industrializing countries. Here we review recent clinical and laboratory data concerning the evolution of antimicrobial resistance, with particular reference to the emergence resistance against fluoroquinolones, third generation cephalosporins, and azithromycin. RECENT FINDINGS: The last 40 years have witnessed the sequential emergence of resistance to all first-line antimicrobials used in the treatment of S. Typhi infections. Multidrug resistance (MDR), defined by resistance to chloramphenicol, amoxicillin, and co-trimoxazole, emerged in the 1990s, followed rapidly by reduced susceptibility to fluoroquinolones. In the current decade, high-level fluoroquinolone resistance has emerged in south Asia and threatens to spread worldwide. Increasing reliance is now being placed on the activity of third generation cephalosporins and azithromycin, but resistance against these agents is developing. Carbapenems and tigecycline may be alternatives, although clinical data are sparse, and in some settings reversion to chloramphenicol and co-trimoxazole susceptibility is occurring. Therefore, older drugs may yet have a role in the treatment of S. Typhi infections. SUMMARY: Good surveillance, improved diagnostics, more prudent use of antimicrobials, and effective vaccines will all be critical to reducing the burden of disease caused by S. Typhi.

Williams PCM, Isaacs D, Berkley JA. 2018. Antimicrobial resistance among children in sub-Saharan Africa. Lancet Infect Dis, 18 (2), pp. e33-e44. | Show Abstract | Read more

Antimicrobial resistance is an important threat to international health. Therapeutic guidelines for empirical treatment of common life-threatening infections depend on available information regarding microbial aetiology and antimicrobial susceptibility, but sub-Saharan Africa lacks diagnostic capacity and antimicrobial resistance surveillance. We systematically reviewed studies of antimicrobial resistance among children in sub-Saharan Africa since 2005. 18 of 1075 articles reviewed met inclusion criteria, providing data from 67 451 invasive bacterial isolates from inconsistently defined populations in predominantly urban tertiary settings. Among neonates, Gram-negative organisms were the predominant cause of early-onset neonatal sepsis, with a high prevalence of extended-spectrum β-lactamase-producing organisms. Gram-positive bacteria were responsible for a high proportion of infections among children beyond the neon atal period, with high reported prevalence of non-susceptibility to treatment advocated by the WHO therapeutic guidelines. There are few up-to-date or representative studies given the magnitude of the problem of antimicrobial resistance, especially regarding community-acquired infections. Research should focus on differentiating resistance in community-acquired versus hospital-acquired infections, implementation of standardised reporting systems, and pragmatic clinical trials to assess the efficacy of alternative treatment regimens.

Andrews KA, Wesche D, McCarthy J, Möhrle JJ, Tarning J, Phillips L, Kern S, Grasela T. 2018. Model-Informed Drug Development for Malaria Therapeutics. Annu Rev Pharmacol Toxicol, 58 (1), pp. 567-582. | Show Abstract | Read more

Malaria is a critical public health problem resulting in substantial morbidity and mortality, particularly in developing countries. Owing to the development of resistance toward current therapies, novel approaches to accelerate the development efforts of new malaria therapeutics are urgently needed. There have been significant advancements in the development of in vitro and in vivo experiments that generate data used to inform decisions about the potential merit of new compounds. A comprehensive disease-drug model capable of integrating discrete data from different preclinical and clinical components would be a valuable tool across all stages of drug development. This could have an enormous impact on the otherwise slow and resource-intensive process of traditional clinical drug development.

Huong VTL, Long HB, Kinh NV, Ngan TTD, Dung VTV, Nadjm B, van Doorn HR, Hoa NT, Horby P, Wertheim HFL. 2018. Long-term outcomes of patients with Streptococcus suis infection in Viet Nam: A case-control study. J Infect, 76 (2), pp. 159-167. | Show Abstract | Read more

OBJECTIVES: Streptococcus suis is a zoonotic cause of severe meningitis and sepsis in humans. We aimed to assess the long-term outcomes in patients who survived S. suis infection, in particular the progress and impact of vestibulocochlear sequelae. METHODS: This case-control study evaluated outcomes of S. suis infection at discharge and 3 and 9 months post-discharge for 47 prospectively enrolled cases and at 11-34 months for 31 retrospectively enrolled cases. Outcomes in patients were compared to 270 controls matched for age, sex and residency. RESULTS: The prevalence ratio (PR) of moderate-to-complete hearing loss was 5.0(95%CI 3.6-7.1) in cases at discharge, 3.7(2.5-5.4) at 3 months, 3.2(2.2-4.7) at 9 months, and 3.1(2.1-4.4) in retrospective cases compared to controls. Hearing improvement occurred mostly within the first 3 months with a change in hearing level of 11.1%(95%CI 7.0-15.1%) compared to discharge. The PR of vestibular dysfunction was 2.4(95%CI 1.7-3.3) at discharge, 2.2(1.4-3.1) at 3 months, 1.8(1.1-2.5) at 9 months, and 1.8(1.1-2.6) for retrospective cases compared to controls. Cases also indicated more problems with mobility, self-care and usual activities. CONCLUSIONS: Both hearing and vestibular impairment were common and persist in cases. Appropriate patient management strategies are needed to reduce the incidence and impact of these sequelae.

Thao LTP, Heemskerk AD, Geskus RB, Mai NTH, Ha DTM, Chau TTH, Phu NH, Chau NVV, Caws M, Lan NH et al. 2018. Prognostic Models for 9-Month Mortality in Tuberculous Meningitis. Clin Infect Dis, 66 (4), pp. 523-532. | Show Abstract | Read more

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection. Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/). Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone. Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care.

Duong VT, Tuyen HT, Van Minh P, Campbell JI, Phuc HL, Nhu TDH, Tu LTP, Chau TTH, Nhi LTQ, Hung NT et al. 2018. No Clinical Benefit of Empirical Antimicrobial Therapy for Pediatric Diarrhea in a High-Usage, High-Resistance Setting. Clin Infect Dis, 66 (4), pp. 504-511. | Show Abstract | Read more

Background: Pediatric diarrheal disease presents a major public health burden in low- to middle-income countries. The clinical benefits of empirical antimicrobial treatment for diarrhea are unclear in settings that lack reliable diagnostics and have high antimicrobial resistance (AMR). Methods: We conducted a prospective multicenter cross-sectional study of pediatric patients hospitalized with diarrhea containing blood and/or mucus in Ho Chi Minh City, Vietnam. Clinical parameters, including disease outcome and treatment, were measured. Shigella, nontyphoidal Salmonella (NTS), and Campylobacter were isolated from fecal samples, and their antimicrobial susceptibility profiles were determined. Statistical analyses, comprising log-rank tests and accelerated failure time models, were performed to assess the effect of antimicrobials on disease outcome. Results: Among 3166 recruited participants (median age 10 months; interquartile range, 6.5-16.7 months), one-third (1096 of 3166) had bloody diarrhea, and 25% (793 of 3166) were culture positive for Shigella, NTS, or Campylobacter. More than 85% of patients (2697 of 3166) were treated with antimicrobials; fluoroquinolones were the most commonly administered antimicrobials. AMR was highly prevalent among the isolated bacteria, including resistance against fluoroquinolones and third-generation cephalosporins. Antimicrobial treatment and multidrug resistance status of the infecting pathogens were found to have no significant effect on outcome. Antimicrobial treatment was significantly associated with an increase in the duration of hospitalization with particular groups of diarrheal diseases. Conclusions: In a setting with high antimicrobial usage and high AMR, our results imply a lack of clinical benefit for treating diarrhea with antimicrobials; adequately powered randomized controlled trials are required to assess the role of antimicrobials for diarrhea.

Berto A, Pham HA, Thao TTN, Vy NHT, Caddy SL, Hiraide R, Tue NT, Goodfellow I, Carrique-Mas JJ, Thwaites GE et al. 2018. Hepatitis E in southern Vietnam: Seroepidemiology in humans and molecular epidemiology in pigs. Zoonoses Public Health, 65 (1), pp. 43-50. | Show Abstract | Read more

Viral pathogens account for a significant proportion of the burden of emerging infectious diseases in humans. The Wellcome Trust-Vietnamese Initiative on Zoonotic Infections (WT-VIZIONS) is aiming to understand the circulation of viral zoonotic pathogens in animals that pose a potential risk to human health. Evidence suggests that human exposure and infections with hepatitis E virus (HEV) genotypes (GT) 3 and 4 results from zoonotic transmission. Hypothesising that HEV GT3 and GT4 are circulating in the Vietnamese pig population and can be transmitted to humans, we aimed to estimate the seroprevalence of HEV exposure in a population of farmers and the general population. We additionally performed sequence analysis of HEV in pig populations in the same region to address knowledge gaps regarding HEV circulation and to evaluate if pigs were a potential source of HEV exposure. We found a high prevalence of HEV GT3 viral RNA in pigs (19.1% in faecal samples and 8.2% in rectal swabs) and a high HEV seroprevalence in pig farmers (16.0%) and a hospital-attending population (31.7%) in southern Vietnam. The hospital population was recruited as a general-population proxy even though this particular population subgroup may introduce bias. The detection of HEV RNA in pigs indicates that HEV may be a zoonotic disease risk in this location, although a larger sample size is required to infer an association between HEV positivity in pigs and seroprevalence in humans.

Jones KDJ, Hachmeister CU, Khasira M, Cox L, Schoenmakers I, Munyi C, Nassir HS, Hunten-Kirsch B, Prentice A, Berkley JA. 2018. Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition MATERNAL AND CHILD NUTRITION, 14 (1), pp. e12452-e12452. | Show Abstract | Read more

© 2017 The Authors Maternal & Child Nutrition Published by John Wiley & Sons Ltd The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub-Saharan Africa describe an endemic vitamin D-independent form that responds to dietary calcium enrichment. The extent to which calcium-deficiency rickets is the dominant form across sub-Saharan Africa and in other low-latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25-hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p =.001), phosphate (p  < .001), 25-hydroxyvitamin D (p =.049), and 1,25-dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear.

Berto A, Anh PH, Carrique-Mas JJ, Simmonds P, Van Cuong N, Tue NT, Van Dung N, Woolhouse ME, Smith I, Marsh GA et al. 2018. Detection of potentially novel paramyxovirus and coronavirus viral RNA in bats and rats in the Mekong Delta region of southern Viet Nam. Zoonoses Public Health, 65 (1), pp. 30-42. | Show Abstract | Read more

Bats and rodents are being increasingly recognized as reservoirs of emerging zoonotic viruses. Various studies have investigated bat viruses in tropical regions, but to date there are no data regarding viruses with zoonotic potential that circulate in bat and rat populations in Viet Nam. To address this paucity of data, we sampled three bat farms and three wet markets trading in rat meat in the Mekong Delta region of southern Viet Nam. Faecal and urine samples were screened for the presence of RNA from paramyxoviruses, coronaviruses and filoviruses. Paramyxovirus RNA was detected in 4 of 248 (1%) and 11 of 222 (4.9%) bat faecal and urine samples, respectively. Coronavirus RNA was detected in 55 of 248 (22%) of bat faecal samples; filovirus RNA was not detected in any of the bat samples. Further, coronavirus RNA was detected in 12 of 270 (4.4%) of rat faecal samples; all samples tested negative for paramyxovirus. Phylogenetic analysis revealed that the bat paramyxoviruses and bat and rat coronaviruses were related to viruses circulating in bat and rodent populations globally, but showed no cross-species mixing of viruses between bat and rat populations within Viet Nam. Our study shows that potentially novel variants of paramyxoviruses and coronaviruses commonly circulate in bat and rat populations in Viet Nam. Further characterization of the viruses and additional human and animal surveillance is required to evaluate the likelihood of viral spillover and to assess whether these viruses pose a risk to human health.

Dondorp AM, Limmathurotsakul D, Ashley EA. 2018. What's wrong in the control of antimicrobial resistance in critically ill patients from low- and middle-income countries? Intensive Care Med, 44 (1), pp. 79-82. | Read more

Török ME, Aljayyoussi G, Waterhouse D, Chau T, Mai N, Phu NH, Hien TT, Hope W, Farrar JJ, Ward SA. 2018. Suboptimal Exposure to Anti-TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy. Clin Pharmacol Ther, 103 (3), pp. 449-457. | Show Abstract | Read more

A placebo-controlled trial that compares the outcomes of immediate vs. deferred initiation of antiretroviral therapy in HIV +ve tuberculous meningitis (TBM) patients was conducted in Vietnam in 2011. Here, the pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were investigated in the presence and absence of anti-HIV treatment in 85 patients. Pharmacokinetic analyses show that HIV therapy has no significant impact on the pharmacokinetics of TB drugs in this cohort. The same population, however, displayed generally low cerebrospinal fluid (CSF) and systemic exposures to rifampicin compared to previously reported HIV -ve cohorts. Elevated CSF concentrations of pyrazinamide, on the other hand, were strongly and independently correlated with increased mortality and neurological toxicity. The findings suggest that the current standard dosing regimens may put the patient at risk of treatment failure from suboptimal rifampicin exposure, and potentially increasing the risk of adverse central nervous system events that are independently correlated with pyrazinamide CSF exposure.

Macharia AW, Mochamah G, Uyoga S, Ndila CM, Nyutu G, Makale J, Tendwa M, Nyatichi E, Ojal J, Shebe M et al. 2018. The clinical epidemiology of sickle cell anemia In Africa American Journal of Hematology, 93 (3), pp. 363-370. | Show Abstract | Read more

© 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc. Sickle cell anemia (SCA) is the commonest severe monogenic disorders of humans. The disease has been highly characterized in high-income countries but not in sub-Saharan Africa where SCA is most prevalent. We conducted a retrospective cohort study of all children 0–13 years admitted from within a defined study area to Kilifi County Hospital in Kenya over a five-year period. Children were genotyped for SCA retrospectively and incidence rates calculated with reference to population data. Overall, 576 of 18,873 (3.1%) admissions had SCA of whom the majority (399; 69.3%) were previously undiagnosed. The incidence of all-cause hospital admission was 57.2/100 person years of observation (PYO; 95%CI 52.6–62.1) in children with SCA and 3.7/100 PYO (95%CI 3.7–3.8) in those without SCA (IRR 15.3; 95%CI 14.1–16.6). Rates were higher for the majority of syndromic diagnoses at all ages beyond the neonatal period, being especially high for severe anemia (hemoglobin < 50 g/L; IRR 58.8; 95%CI 50.3–68.7), stroke (IRR 486; 95%CI 68.4–3,450), bacteremia (IRR 23.4; 95%CI 17.4–31.4), and for bone (IRR 607; 95%CI 284–1,300), and joint (IRR 80.9; 95%CI 18.1–362) infections. The use of an algorithm based on just five clinical features would have identified approximately half of all SCA cases among hospital-admitted children with a number needed to test to identify each affected patient of only fourteen. Our study illustrates the clinical epidemiology of SCA in a malaria-endemic environment without specific interventions. The targeted testing of hospital-admitted children using the Kilifi Algorithm provides a pragmatic approach to early diagnosis in high-prevalence countries where newborn screening is unavailable.

Thanh NT, Vinh LD, Liem NT, Shikuma C, Day JN, Thwaites G, Le T. 2018. Clinical features of three patients with paradoxical immune reconstitution inflammatory syndrome associated with Talaromyces marneffei infection. Med Mycol Case Rep, 19 pp. 33-37. | Show Abstract | Read more

Talaromyces marneffei infection is a major cause of death in HIV-infected individuals in South and Southeast Asia. Talaromycosis immune reconstitution inflammatory syndrome has not been well described. Here we report the clinical features, management, and outcomes of three HIV-infected patients with talaromycosis-associated paradoxical immune reconstitution inflammatory syndrome in Ho Chi Minh City, Vietnam.

Wei Y, Kypraios T, O'Neill PD, Huang SS, Rifas-Shiman SL, Cooper BS. 2018. Evaluating hospital infection control measures for antimicrobial-resistant pathogens using stochastic transmission models: Application to vancomycin-resistant enterococci in intensive care units. Stat Methods Med Res, 27 (1), pp. 269-285. | Show Abstract | Read more

Nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) are the cause of significant morbidity and mortality among hospital patients. It is important to be able to assess the efficacy of control measures using data on patient outcomes. In this paper, we describe methods for analysing such data using patient-level stochastic models which seek to describe the underlying unobserved process of transmission. The methods are applied to detailed longitudinal patient-level data on vancomycin-resistant Enterococci from a study in a US hospital with eight intensive care units (ICUs). The data comprise admission and discharge dates, dates and results of screening tests, and dates during which precautionary measures were in place for each patient during the study period. Results include estimates of the efficacy of the control measures, the proportion of unobserved patients colonized with vancomycin-resistant Enterococci, and the proportion of patients colonized on admission.

Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, Wilkes CS, Patel K, Chandna A, Price RN et al. 2018. Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria: An Open-Label Randomized Controlled Trial CAN KNOW. Clin Infect Dis, 66 (2), pp. 229-236. | Show Abstract | Read more

Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria. Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis. Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events. Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia. Clinical trials registration: NCT02001012.

Ssewanyana D, Mwangala PN, Marsh V, Jao I, van Baar A, Newton CR, Abubakar A. 2018. Young people's and stakeholders' perspectives of adolescent sexual risk behavior in Kilifi County, Kenya: A qualitative study. J Health Psychol, 23 (2), pp. 188-205. | Show Abstract | Read more

A lack of research exists around the most common forms of sexual risk behaviors among adolescents, including their underlying factors, in Sub-Saharan Africa. Using an Ecological Model of Adolescent Behavior, we explore the perceptions of 85 young people and 10 stakeholders on sexual risk behavior of adolescents in Kilifi County on the coast of Kenya. Our findings show that transactional sex, early sexual debut, coerced sex, and multiple sexual partnerships are prevalent. An urgent need exists to develop measures to counter sexual risk behaviors. The results contribute to understanding the range of risks and protective factors in differing contexts, tackling underlying issues at individual, family, local institutional, wider socio-economic, and political levels.

D'Alessandro U, Hill J, Tarning J, Pell C, Webster J, Gutman J, Sevene E. 2018. Treatment of uncomplicated and severe malaria during pregnancy. Lancet Infect Dis, | Show Abstract | Read more

Over the past 10 years, the available evidence on the treatment of malaria during pregnancy has increased substantially. Owing to their relative ease of use, good sensitivity and specificity, histidine rich protein 2 based rapid diagnostic tests are appropriate for symptomatic pregnant women; however, such tests are less appropriate for systematic screening because they will not detect an important proportion of infections among asymptomatic women. The effect of pregnancy on the pharmacokinetics of antimalarial drugs varies greatly between studies and class of antimalarial drugs, emphasising the need for prospective studies in pregnant and non-pregnant women. For the treatment of malaria during the first trimester, international guidelines are being reviewed by WHO. For the second and third trimester of pregnancy, results from several trials have confirmed that artemisinin-based combination treatments are safe and efficacious, although tolerability and efficacy might vary by treatment. It is now essential to translate such evidence into policies and clinical practice that benefit pregnant women in countries where malaria is endemic. Access to parasitological diagnosis or appropriate antimalarial treatment remains low in many countries and regions. Therefore, there is a pressing need for research to identify quality improvement interventions targeting pregnant women and health providers. In addition, efficient and practical systems for pharmacovigilance are needed to further expand knowledge on the safety of antimalarial drugs, particularly in the first trimester of pregnancy.

Akech S, Rotich B, Chepkirui M, Ayieko P, Irimu G, English M. 2018. The Prevalence and Management of Dehydration amongst Neonatal Admissions to General Paediatric Wards in Kenya-A Clinical Audit. J Trop Pediatr, | Show Abstract | Read more

An audit of randomly selected case records of 810 patients admitted to 13 hospitals between December 2015 and November 2016 was done. Prevalence of dehydration was 19.7% (2293 of 11 636) [95% CI: 17.1-22.6%], range across hospitals was 9.4% to 27.0%. Most cases with dehydration were clinically diagnosed (82 of 153; 53.6%), followed by excessive weight loss (54 of 153; 35.3%) and abnormal urea/electrolytes/creatinine (23 of 153; 15.0%). Documentation of fluids prescribed was poor but, where data were available, Ringers lactate (30 of 153; 19.6%) and 10% dextrose (18 of 153; 11.8%) were mostly used. Only 17 of 153 (11.1%) children had bolus fluid prescription, and Ringer's lactate was most commonly used for bolus at a median volume per kilogram body weight of 20 ml/kg (interquartile range, 12-30 ml/kg). Neonatal dehydration is common, but current documentation may underestimate the burden. Heterogeneity in practice likely reflects the absence of guidelines that in turn reflects a lack of research informing practical treatment guidelines.

Opondo C, Allen E, Todd J, English M. 2018. Association of the Paediatric Admission Quality of Care score with mortality in Kenyan hospitals: a validation study. Lancet Glob Health, 6 (2), pp. e203-e210. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Measuring the quality of hospital admission care is essential to ensure that standards of practice are met and continuously improved to reduce morbidity and mortality associated with the illnesses most responsible for inpatient deaths. The Paediatric Admission Quality of Care (PAQC) score is a tool for measuring adherence to guidelines for children admitted with acute illnesses in a low-income setting. We aimed to explore the external and criterion-related validity of the PAQC score by investigating its association with mortality using data drawn from a diverse sample of Kenyan hospitals. METHODS: We identified children admitted to Kenyan hospitals for treatment of malaria, pneumonia, diarrhoea, or dehydration from datasets from three sources: an observational study, a clinical trial, and a national cross-sectional survey. We extracted variables describing the process of care provided to patients at admission and their eventual outcomes from these data. We applied the PAQC scoring algorithm to the data to obtain a quality-of-care score for each child. We assessed external validity of the PAQC score by its systematic replication in datasets that had not been previously used to investigate properties of the PAQC score. We assessed criterion-related validity by using hierarchical logistic regression to estimate the association between PAQC score and the outcome of mortality, adjusting for other factors thought to be predictive of the outcome or responsible for heterogeneity in quality of care. FINDINGS: We found 19 065 eligible admissions in the three validation datasets that covered 27 hospitals, of which 12 969 (68%) were complete cases. Greater guideline adherence, corresponding to higher PAQC scores, was associated with a reduction in odds of death across the three datasets, ranging between 9% (odds ratio 0·91, 95% CI 0·84-0·99; p=0·031) and 30% (0·70, 0·63-0·78; p<0·0001) adjusted reduction per unit increase in the PAQC score, with a pooled estimate of 17% (0·83, 0·78-0·89; p<0·0001). These findings were consistent with a multiple imputation analysis that used information from all observations in the combined dataset. INTERPRETATION: The PAQC score, designed as an index of the technical quality of care for the three commonest causes of admission in children, is also associated with mortality. This finding suggests that it could be a meaningful summary measure of the quality of care for common inpatient conditions and supports a link between process quality and outcome. It might have potential for application in low-income countries with similar disease profiles and in which paediatric practice recommendations are based on WHO guidelines. FUNDING: The Wellcome Trust.

Ouma PO, Maina J, Thuranira PN, Macharia PM, Alegana VA, English M, Okiro EA, Snow RW. 2018. Access to emergency hospital care provided by the public sector in sub-Saharan Africa in 2015: a geocoded inventory and spatial analysis. Lancet Glob Health, | Show Abstract | Read more

BACKGROUND: Timely access to emergency care can substantially reduce mortality. International benchmarks for access to emergency hospital care have been established to guide ambitions for universal health care by 2030. However, no Pan-African database of where hospitals are located exists; therefore, we aimed to complete a geocoded inventory of hospital services in Africa in relation to how populations might access these services in 2015, with focus on women of child bearing age. METHODS: We assembled a geocoded inventory of public hospitals across 48 countries and islands of sub-Saharan Africa, including Zanzibar, using data from various sources. We only included public hospitals with emergency services that were managed by governments at national or local levels and faith-based or non-governmental organisations. For hospital listings without geographical coordinates, we geocoded each facility using Microsoft Encarta (version 2009), Google Earth (version 7.3), Geonames, Fallingrain, OpenStreetMap, and other national digital gazetteers. We obtained estimates for total population and women of child bearing age (15-49 years) at a 1 km2 spatial resolution from the WorldPop database for 2015. Additionally, we assembled road network data from Google Map Maker Project and OpenStreetMap using ArcMap (version 10.5). We then combined the road network and the population locations to form a travel impedance surface. Subsequently, we formulated a cost distance algorithm based on the location of public hospitals and the travel impedance surface in AccessMod (version 5) to compute the proportion of populations living within a combined walking and motorised travel time of 2 h to emergency hospital services. FINDINGS: We consulted 100 databases from 48 sub-Saharan countries and islands, including Zanzibar, and identified 4908 public hospitals. 2701 hospitals had either full or partial information about their geographical coordinates. We estimated that 287 282 013 (29·0%) people and 64 495 526 (28·2%) women of child bearing age are located more than 2-h travel time from the nearest hospital. Marked differences were observed within and between countries, ranging from less than 25% of the population within 2-h travel time of a public hospital in South Sudan to more than 90% in Nigeria, Kenya, Cape Verde, Swaziland, South Africa, Burundi, Comoros, São Tomé and Príncipe, and Zanzibar. Only 16 countries reached the international benchmark of more than 80% of their populations living within a 2-h travel time of the nearest hospital. INTERPRETATION: Physical access to emergency hospital care provided by the public sector in Africa remains poor and varies substantially within and between countries. Innovative targeting of emergency care services is necessary to reduce these inequities. This study provides the first spatial census of public hospital services in Africa. FUNDING: Wellcome Trust and the UK Department for International Development.

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