@Oxford Publications 2014

Ding H, Chen Y, Yu Z, Horby PW, Wang F, Hu J, Yang X, Mao H, Qin S, Chai C et al. 2014. A family cluster of three confirmed cases infected with avian influenza A (H7N9) virus in Zhejiang Province of China. BMC Infect Dis, 14 (1), pp. 698. | Citations: 9 (Scopus) | Show Abstract | Read more

BACKGROUND: A total of 453 laboratory-confirmed cases infected with avian influenza A (H7N9) virus (including 175 deaths) have been reported till October 2,2014, of which 30.68% (139/453) of the cases were identified from Zhejiang Province. We describe the largest reported cluster of virologically confirmed H7N9 cases, comprised by a fatal Index case and two mild secondary cases. METHODS: A retrospective investigation was conducted in January of 2014. Three confirmed cases, their close contacts, and relevant environments samples were tested by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), viral culture, and sequencing. Serum samples were tested by haemagglutination inhibition (HI) assay. RESULTS: The Index case, a 49-year-old farmer with type II diabetes, who lived with his daughter (Case 2, aged 24) and wife (Case 3, aged 43) and his son-in-law (H7N9 negative). The Index case and Case 3 worked daily in a live bird market. Onset of illness in Index case occurred in January 13, 2014 and subsequently, he died of multi-organ failure on January 20. Case 2 presented with mild symptoms on January 20 following frequent unprotected bed-side care of the Index case between January 14 to 19, and exposed to live bird market on January 17. Case 3 became unwell on January 23 after providing bedside care to the Index case on January 17 to 18, and following the contact with Case 2 during January 21 to 22 at the funeral of the Index case. The two secondary cases were discharged on February 2 and 5 separately after early treatment with antiviral medication. Four virus strains were isolated and genome analyses showed 99.6 ~100% genetic homology, with two amino mutations (V192I in NS and V280A in NP). 42% (11/26) of environmental samples collected in January were H7N9 positive. Twenty-five close contacts remained well and were negative for H7N9 infection by RT-PCR and HI assay. CONCLUSIONS: In the present study, the Index case was infected from a live bird market while the two secondary cases were infected by the Index case during unprotected exposure. This family cluster is, therefore, compatible with non-sustained person-to-person transmission of avian influenza A/H7N9.

Kamuya DM, Marsh V, Njuguna P, Munywoki P, Parker M, Molyneux S. 2014. "When they see us, it's like they have seen the benefits!": experiences of study benefits negotiations in community-based studies on the Kenyan Coast. BMC Med Ethics, 15 (1), pp. 90. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Benefit sharing in health research has been the focus of international debates for many years, particularly in developing countries. Whilst increasing attention is being given to frameworks that can guide researchers to determine levels of benefits to participants, there is little empirical research from developing countries on the practical application of these frameworks, including in situations of extreme poverty and vulnerability. In addition, the voices of those who often negotiate and face issues related to benefits in practice - frontline researchers and fieldworkers (FWs) - are rarely included in these debates. Against this background, this paper reports on experiences of negotiating research participation and benefits as described by fieldworkers, research participants and researchers in two community based studies. METHODS: The findings reported here are from a broader social science study that explored the nature of interactions between fieldworkers and participants in two community based studies on the Kenyan Coast. Between January and July 2010, data were collected using participant observation, and through group discussions and in-depth interviews with 42 fieldworkers, 4 researchers, and 40 study participants. RESULTS: Participants highly appreciated the benefits provided by studies, particularly health care benefits. Fieldworkers were seen by participants and other community members as the gatekeepers and conduits of benefits, even though those were not their formal roles. Fieldworkers found it challenging to ignore participant and community requests for more benefits, especially in situations of extreme poverty. However, responding to requests by providing different sorts and levels of benefits over time, as inadvertently happened in one study, raised expectations of further benefits and led to continuous negotiations between fieldworkers and participants. CONCLUSIONS: Fieldworkers play an important intermediary role in research; a role imbued with multiple challenges and ethical dilemmas for which they require appropriate support. Further more specific empirical research is needed to inform the development of guidance for researchers on benefit sharing, and on responding to emergency humanitarian needs for this and other similar settings.

Olotu A, Clement F, Jongert E, Vekemans J, Njuguna P, Ndungu FM, Marsh K, Leroux-Roels G, Bejon P. 2014. Avidity of anti-circumsporozoite antibodies following vaccination with RTS,S/AS01E in young children. PLoS One, 9 (12), pp. e115126. | Citations: 9 (Scopus) | Show Abstract | Read more

BACKGROUND: The nature of protective immune responses elicited by immunization with the candidate malaria vaccine RTS,S is still incompletely understood. Antibody levels correlate with protection against malaria infection, but considerable variation in outcome is unexplained (e.g., children may experience malaria despite high anti-circumsporozoite [CS] titers). METHODS AND FINDINGS: We measured the avidity index (AI) of the anti-CS antibodies raised in subgroup of 5-17 month old children in Kenya who were vaccinated with three doses of RTS,S/AS01E between March and August 2007. We evaluated the association between the AI and the subsequent risk of clinical malaria. We selected 19 cases (i.e., with clinical malaria) and 42 controls (i.e., without clinical malaria), matching for anti-CS antibody levels and malaria exposure. We assessed their sera collected 1 month after the third dose of the vaccine, in March 2008 (range 4-10 months after the third vaccine), and at 12 months after the third vaccine dose. The mean AI was 45.2 (95% CI: 42.4 to 48.1), 45.3 (95% CI: 41.4 to 49.1) and 46.2 (95% CI; 43.2 to 49.3) at 1 month, in March 2008 (4-10 months), and at 12 months after the third vaccination, respectively (p = 0.9 by ANOVA test for variation over time). The AI was not associated with protection from clinical malaria (OR = 0.90; 95% CI: 0.49 to 1.66; p = 0.74). The AI was higher in children with high malaria exposure, as measured using the weighted local prevalence of malaria, compared to those with low malaria exposure at 1 month post dose 3 (p = 0.035). CONCLUSION: Our data suggest that in RTS,S/AS01E-vaccinated children residing in malaria endemic countries, the avidity of anti-circumsporozoite antibodies, as measured using an elution ELISA method, was not associated with protection from clinical malaria. Prior natural malaria exposure might have primed the response to RTS,S/AS01E vaccination.

Okombo J, Kamau AW, Marsh K, Sutherland CJ, Ochola-Oyier LI. 2014. Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya. Int J Parasitol Drugs Drug Resist, 4 (3), pp. 152-163. | Citations: 13 (Scopus) | Show Abstract | Read more

Molecular surveillance of drug resistance markers through time provides crucial information on genomic adaptations, especially in parasite populations exposed to changing drug pressures. To assess temporal trends of established genotypes associated with tolerance to clinically important antimalarials used in Kenya over the last two decades, we sequenced a region of the pfcrt locus encompassing codons 72-76 of the Plasmodium falciparum chloroquine resistance transporter, full-length pfmdr1 - encoding multi-drug resistance protein, P-glycoprotein homolog (Pgh1) and pfdhfr encoding dihydrofolate reductase, in 485 archived Plasmodium falciparum positive blood samples collected in coastal Kenya at four different time points between 1995 and 2013. Microsatellite loci were also analyzed to compare the genetic backgrounds of parasite populations circulating before and after the withdrawal of chloroquine and sulfadoxine/pyrimethamine. Our results reveal a significant increase in the prevalence of the pfcrt K76 wild-type allele between 1995 and 2013 from 38% to 81.7% (p < 0.0001). In contrast, we noted a significant decline in wild-type pfdhfr S108 allele (p < 0.0001) culminating in complete absence of this allele in 2013. We also observed a significant increase in the prevalence of the wild-type pfmdr1 N86/Y184/D1246 haplotype from 14.6% in 1995 to 66.0% in 2013 (p < 0.0001) and a corresponding decline of the mutant pfmdr1 86Y/184Y/1246Y allele from 36.4% to 0% in 19 years (p < 0.0001). We also show extensive genetic heterogeneity among the chloroquine-sensitive parasites before and after the withdrawal of the drug in contrast to a selective sweep around the triple mutant pfdhfr allele, leading to a mono-allelic population at this locus. These findings highlight the importance of continual surveillance and characterization of parasite genotypes as indicators of the therapeutic efficacy of antimalarials, particularly in the context of changes in malaria treatment policy.

Nguyen DNT, Nguyen TV, Dao TT, Nguyen LT, Horby P, Nguyen KV, Wertheim HFL. 2014. One year experience using mycobacterial blood cultures to diagnose tuberculosis in patients with prolonged fever in Vietnam. J Infect Dev Ctries, 8 (12), pp. 1620-1624. | Show Abstract | Read more

INTRODUCTION: To evaluate the use of mycobacterial blood cultures (MBC) in diagnosing tuberculosis (TB) in patients with prolonged fever admitted to a Vietnamese referral hospital. RESULTS: MBCs from 94 patients (66% male; median age 33 years; 75% HIV positive) were evaluated: 14 were mycobacterium positive (all HIV positive), and MBC was the only positive specimen in 9 cases (41%). Three positive cases were identified as Mycobacterium avium and the remaining M. tuberculosis (one case could not be identified). CONCLUSION: MBC can be a valuable additional method to diagnose TB, particularly in immunosuppressed HIV patients when sputum cannot be collected.

Kihuba E, Gathara D, Mwinga S, Mulaku M, Kosgei R, Mogoa W, Nyamai R, English M. 2014. Assessing the ability of health information systems in hospitals to support evidence-informed decisions in Kenya. Glob Health Action, 7 (1), pp. 24859. | Show Abstract | Read more

Background Hospital management information systems (HMIS) is a key component of national health information systems (HIS), and actions required of hospital management to support information generation in Kenya are articulated in specific policy documents. We conducted an evaluation of core functions of data generation and reporting within hospitals in Kenya to facilitate interpretation of national reports and to provide guidance on key areas requiring improvement to support data use in decision making. Design The survey was a cross-sectional, cluster sample study conducted in 22 hospitals in Kenya. The statistical analysis was descriptive with adjustment for clustering. Results Most of the HMIS departments complied with formal guidance to develop departmental plans. However, only a few (3/22) had carried out a data quality audit in the 12 months prior to the survey. On average 3% (range 1-8%) of the total hospital income was allocated to the HMIS departments. About half of the records officer positions were filled and about half (13/22) of hospitals had implemented some form of electronic health record largely focused on improving patient billing and not linked to the district HIS. Completeness of manual patient registers varied, being 90% (95% CI 80.1-99.3%), 75.8% (95% CI 68.7-82.8%), and 58% (95% CI 50.4-65.1%) in maternal child health clinic, maternity, and pediatric wards, respectively. Vital events notification rates were low with 25.7, 42.6, and 71.3% of neonatal deaths, infant deaths, and live births recorded, respectively. Routine hospital reports suggested slight over-reporting of live births and under-reporting of fresh stillbirths and neonatal deaths. Conclusions Study findings indicate that the HMIS does not deliver quality data. Significant constraints exist in data quality assurance, supervisory support, data infrastructure in respect to information and communications technology application, human resources, financial resources, and integration.

Fonville JM, Wilks SH, James SL, Fox A, Ventresca M, Aban M, Xue L, Jones TC, Le NMH, Pham QT et al. 2014. Antibody landscapes after influenza virus infection or vaccination. Science, 346 (6212), pp. 996-1000. | Citations: 75 (Web of Science Lite) | Show Abstract | Read more

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.

Malaria Genomic Epidemiology Network, Malaria Genomic Epidemiology Network. 2014. Reappraisal of known malaria resistance loci in a large multicenter study. Nat Genet, 46 (11), pp. 1197-1204. | Citations: 63 (Scopus) | Show Abstract | Read more

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Tuyisenge L, Kyamanya P, Van Steirteghem S, Becker M, English M, Lissauer T. 2014. Knowledge and skills retention following emergency triage, assessment and treatment plus admission course for final year medical students in Rwanda: A longitudinal cohort study Archives of Disease in Childhood, 99 (11), pp. 993-997. | Citations: 8 (Scopus) | Show Abstract | Read more

© 2014, BMJ Publishing Group. All rights reserved. Aim: To determine whether, after the Emergency Triage, Assessment and Treatment plus Admission (ETAT+) course, a comprehensive paediatric life support course, final year medical undergraduates in Rwanda would achieve a high level of knowledge and practical skills and if these were retained. To guide further course development, student feedback was obtained. Methods: Longitudinal cohort study of knowledge and skills of all final year medical undergraduates at the University of Rwanda in academic year 2011-2012 who attended a 5-day ETAT+ course. Students completed a precourse knowledge test. Knowledge and clinical skills assessments, using standardised marking, were performed immediately postcourse and 3-9 months later. Feedback was obtained using printed questionnaires. Results: 84 students attended the course and reevaluation. Knowledge test showed a significant improvement, from median 47% to 71% correct answers (p < 0.001). For two clinical skills scenarios, 98% passed both scenarios, 37% after a retake, 2% failed both scenarios. Three to nine months later, students were reevaluated, median score for knowledge test 67%, not significantly different from postcourse (p > 0.1). For clinical skills, 74% passed, with 32% requiring a retake, 8% failed after retake, 18% failed both scenarios, a significant deterioration (p < 0.0001). Conclusions Students performed well on knowledge and skills immediately after a comprehensive ETAT+ course. Knowledge was maintained 3-9 months later. Clinical skills, which require detailed sequential steps, declined, but most were able to perform them satisfactorily after feedback. The course was highly valued, but several short courses and more practical teaching were advocated.

Huong VTL, Hoa NT, Horby P, Bryant JE, Van Kinh N, Toan TK, Wertheim HFL. 2014. Raw pig blood consumption and potential risk for Streptococcus suis infection, Vietnam. Emerg Infect Dis, 20 (11), pp. 1895-1898. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

We assessed consumption of raw pig blood, which is a risk factor for Streptococcus suis infection in Vietnam, by using a mix-method design. Factors associated with consumption included rural residency, age, sex, occupation, income, and marital status. We identified risk groups and practices and perceptions that should be targeted by communication programs.

Furtado T, Franzen S, van Loggerenberg F, Carn G, Grahek S, McBride M, Power M, O'Reilly J, Savarese B, Snowden MA et al. 2014. Strengthening neglected tropical disease research through enhancing research-site capacity: an evaluation of a novel web application to facilitate research collaborations. PLoS Negl Trop Dis, 8 (11), pp. e3225. | Citations: 3 (Web of Science Lite) | Read more

Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy J-F, Heymann D, Horby P, Kaleebu P, Tamfum J-JM et al. 2014. Randomised controlled trials for Ebola: practical and ethical issues. Lancet, 384 (9952), pp. 1423-1424. | Citations: 75 (Web of Science Lite) | Read more

Terheggen U, Drew DR, Hodder AN, Cross NJ, Mugyenyi CK, Barry AE, Anders RF, Dutta S, Osier FHA, Elliott SR et al. 2014. Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines. BMC Med, 12 (1), pp. 183. | Citations: 23 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Polymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies. METHODS: We aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence. RESULTS: We found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis. CONCLUSIONS: Antigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines.

Warimwe GM, Fegan G, Kiragu EW, Musyoki JN, Macharia AW, Marsh K, Williams TN, Bull PC. 2014. An assessment of the impact of host polymorphisms on Plasmodium falciparum var gene expression patterns among Kenyan children. BMC Infect Dis, 14 (1), pp. 524. | Show Abstract | Read more

BACKGROUND: Host genotype accounts for a component of the variability in susceptibility to childhood Plasmodium falciparum malaria. However, despite numerous examples of host polymorphisms associated with tolerance or resistance to infection, direct evidence for an impact of host genetic polymorphisms on the in vivo parasite population is difficult to obtain. Parasite molecules whose expression is most likely to be associated with such adaptation are those that are directly involved in the host-parasite interaction. A prime candidate is the family of parasite var gene-encoded molecules on P. falciparum-infected erythrocytes, PfEMP1, which binds various host molecules and facilitates parasite sequestration in host tissues to avoid clearance by the spleen. METHODS: To assess the impact of host genotype on the infecting parasite population we used a published parasite var gene sequence dataset to compare var gene expression patterns between parasites from children with polymorphisms in molecules thought to interact with or modulate display of PfEMP1 on the infected erythrocyte surface: ABO blood group, haemoglobin S, alpha-thalassaemia, the T188G polymorphism of CD36 and the K29M polymorphism of ICAM1. RESULTS: Expression levels of 'group A-like' var genes, which encode a specific group of PfEMP1 variants previously associated with low host immunity and severe malaria, showed signs of elevation among children of blood group AB. No other host factor tested showed evidence for an association with var expression. CONCLUSIONS: Our preliminary findings suggest that host ABO blood group may have a measurable impact on the infecting parasite population. This needs to be verified in larger studies.

Pigott DM, Golding N, Mylne A, Huang Z, Henry AJ, Weiss DJ, Brady OJ, Kraemer MUG, Smith DL, Moyes CL et al. 2014. Mapping the zoonotic niche of Ebola virus disease in Africa. Elife, 3 pp. e04395. | Citations: 168 (Web of Science Lite) | Show Abstract | Read more

Ebola virus disease (EVD) is a complex zoonosis that is highly virulent in humans. The largest recorded outbreak of EVD is ongoing in West Africa, outside of its previously reported and predicted niche. We assembled location data on all recorded zoonotic transmission to humans and Ebola virus infection in bats and primates (1976-2014). Using species distribution models, these occurrence data were paired with environmental covariates to predict a zoonotic transmission niche covering 22 countries across Central and West Africa. Vegetation, elevation, temperature, evapotranspiration, and suspected reservoir bat distributions define this relationship. At-risk areas are inhabited by 22 million people; however, the rarity of human outbreaks emphasises the very low probability of transmission to humans. Increasing population sizes and international connectivity by air since the first detection of EVD in 1976 suggest that the dynamics of human-to-human secondary transmission in contemporary outbreaks will be very different to those of the past.

Van Nguyen K, Zhang T, Thi Vu BN, Dao TT, Tran TK, Thi Nguyen DN, Thi Tran HK, Thi Nguyen CK, Fox A, Horby P, Wertheim H. 2014. Staphylococcus aureus nasopharyngeal carriage in rural and urban northern Vietnam. Trans R Soc Trop Med Hyg, 108 (12), pp. 783-790. | Citations: 8 (Scopus) | Show Abstract | Read more

BACKGROUND: Staphylococcus aureus is a common human pathogen that can colonise the respiratory tract and cause infection. Here we investigate the risk factors associated with nasopharyngeal carriage of S. aureus (including methicillin-resistant S. aureus [MRSA]) in Vietnam. METHODS: Between February and June 2012, nasal and pharyngeal swabs for S. aureus culture, and demographic and socioeconomic data were taken from 1016 participants in urban and rural northern Vietnam, who were randomly selected from pre-specified age strata. RESULTS: Overall S. aureus prevalence was 303/1016 (29.8%; adjusted for age: 33.8%). Carriage in the main cohort was found to be associated with younger age (≤5 years [OR 3.13, CI 1.62-6.03]; 6-12 [OR 6.87, CI 3.95-11.94]; 13-19 [OR 6.47, CI 3.56-11.74]; 20-29 [OR 4.73, CI 2.40-9.31]; 30-59 [OR 1.74, CI 1.04-2.92); with ≥60 as reference), living in an urban area (OR 1.36, CI 1.01-1.83) and antibiotics use (OR 0.69, CI 0.49-0.96). MRSA was detected in 80/1016 (7.9%). Being aged ≤5 years (OR 4.84, CI 1.47-15.97); 6-12 (OR 10.21, CI 3.54-29.50); 20-29 (OR 4.01, CI 1.09-14.77) and wealth (>3/5 wealth index, OR 1.63 CI 1.01-2.62) were significant risk factors for MRSA carriage. CONCLUSIONS: Nasopharyngeal carriage of S. aureus is present in one-third of the Vietnamese population, and is more prevalent among children. Pharyngeal carriage is more common than nasal carriage. Risk factors for S. aureus (including MRSA) carriage are identified in the community.

Zhang W, Wan J, Qian K, Liu X, Xiao Z, Sun J, Zeng Z, Wang Q, Zhang J, Jiang G et al. 2014. Clinical characteristics of human infection with a novel avian-origin influenza A(H10N8) virus. Chin Med J (Engl), 127 (18), pp. 3238-3242. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Novel influenza A viruses of avian-origin may be the precursors of pandemic strains. This descriptive study aims to introduce a novel avian-origin influenza A (H10N8) virus which can infect humans and cause severe diseases. METHODS: Collecting clinical data of three cases of human infection with a novel reassortment avian influenza A (H10N8) virus in Nanchang, Jiangxi Province, China. RESULTS: Three cases of human infection with a new reassortment avian influenza A(H10N8) virus were described, of which two were fatal cases, and one was severe case. These cases presented with severe pneumonia that progressed to acute respiratory distress syndrome (ARDS) and intractable respiratory failure. CONCLUSION: This novel reassortment avian influenza A (H10N8) virus in China resulted in fatal human infections, and should be added to concerns in clinical practice.

Balasingam S, Horby P, Wilder-Smith A. 2014. The potential for a controlled human infection platform in Singapore. Singapore Med J, 55 (9), pp. 456-461. | Citations: 3 (Scopus) | Show Abstract | Read more

For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies.

Cauchemez S, Ferguson NM, Fox A, Mai LQ, Thanh LT, Thai PQ, Thoang DD, Duong TN, Minh Hoa LN, Tran Hien N, Horby P. 2014. Determinants of influenza transmission in South East Asia: insights from a household cohort study in Vietnam. PLoS Pathog, 10 (8), pp. e1004310. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza in the community or in the household. Here, we analyse a large household cohort study conducted in 2007-2010 in Vietnam using innovative statistical methods to ascertain in an integrative framework the relative contribution of variables that influence the transmission of seasonal (H1N1, H3N2, B) and pandemic H1N1pdm09 influenza. Influenza infection was diagnosed by haemagglutination-inhibition (HI) antibody assay of paired serum samples. We used a Bayesian data augmentation Markov chain Monte Carlo strategy based on digraphs to reconstruct unobserved chains of transmission in households and estimate transmission parameters. The probability of transmission from an infected individual to another household member was 8% (95% CI, 6%, 10%) on average, and varied with pre-season titers, age and household size. Within households of size 3, the probability of transmission from an infected member to a child with low pre-season HI antibody titers was 27% (95% CI 21%-35%). High pre-season HI titers were protective against infection, with a reduction in the hazard of infection of 59% (95% CI, 44%-71%) and 87% (95% CI, 70%-96%) for intermediate (1∶20-1∶40) and high (≥1∶80) HI titers, respectively. Even after correcting for pre-season HI titers, adults had half the infection risk of children. Twenty six percent (95% CI: 21%, 30%) of infections may be attributed to household transmission. Our results highlight the importance of integrated analysis by influenza sub-type, age and pre-season HI titers in order to infer influenza transmission risks in and outside of the household.

Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B et al. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 371 (5), pp. 411-423. | Citations: 600 (Scopus) | Show Abstract | Read more

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

Waddington CS, Darton TC, Angus B, Pollard AJ. 2014. Reply to Farmakiotis et al. Clin Infect Dis, 59 (8), pp. 1198-1199. | Read more

Osier FH, Mackinnon MJ, Crosnier C, Fegan G, Kamuyu G, Wanaguru M, Ogada E, McDade B, Rayner JC, Wright GJ, Marsh K. 2014. New antigens for a multicomponent blood-stage malaria vaccine. Sci Transl Med, 6 (247), pp. 247ra102. | Citations: 57 (Scopus) | Show Abstract | Read more

An effective blood-stage vaccine against Plasmodium falciparum remains a research priority, but the number of antigens that have been translated into multicomponent vaccines for testing in clinical trials remains limited. Investigating the large number of potential targets found in the parasite proteome has been constrained by an inability to produce natively folded recombinant antigens for immunological studies. We overcame these constraints by generating a large library of biochemically active merozoite surface and secreted full-length ectodomain proteins. We then systematically examined the antibody reactivity against these proteins in a cohort of Kenyan children (n = 286) who were sampled at the start of a malaria transmission season and prospectively monitored for clinical episodes of malaria over the ensuing 6 months. We found that antibodies to previously untested or little-studied proteins had superior or equivalent potential protective efficacy to the handful of current leading malaria vaccine candidates. Moreover, cumulative responses to combinations comprising 5 of the 10 top-ranked antigens, including PF3D7_1136200, MSP2, RhopH3, P41, MSP11, MSP3, PF3D7_0606800, AMA1, Pf113, and MSRP1, were associated with 100% protection against clinical episodes of malaria. These data suggest not only that there are many more potential antigen candidates for the malaria vaccine development pipeline but also that effective vaccination may be achieved by combining a selection of these antigens.

Venkatesan M, Gadalla NB, Stepniewska K, Dahal P, Nsanzabana C, Moriera C, Price RN, Mårtensson A, Rosenthal PJ, Dorsey G et al. 2014. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. Am J Trop Med Hyg, 91 (4), pp. 833-843. | Citations: 53 (Scopus) | Show Abstract | Read more

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Mwaniki P, Ayieko P, Todd J, English M. 2014. Assessment of paediatric inpatient care during a multifaceted quality improvement intervention in Kenyan district hospitals--use of prospectively collected case record data. BMC Health Serv Res, 14 (1), pp. 312. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In assessing quality of care in developing countries, retrospectively collected data are usually used given their availability. Retrospective data however suffer from such biases as recall bias and non-response bias. Comparing results obtained using prospectively and retrospectively collected data will help validate the use of the easily available retrospective data in assessing quality of care in past and future studies. METHODS: Prospective and retrospective datasets were obtained from a cluster randomized trial of a multifaceted intervention aimed at improving paediatric inpatient care conducted in eight rural Kenyan district hospitals by improving management of children admitted with pneumonia, malaria and diarrhea and/or dehydration. Four hospitals received a full intervention and four a partial intervention. Data were collected through 3 two weeks surveys conducted at baseline, after 6 and 18 months. Retrospective data was sampled from paediatric medical records of patients discharged in the preceding six months of the survey while prospective data was collected from patients discharged during the two week period of each survey. Risk Differences during post-intervention period of 16 quality of care indicators were analyzed separately for prospective and retrospective datasets and later plotted side by side for comparison. RESULTS: For the prospective data there was strong evidence of an intervention effect for 8 of the indicators and weaker evidence of an effect for one indicator, with magnitude of effect sizes varying from 23% to 60% difference. For the retrospective data, 10 process (these include the 8 indicators found to be statistically significant in prospective data analysis) indicators had statistically significant differences with magnitude of effects varying from 10% to 42%. The bar-graph comparing results from the prospective and retrospective datasets showed similarity in terms of magnitude of effects and statistical significance for all except two indicators. CONCLUSION: Multifaceted interventions can help improve adoption of clinical guidelines and hence improve the quality of care. The similar inference reached after analyses based on prospective assessment of case management is a useful finding as it supports the utility of work based on examination of retrospectively assembled case records allowing longer time periods to be studied while constraining costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42996612. Trial registration date: 20/11/2008.

HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L et al. 2014. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med, 371 (3), pp. 203-212. | Citations: 567 (Scopus) | Show Abstract | Read more

BACKGROUND: Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain. METHODS: After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). RESULTS: During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001). CONCLUSIONS: Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.).

Thanh THT, Ngoc SD, Viet NN, Van HN, Horby P, Cobelens FGJ, Wertheim HFL. 2014. A household survey on screening practices of household contacts of smear positive tuberculosis patients in Vietnam. BMC Public Health, 14 (1), pp. 713. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Close contacts of tuberculosis (TB) patients are at increased risk of developing tuberculosis. Although passive contact screening guidelines are incorporated in the national TB control program, currently it is unknown how frequent close contacts are screened for TB in Vietnam. This study assesses current contact screening practices in Vietnam and determines the proportion of household contacts screened of newly registered TB patients. METHOD: Survey of household contacts of smear-positive TB patients (index patients) registered for treatment in 2008 in three Vietnamese cities. Households were interviewed in 2010 about screening for TB since treatment registration date of the index patient. RESULTS: We interviewed 4,118 household contacts of 1,091 identified index cases. Contact screening mainly relied on self-referral by household contacts. Of the 4,118 household contacts, 474 (11.5%) self-referred for TB screening, while this screening proportion was only 5.5% among contacts under 5 years old (16/293). Sputum examinations were performed in 374 (78.9%) of the screened contacts. Contact screening identified 27 cases of pulmonary TB (0.7%; or 656 cases/100,000 contacts), of which 20 were detected by sputum smear. CONCLUSIONS: The low proportion of household TB contacts screened for TB illustrates the limitations of passive contact screening as currently practiced in Vietnam. Children under 5 years of age are particularly neglected with this approach. Active contact screening with fixed follow-up times of close contacts of newly diagnosed TB patients should be considered in Vietnam, particularly in case of young children and drug-resistant TB.

Huong VTL, Ha N, Huy NT, Horby P, Nghia HDT, Thiem VD, Zhu X, Hoa NT, Hien TT, Zamora J et al. 2014. Epidemiology, clinical manifestations, and outcomes of Streptococcus suis infection in humans. Emerg Infect Dis, 20 (7), pp. 1105-1114. | Citations: 46 (Scopus) | Show Abstract | Read more

Streptococcus suis, a bacterium that affects pigs, is a neglected pathogen that causes systemic disease in humans. We conducted a systematic review and meta-analysis to summarize global estimates of the epidemiology, clinical characteristics, and outcomes of this zoonosis. We searched main literature databases for all studies through December 2012 using the search term "streptococcus suis." The prevalence of S. suis infection is highest in Asia; the primary risk factors are occupational exposure and eating of contaminated food. The pooled proportions of case-patients with pig-related occupations and history of eating high-risk food were 38.1% and 37.3%, respectively. The main clinical syndrome was meningitis (pooled rate 68.0%), followed by sepsis, arthritis, endocarditis, and endophthalmitis. The pooled case-fatality rate was 12.8%. Sequelae included hearing loss (39.1%) and vestibular dysfunction (22.7%). Our analysis identified gaps in the literature, particularly in assessing risk factors and sequelae of this infection.

Osier FH, Feng G, Boyle MJ, Langer C, Zhou J, Richards JS, McCallum FJ, Reiling L, Jaworowski A, Anders RF et al. 2014. Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria. BMC Med, 12 (1), pp. 108. | Citations: 68 (Scopus) | Show Abstract | Read more

BACKGROUND: An understanding of the mechanisms mediating protective immunity against malaria in humans is currently lacking, but critically important to advance the development of highly efficacious vaccines. Antibodies play a key role in acquired immunity, but the functional basis for their protective effect remains unclear. Furthermore, there is a strong need for immune correlates of protection against malaria to guide vaccine development. METHODS: Using a validated assay to measure opsonic phagocytosis of Plasmodium falciparum merozoites, we investigated the potential role of this functional activity in human immunity against clinical episodes of malaria in two independent cohorts (n = 109 and n = 287) experiencing differing levels of malaria transmission and evaluated its potential as a correlate of protection. RESULTS: Antibodies promoting opsonic phagocytosis of merozoites were cytophilic immunoglobulins (IgG1 and IgG3), induced monocyte activation and production of pro-inflammatory cytokines, and were directed against major merozoite surface proteins (MSPs). Consistent with protective immunity in humans, opsonizing antibodies were acquired with increasing age and malaria exposure, were boosted on re-infection, and levels were related to malaria transmission intensity. Opsonic phagocytosis was strongly associated with a reduced risk of clinical malaria in longitudinal studies in children with current or recent infections. In contrast, antibodies to the merozoite surface in standard immunoassays, or growth-inhibitory antibodies, were not significantly associated with protection. In multivariate analyses including several antibody responses, opsonic phagocytosis remained significantly associated with protection against malaria, highlighting its potential as a correlate of immunity. Furthermore, we demonstrate that human antibodies against MSP2 and MSP3 that are strongly associated with protection in this population are effective in opsonic phagocytosis of merozoites, providing a functional link between these antigen-specific responses and protection for the first time. CONCLUSIONS: Opsonic phagocytosis of merozoites appears to be an important mechanism contributing to protective immunity in humans. The opsonic phagocytosis assay appears to be a strong correlate of protection against malaria, a valuable biomarker of immunity, and provides a much-needed new tool for assessing responses to blood-stage malaria vaccines and measuring immunity in populations.

Muinga N, Ayieko P, Opondo C, Ntoburi S, Todd J, Allen E, English M. 2014. Using health worker opinions to assess changes in structural components of quality in a Cluster Randomized Trial. BMC Health Serv Res, 14 (1), pp. 282. | Show Abstract | Read more

BACKGROUND: The 'resource readiness' of health facilities to provide effective services is captured in the structure component of the classical Donabedian paradigm often used for assessment of the quality of care in the health sector. Periodic inventories are commonly used to confirm the presence (or absence) of equipment or drugs by physical observation or by asking those in charge to indicate whether an item is present or not. It is then assumed that this point observation is representative of the everyday status. However the availability of an item (consumables) may vary. Arguably therefore a more useful assessment for resources would be one that captures this fluctuation in time. Here we report an approach that may circumvent these difficulties. METHODS: We used self-administered questionnaires (SAQ) to seek health worker views of availability of key resources supporting paediatric care linked to a cluster randomized trial of a multifaceted intervention aimed at improving this care conducted in eight rural Kenyan district hospitals. Four hospitals received a full intervention and four a partial intervention. Data were collected pre-intervention and after 6 and 18 months from health workers in three clinical areas asked to score item availability using an 11-point scale. Mean scores for items common to all 3 areas and mean scores for items allocated to domains identified using exploratory factor analysis (EFA) were used to describe availability and explore changes over time. RESULTS: SAQ were collected from 1,156 health workers. EFA identified 11 item domains across the three departments. Mean availability scores for these domains were often <5/10 at baseline reflecting lack of basic resources such as oxygen, nutrition and second line drugs. An improvement in mean scores occurred in 8 out of 11 domains in both control and intervention groups. A calculation of difference in difference of means for intervention vs. control suggested an intervention effect resulting in greater changes in 5 out of 11 domains. CONCLUSION: Using SAQ data to assess resource availability experienced by health workers provides an alternative to direct observations that provide point prevalence estimates. Further the approach was able to demonstrate poor access to resources, change over time and variability across place.

Kloprogge F, Jullien V, Piola P, Dhorda M, Muwanga S, Nosten F, Day NPJ, White NJ, Guerin PJ, Tarning J. 2014. Population pharmacokinetics of quinine in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda. J Antimicrob Chemother, 69 (11), pp. 3033-3040. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: Oral quinine is used for the treatment of uncomplicated malaria during pregnancy, but few pharmacokinetic data are available for this population. Previous studies have reported a substantial effect of malaria on the pharmacokinetics of quinine resulting from increased α-1-acid glycoprotein levels and decreased cytochrome P450 3A4 activity. The aim of this study was to investigate the pharmacokinetic properties of oral quinine in pregnant women with uncomplicated malaria in Uganda using a population approach. METHODS: Data from 22 women in the second and third trimesters of pregnancy with uncomplicated Plasmodium falciparum malaria were analysed. Patients received quinine sulphate (10 mg of salt/kg) three times daily (0, 8 and 16 h) for 7 days. Plasma samples were collected daily and at frequent intervals after the first and last doses. A population pharmacokinetic model for quinine was developed accounting for different disposition, absorption, error and covariate models. RESULTS: Parasitaemia, as a time-varying covariate affecting relative bioavailability, and body temperature on admission as a covariate on elimination clearance, explained the higher exposure to quinine during acute malaria compared with the convalescent phase. Neither the estimated gestational age nor the trimester influenced the pharmacokinetic properties of quinine significantly. CONCLUSIONS: A population model was developed that adequately characterized quinine pharmacokinetics in pregnant Ugandan women with acute malaria. Quinine exposure was lower than previously reported in patients who were not pregnant. The measurement of free quinine concentration will be necessary to determine the therapeutic relevance of these observations.

Ocholla H, Preston MD, Mipando M, Jensen ATR, Campino S, MacInnis B, Alcock D, Terlouw A, Zongo I, Oudraogo J-B et al. 2014. Whole-genome scans provide evidence of adaptive evolution in Malawian Plasmodium falciparum isolates. J Infect Dis, 210 (12), pp. 1991-2000. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation. METHODS: We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection. RESULTS: High genetic diversity (π = 2.4 × 10(-4)), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens. Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between Africa and Asia, within Southeast Asia, and within Africa. Haplotype-based tests of selection to sequence data from all 6 populations identified signals of directional selection at known drug-resistance loci, including pfcrt, pfdhps, pfmdr1, and pfgch1. CONCLUSIONS: The sequence variations observed at drug-resistance loci reflect differences in each country's historical use of antimalarial drugs and may be useful in formulating local malaria treatment guidelines.

Glover M, Kira A, Gentles D, Cowie N, Paton C, Moetara W. 2014. The WERO group stop smoking competition: main outcomes of a pre- and post- study. BMC Public Health, 14 (1), pp. 599. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: One potential promising strategy for increasing smoking cessation for Māori (Indigenous New Zealanders) and New Zealand resident Pacific Island people is Quit and Win competitions. The current uncontrolled pre and post study, WERO (WERO in Māori language means challenge), differs from previous studies in that it aims to investigate if a stop smoking contest, using both within team support, external support from a team coach and cessation experts, and technology, would be effective in prompting and sustaining quitting. METHOD: Fifteen teams, recruited from urban Māori, rural Māori and urban Pacific communities, competed to win a NZ$5000 (about € 3,000, £ 2600) prize for a charity or community group of their choice. People were eligible if they were aged 18 years and over and identified as smokers. Smoking status was biochemically validated at the start and end of the 3 month competition. At 3-months post competition self-reported smoking status was collected. RESULTS: Fourteen teams with 10 contestants and one team with eight contestants were recruited. At the end of the competition the biochemically verified quit rate was 36%. The 6 months self-reported quit rate was 26%. The Pacific and rural Māori teams had high end of competition and 6 months follow-up quit rates (46% and 44%, and 36% and 29%). CONCLUSION: WERO appeared to be successful in prompting quitting among high smoking prevalence groups. WERO combined several promising strategies for supporting cessation: peer support, cessation provider support, incentives, competition and interactive internet and mobile tools. Though designed for Māori and Pacific people, WERO could potentially be effective for other family- and community-centred cultures.

Tuyisenge L, Kyamanya P, Van Steirteghem S, Becker M, English M, Lissauer T. 2014. Knowledge and skills retention following Emergency Triage, Assessment and Treatment plus Admission course for final year medical students in Rwanda: a longitudinal cohort study. Arch Dis Child, 99 (11), pp. 993-997. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

AIM: To determine whether, after the Emergency Triage, Assessment and Treatment plus Admission (ETAT+) course, a comprehensive paediatric life support course, final year medical undergraduates in Rwanda would achieve a high level of knowledge and practical skills and if these were retained. To guide further course development, student feedback was obtained. METHODS: Longitudinal cohort study of knowledge and skills of all final year medical undergraduates at the University of Rwanda in academic year 2011-2012 who attended a 5-day ETAT+ course. Students completed a precourse knowledge test. Knowledge and clinical skills assessments, using standardised marking, were performed immediately postcourse and 3-9 months later. Feedback was obtained using printed questionnaires. RESULTS: 84 students attended the course and re-evaluation. Knowledge test showed a significant improvement, from median 47% to 71% correct answers (p<0.001). For two clinical skills scenarios, 98% passed both scenarios, 37% after a retake, 2% failed both scenarios. Three to nine months later, students were re-evaluated, median score for knowledge test 67%, not significantly different from postcourse (p>0.1). For clinical skills, 74% passed, with 32% requiring a retake, 8% failed after retake, 18% failed both scenarios, a significant deterioration (p<0.0001). CONCLUSIONS: Students performed well on knowledge and skills immediately after a comprehensive ETAT+ course. Knowledge was maintained 3-9 months later. Clinical skills, which require detailed sequential steps, declined, but most were able to perform them satisfactorily after feedback. The course was highly valued, but several short courses and more practical teaching were advocated.

Näsström E, Vu Thieu NT, Dongol S, Karkey A, Voong Vinh P, Ha Thanh T, Johansson A, Arjyal A, Thwaites G, Dolecek C et al. 2014. Salmonella Typhi and Salmonella Paratyphi A elaborate distinct systemic metabolite signatures during enteric fever. Elife, 3 | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

The host-pathogen interactions induced by Salmonella Typhi and Salmonella Paratyphi A during enteric fever are poorly understood. This knowledge gap, and the human restricted nature of these bacteria, limit our understanding of the disease and impede the development of new diagnostic approaches. To investigate metabolite signals associated with enteric fever we performed two dimensional gas chromatography with time-of-flight mass spectrometry (GCxGC/TOFMS) on plasma from patients with S. Typhi and S. Paratyphi A infections and asymptomatic controls, identifying 695 individual metabolite peaks. Applying supervised pattern recognition, we found highly significant and reproducible metabolite profiles separating S. Typhi cases, S. Paratyphi A cases, and controls, calculating that a combination of six metabolites could accurately define the etiological agent. For the first time we show that reproducible and serovar specific systemic biomarkers can be detected during enteric fever. Our work defines several biologically plausible metabolites that can be used to detect enteric fever, and unlocks the potential of this method in diagnosing other systemic bacterial infections.

Thai PQ, Mai LQ, Welkers MRA, Hang NLK, Thanh LT, Dung VTV, Yen NTT, Duong TN, Hoa LNM, Thoang DD et al. 2014. Pandemic H1N1 virus transmission and shedding dynamics in index case households of a prospective Vietnamese cohort. J Infect, 68 (6), pp. 581-590. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: Influenza household transmission studies are required to guide prevention strategies but most passively recruit index cases that seek healthcare. We investigated A(H1N1)pdm09 transmission in a household-based cohort during 2009. METHODS: Health-workers visited 270 households weekly, and collected swabs from influenza-like-illness cases. If A(H1N1)pdm09 was RT-PCR-confirmed, all household members had symptoms assessed and swabs collected daily for 10-15 days. Viral RNA was quantified and sequenced and serology performed on pre-pandemic sera. RESULTS: Index cases were detected in 20 households containing 81 people. 98.5% lacked A(H1N1)pdm09 neutralizing antibodies in pre-pandemic sera. Eleven (18.6%, 95% CI 10.7-30.4%) of 59 contacts were infected. Virus genetic diversity within households was negligible and less than between households. Index and secondary cases were distributed between mothers, daughters and sons, and had similar virus-RNA shedding and symptom dynamics. Fathers were rarely infected. Five secondary cases (45%) had no apparent symptoms and three shed virus before symptoms. Secondary infection was associated with index case wet cough (OR 1.56, 95% CI 1.22-1.99). CONCLUSIONS: In this cohort of A(H1N1)pdm09 susceptible persons, virus sequencing was capable of discriminating household from community transmission. Household transmission involved mothers and children but rarely fathers. Asymptomatic or pre-symptomatic shedding was common.

Horby P. 2014. Systematic review and meta-analysis: For some groups traditionally considered to be 'high risk', the evidence of an increased risk of severe influenza-associated illness is poor quality Evidence-Based Medicine, 19 (3), pp. 110. | Read more

Horby PW. 2014. Community studies of influenza: new knowledge, new questions. Lancet Respir Med, 2 (6), pp. 430-431. | Citations: 1 (Scopus) | Read more

Angus B. 2014. Novel anti-malarial combinations and their toxicity. Expert Rev Clin Pharmacol, 7 (3), pp. 299-316. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

Artemisinin combination therapy for the treatment of uncomplicated malaria includes artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, artesunate plus sulfadoxine-pyrimethamine and dihydroartemisinin plus piperaquine. These drugs are safe and efficacious at present. The emergence of artemisinin resistant parasites in SE Asia means that there is a need to optimise drug dosing and investigate novel therapies to maintain the impressive reduction in malaria mortality which has been seen in the past decade.

English M, Gathara D, Mwinga S, Ayieko P, Opondo C, Aluvaala J, Kihuba E, Mwaniki P, Were F, Irimu G et al. 2014. Adoption of recommended practices and basic technologies in a low-income setting Archives of Disease in Childhood, 99 (5), pp. 452-456. | Citations: 14 (Scopus) | Show Abstract | Read more

Objective: In global health considerable attention is focused on the search for innovations; however, reports tracking their adoption in routine hospital settings from low-income countries are absent. Design and setting: We used data collected on a consistent panel of indicators during four separate cross-sectional, hospital surveys in Kenya to track changes over a period of 11 years (2002-2012). Main outcome measures: Basic resource availability, use of diagnostics and uptake of recommended practices. Results: There appeared little change in availability of a panel of 28 basic resources (median 71% in 2002 to 82% in 2012) although availability of specific feeds for severe malnutrition and vitamin K improved. Use of blood glucose and HIV testing increased but remained inappropriately low throughout. Commonly (malaria) and uncommonly (lumbar puncture) performed diagnostic tests frequently failed to inform practice while pulse oximetry, a simple and cheap technology, was rarely available even in 2012. However, increasing adherence to prescribing guidance occurred during a period from 2006 to 2012 in which efforts were made to disseminate guidelines. Conclusions: Findings suggest changes in clinical practices possibly linked to dissemination of guidelines at reasonable scale. However, full availability of basic resources was not attained and major gaps likely exist between the potential and actual impacts of simple diagnostics and technologies representing problems with availability, adoption and successful utilisation. These findings are relevant to debates on scaling up in low-income settings and to those developing novel therapeutic or diagnostic interventions.

Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. 2014. Advancing the management and control of typhoid fever: A review of the historical role of human challenge studies Journal of Infection, 68 (5), pp. 405-418. | Citations: 20 (Scopus) | Show Abstract | Read more

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design. © 2014.

Peto L, Nadjm B, Horby P, Ngan TTD, van Doorn R, Van Kinh N, Wertheim HFL. 2014. The bacterial aetiology of adult community-acquired pneumonia in Asia: a systematic review. Trans R Soc Trop Med Hyg, 108 (6), pp. 326-337. | Citations: 26 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of adult mortality in Asia. Appropriate empirical treatment depends on knowledge of the pathogens commonly responsible. However, assessing the aetiological significance of identified organisms is often difficult, particularly with sputum isolates that might represent contamination with oropharyngeal flora. METHODS: A systematic review of all adult CAP aetiology studies from Asia, excluding the Middle East, published in English between 1 January 1990 and 1 March 2012 was conducted. Forty-eight studies reporting on 10 423 patients were included, representing data from China, India, Indonesia, Japan, Malaysia, The Philippines, Singapore, South Korea, Taiwan, Thailand and Vietnam. Data from large parts of Asia were unavailable and there was substantial heterogeneity in methodology. RESULTS: As in western studies, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella spp. and Haemophilus influenzae were all significant pathogens. However, compared with western studies, S. pneumoniae was of less relative importance. Gram-negative bacilli and Mycobacterium tuberculosis were more important, and in northeast Thailand Burkholderia pseudomallei was a major pathogen. CONCLUSION: These data have major implications for diagnostic strategies and empirical treatment. Narrow-spectrum antibiotics targeting S. pneumoniae may be inappropriate in many Asian settings, and agents active against TB may lead to partial response and delayed TB diagnosis.

Lourens C, Lindegardh N, Barnes KI, Guerin PJ, Sibley CH, White NJ, Tarning J. 2014. Benefits of a pharmacology antimalarial reference standard and proficiency testing program provided by the Worldwide Antimalarial Resistance Network (WWARN). Antimicrob Agents Chemother, 58 (7), pp. 3889-3894. | Citations: 9 (Scopus) | Show Abstract | Read more

Comprehensive assessment of antimalarial drug resistance should include measurements of antimalarial blood or plasma concentrations in clinical trials and in individual assessments of treatment failure so that true resistance can be differentiated from inadequate drug exposure. Pharmacometric modeling is necessary to assess pharmacokinetic-pharmacodynamic relationships in different populations to optimize dosing. To accomplish both effectively and to allow comparison of data from different laboratories, it is essential that drug concentration measurement is accurate. Proficiency testing (PT) of laboratory procedures is necessary for verification of assay results. Within the Worldwide Antimalarial Resistance Network (WWARN), the goal of the quality assurance/quality control (QA/QC) program is to facilitate and sustain high-quality antimalarial assays. The QA/QC program consists of an international PT program for pharmacology laboratories and a reference material (RM) program for the provision of antimalarial drug standards, metabolites, and internal standards for laboratory use. The RM program currently distributes accurately weighed quantities of antimalarial drug standards, metabolites, and internal standards to 44 pharmacology, in vitro, and drug quality testing laboratories. The pharmacology PT program has sent samples to eight laboratories in four rounds of testing. WWARN technical experts have provided advice for correcting identified problems to improve performance of subsequent analysis and ultimately improved the quality of data. Many participants have demonstrated substantial improvements over subsequent rounds of PT. The WWARN QA/QC program has improved the quality and value of antimalarial drug measurement in laboratories globally. It is a model that has potential to be applied to strengthening laboratories more widely and improving the therapeutics of other infectious diseases.

Bejon P, Williams TN, Nyundo C, Hay SI, Benz D, Gething PW, Otiende M, Peshu J, Bashraheil M, Greenhouse B et al. 2014. A micro-epidemiological analysis of febrile malaria in Coastal Kenya showing hotspots within hotspots. Elife, 3 pp. e02130. | Citations: 43 (Web of Science Lite) | Show Abstract | Read more

Malaria transmission is spatially heterogeneous. This reduces the efficacy of control strategies, but focusing control strategies on clusters or 'hotspots' of transmission may be highly effective. Among 1500 homesteads in coastal Kenya we calculated (a) the fraction of febrile children with positive malaria smears per homestead, and (b) the mean age of children with malaria per homestead. These two measures were inversely correlated, indicating that children in homesteads at higher transmission acquire immunity more rapidly. This inverse correlation increased gradually with increasing spatial scale of analysis, and hotspots of febrile malaria were identified at every scale. We found hotspots within hotspots, down to the level of an individual homestead. Febrile malaria hotspots were temporally unstable, but 4 km radius hotspots could be targeted for 1 month following 1 month periods of surveillance.DOI: http://dx.doi.org/10.7554/eLife.02130.001.

Tabernero P, Fernández FM, Green M, Guerin PJ, Newton PN. 2014. Mind the gaps--the epidemiology of poor-quality anti-malarials in the malarious world--analysis of the WorldWide Antimalarial Resistance Network database. Malar J, 13 (1), pp. 139. | Citations: 39 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Poor quality medicines threaten the lives of millions of patients and are alarmingly common in many parts of the world. Nevertheless, the global extent of the problem remains unknown. Accurate estimates of the epidemiology of poor quality medicines are sparse and are influenced by sampling methodology and diverse chemical analysis techniques. In order to understand the existing data, the Antimalarial Quality Scientific Group at WWARN built a comprehensive, open-access, global database and linked Antimalarial Quality Surveyor, an online visualization tool. Analysis of the database is described here, the limitations of the studies and data reported, and their public health implications discussed. METHODS: The database collates customized summaries of 251 published anti-malarial quality reports in English, French and Spanish by time and location since 1946. It also includes information on assays to determine quality, sampling and medicine regulation. RESULTS: No publicly available reports for 60.6% (63) of the 104 malaria-endemic countries were found. Out of 9,348 anti-malarials sampled, 30.1% (2,813) failed chemical/packaging quality tests with 39.3% classified as falsified, 2.3% as substandard and 58.3% as poor quality without evidence available to categorize them as either substandard or falsified. Only 32.3% of the reports explicitly described their definitions of medicine quality and just 9.1% (855) of the samples collected in 4.6% (six) surveys were conducted using random sampling techniques. Packaging analysis was only described in 21.5% of publications and up to twenty wrong active ingredients were found in falsified anti-malarials. CONCLUSIONS: There are severe neglected problems with anti-malarial quality but there are important caveats to accurately estimate the prevalence and distribution of poor quality anti-malarials. The lack of reports in many malaria-endemic areas, inadequate sampling techniques and inadequate chemical analytical methods and instrumental procedures emphasizes the need to interpret medicine quality results with caution. The available evidence demonstrates the need for more investment to improve both sampling and analytical methodology and to achieve consensus in defining different types of poor quality medicines.

Abdi AI, Fegan G, Muthui M, Kiragu E, Musyoki JN, Opiyo M, Marsh K, Warimwe GM, Bull PC. 2014. Plasmodium falciparum antigenic variation: relationships between widespread endothelial activation, parasite PfEMP1 expression and severe malaria. BMC Infect Dis, 14 (1), pp. 170. | Citations: 9 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) is a family of variant surface antigens (VSA) that mediate the adhesion of parasite infected erythrocytes to capillary endothelial cells within host tissues. Opinion is divided over the role of PfEMP1 in the widespread endothelial activation associated with severe malaria. In a previous study we found evidence for differential associations between defined VSA subsets and specific syndromes of severe malaria: group A-like PfEMP1 expression and the "rosetting" phenotype were associated with impaired consciousness and respiratory distress, respectively. This study explores the involvement of widespread endothelial activation in these associations. METHODS: We used plasma angiopoietin-2 as a marker of widespread endothelial activation. Using logistic regression analysis, we explored the relationships between plasma angiopoietin-2 levels, parasite VSA expression and the two syndromes of severe malaria, impaired consciousness and respiratory distress. RESULTS: Plasma angiopoietin-2 was associated with both syndromes. The rosetting phenotype did not show an independent association with respiratory distress when adjusted for angiopoietin-2, consistent with a single pathogenic mechanism involving widespread endothelial activation. In contrast, group A-like PfEMP1 expression and angiopoietin-2 maintained independent associations with impaired consciousness when adjusted for each other. CONCLUSION: The results are consistent with multiple pathogenic mechanisms leading to severe malaria and heterogeneity in the pathophysiology of impaired consciousness. The observed association between group A-like PfEMP1 and impaired consciousness does not appear to involve widespread endothelial activation.

Taylor AR, Flegg JA, Nsobya SL, Yeka A, Kamya MR, Rosenthal PJ, Dorsey G, Sibley CH, Guerin PJ, Holmes CC. 2014. Estimation of malaria haplotype and genotype frequencies: a statistical approach to overcome the challenge associated with multiclonal infections. Malar J, 13 (1), pp. 102. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Reliable measures of anti-malarial resistance are crucial for malaria control. Resistance is typically a complex trait: multiple mutations in a single parasite (a haplotype or genotype) are necessary for elaboration of the resistant phenotype. The frequency of a genetic motif (proportion of parasite clones in the parasite population that carry a given allele, haplotype or genotype) is a useful measure of resistance. In areas of high endemicity, malaria patients generally harbour multiple parasite clones; they have multiplicities of infection (MOIs) greater than one. However, most standard experimental procedures only allow measurement of marker prevalence (proportion of patient blood samples that test positive for a given mutation or combination of mutations), not frequency. It is misleading to compare marker prevalence between sites that have different mean MOIs; frequencies are required instead. METHODS: A Bayesian statistical model was developed to estimate Plasmodium falciparum genetic motif frequencies from prevalence data collected in the field. To assess model performance and computational speed, a detailed simulation study was implemented. Application of the model was tested using datasets from five sites in Uganda. The datasets included prevalence data on markers of resistance to sulphadoxine-pyrimethamine and an average MOI estimate for each study site. RESULTS: The simulation study revealed that the genetic motif frequencies that were estimated using the model were more accurate and precise than conventional estimates based on direct counting. Importantly, the model did not require measurements of the MOI in each patient; it used the average MOI in the patient population. Furthermore, if a dataset included partially genotyped patient blood samples, the model imputed the data that were missing. Using the model and the Ugandan data, genotype frequencies were estimated and four biologically relevant genotypes were identified. CONCLUSIONS: The model allows fast, accurate, reliable estimation of the frequency of genetic motifs associated with resistance to anti-malarials using prevalence data collected from malaria patients. The model does not require per-patient MOI measurements and can easily analyse data from five markers. The model will be a valuable tool for monitoring markers of anti-malarial drug resistance, including markers of resistance to artemisinin derivatives and partner drugs.

Fox A, Whitehead S, Anders KL, Hoa LNM, Mai LQ, Thai PQ, Yen NT, Duong TN, Thoang DD, Farrar J et al. 2014. Investigation of dengue and Japanese encephalitis virus transmission in Hanam, Viet Nam. Am J Trop Med Hyg, 90 (5), pp. 892-896. | Citations: 3 (Scopus) | Show Abstract | Read more

This study investigated whether a large dengue epidemic that struck Hanoi in 2009 also affected a nearby semirural area. Seroconversion (dengue virus-reactive immunoglobulin G enzyme-linked immunosorbent assay) was high during 2009 compared with 2008, but neutralization assays showed that it was caused by both dengue virus and Japanese encephalitis virus infections. The findings highlight the importance of continued Japanese encephalitis virus vaccination and dengue surveillance.

Angwenyi V, Kamuya D, Mwachiro D, Kalama B, Marsh V, Njuguna P, Molyneux S. 2014. Complex realities: community engagement for a paediatric randomized controlled malaria vaccine trial in Kilifi, Kenya. Trials, 15 (1), pp. 65. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Community engagement (CE) is increasingly promoted for biomedical research conducted in resource poor settings for both intrinsic and instrumental purposes. Given the potential importance of CE, but also complexities and possibility of unexpected negative outcomes, there is need for more documentation of CE processes in practice. We share experiences of formal CE for a paediatric randomized controlled malaria vaccine trial conducted in three sites within Kilifi County, Kenya. METHODS: Social scientists independent of the trial held in-depth individual interviews with trial researchers (n=5), community leaders (n=8) and parents (15 with enrolled children and 4 without); and group discussions with fieldworkers (n=6) and facility staff (n=2). We conducted a survey of participating households (n=200) and observed over 150 CE activities. RESULTS: The overall CE plan was similar across the three study sites, although less community-based information in site C. Majority perceived CE activities to clear pre-existing concerns and misconceptions; increase visibility, awareness of and trust in trial staff. Challenges included: some community leaders attempting to exert pressure on people to enrol; local wording in information sheets and consent forms feeding into serious anxieties about the trial; and concerns about reduced CE over time. Negative effects of these challenges were mitigated through changes to on-going CE activities, and final information sharing and consent being conducted individually by trained clinical staff. One year after enrolment, 31% (n = 62) of participants' parents reported malaria prevention as the main aim of the activities their children were involved in, and 93% wanted their children to remain involved. CONCLUSION: The trial teams' goals for CE were relatively clear from the outset. Other actors' hopes and expectations (like higher allowances and future employment) were not openly discussed, but emerged over the course of engagements. Encouraging open discussion of all actors' intentions and goals from the outset takes time, risks raising expectations that cannot be met, and is complex. However, doing so in future similar trials may allow successes here to be built upon, and some challenges minimized or avoided. TRIAL REGISTRATION: ClinicalTrials.gov NCT00866619 (registration 19-Mar-2009).

Nga DTT, Chuc NTK, Hoa NP, Hoa NQ, Nguyen NTT, Loan HT, Toan TK, Phuc HD, Horby P, Van Yen N et al. 2014. Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study. BMC Pharmacol Toxicol, 15 (1), pp. 6. | Citations: 35 (Scopus) | Show Abstract | Read more

BACKGROUND: The irrational overuse of antibiotics should be minimized as it drives the development of antibiotic resistance, but changing these practices is challenging. A better understanding is needed of practices and economic incentives for antibiotic dispensing in order to design effective interventions to reduce inappropriate antibiotic use. Here we report on both quantitative and qualitative aspects of antibiotic sales in private pharmacies in northern Vietnam. METHOD: A cross-sectional study was conducted in which all drug sales were observed and recorded for three consecutive days at thirty private pharmacies, 15 urban and 15 rural, in the Hanoi region in 2010. The proportion of antibiotics to total drug sales was assessed and the revenue was calculated for rural and urban settings. Pharmacists and drug sellers were interviewed by a semi-structured questionnaire and in-depth interviews to understand the incentive structure of antibiotic dispensing. RESULTS: In total 2953 drug sale transactions (2083 urban and 870 rural) were observed. Antibiotics contributed 24% and 18% to the total revenue of pharmacies in urban and rural, respectively. Most antibiotics were sold without a prescription: 88% in urban and 91% in rural pharmacies. The most frequent reported reason for buying antibiotics was cough in the urban setting (32%) and fever in the rural area (22%). Consumers commonly requested antibiotics without having a prescription: 50% in urban and 28% in rural area. The qualitative data revealed that drug sellers and customer's knowledge of antibiotics and antibiotic resistance were low, particularly in rural area. CONCLUSION: Over the counter sales of antibiotic without a prescription remains a major problem in Vietnam. Suggested areas of improvement are enforcement of regulations and pricing policies and educational programs to increase the knowledge of drug sellers as well as to increase community awareness to reduce demand-side pressure for drug sellers to dispense antibiotics inappropriately.

Waddington CS, Darton TC, Jones C, Haworth K, Peters A, John T, Thompson BAV, Kerridge SA, Kingsley RA, Zhou L et al. 2014. An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis, 58 (9), pp. 1230-1240. | Citations: 52 (Scopus) | Show Abstract | Read more

BACKGROUND: Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution. METHODS: Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature ≥38°C sustained ≥12 hours or bacteremia) or at day 14 in those remaining untreated. RESULTS: Two dose levels (10(3) or 10(4) colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected. CONCLUSIONS: Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control.

Irimu GW, Greene A, Gathara D, Kihara H, Maina C, Mbori-Ngacha D, Zurovac D, Migiro S, English M. 2014. Factors influencing performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital--participatory action research. BMC Health Serv Res, 14 (1), pp. 59. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Implementation of World Health Organization case management guidelines for serious childhood illnesses remains a challenge in hospitals in low-income countries. Facilitators of and barriers to implementation of locally adapted clinical practice guidelines (CPGs) have not been explored. METHODS: This ethnographic study based on the theory of participatory action research (PAR) was conducted in Kenyatta National Hospital, Kenya's largest teaching hospital. The primary intervention consisted of dissemination of locally adapted CPGs. The PRECEDE-PROCEED health education model was used as the conceptual framework to guide and examine further reinforcement activities to improve the uptake of the CPGs. Activities focussed on introduction of routine clinical audits and tailored educational sessions. Data were collected by a participant observer who also facilitated the PAR over an eighteen-month period. Naturalistic inquiry was utilized to obtain information from all hospital staff encountered while theoretical sampling allowed in-depth exploration of emerging issues. Data were analysed using interpretive description. RESULTS: Relevance of the CPGs to routine work and emergence of a champion of change facilitated uptake of best-practices. Mobilization of basic resources was relatively easily undertaken while activities that required real intellectual and professional engagement of the senior staff were a challenge. Accomplishments of the PAR were largely with the passive rather than active involvement of the hospital management. Barriers to implementation of best-practices included i) mismatch between the hospital's vision and reality, ii) poor communication, iii) lack of objective mechanisms for monitoring and evaluating quality of clinical care, iv) limited capacity for planning strategic change, v) limited management skills to introduce and manage change, vi) hierarchical relationships, and vii) inadequate adaptation of the interventions to the local context. CONCLUSIONS: Educational interventions, often regarded as 'quick-fixes' to improve care in low-income countries, may be necessary but are unlikely to be sufficient to deliver improved services. We propose that an understanding of organizational issues that influence the behaviour of individual health professionals should guide and inform the implementation of best-practices.

Irimu GW, Greene A, Gathara D, Kihara H, Maina C, Mbori-Ngacha D, Zurovac D, Migiro S, English M. 2014. Factors influencing performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital - Participatory action research BMC Health Services Research, 14 | Citations: 5 (Scopus) | Show Abstract | Read more

Background: Implementation of World Health Organization case management guidelines for serious childhood illnesses remains a challenge in hospitals in low-income countries. Facilitators of and barriers to implementation of locally adapted clinical practice guidelines (CPGs) have not been explored. Methods. This ethnographic study based on the theory of participatory action research (PAR) was conducted in Kenyatta National Hospital, Kenya's largest teaching hospital. The primary intervention consisted of dissemination of locally adapted CPGs. The PRECEDE-PROCEED health education model was used as the conceptual framework to guide and examine further reinforcement activities to improve the uptake of the CPGs. Activities focussed on introduction of routine clinical audits and tailored educational sessions. Data were collected by a participant observer who also facilitated the PAR over an eighteen-month period. Naturalistic inquiry was utilized to obtain information from all hospital staff encountered while theoretical sampling allowed in-depth exploration of emerging issues. Data were analysed using interpretive description. Results: Relevance of the CPGs to routine work and emergence of a champion of change facilitated uptake of best-practices. Mobilization of basic resources was relatively easily undertaken while activities that required real intellectual and professional engagement of the senior staff were a challenge. Accomplishments of the PAR were largely with the passive rather than active involvement of the hospital management. Barriers to implementation of best-practices included i) mismatch between the hospital's vision and reality, ii) poor communication, iii) lack of objective mechanisms for monitoring and evaluating quality of clinical care, iv) limited capacity for planning strategic change, v) limited management skills to introduce and manage change, vi) hierarchical relationships, and vii) inadequate adaptation of the interventions to the local context. Conclusions: Educational interventions, often regarded as 'quick-fixes' to improve care in low-income countries, may be necessary but are unlikely to be sufficient to deliver improved services. We propose that an understanding of organizational issues that influence the behaviour of individual health professionals should guide and inform the implementation of best-practices. © 2014 Irimu et al.; licensee BioMed Central Ltd.

Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. 2014. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J Infect, 68 (5), pp. 405-418. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design.

Wang C, Yu H, Horby PW, Cao B, Wu P, Yang S, Gao H, Li H, Tsang TK, Liao Q et al. 2014. Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1. Clin Infect Dis, 58 (8), pp. 1095-1103. | Citations: 52 (Scopus) | Show Abstract | Read more

BACKGROUND: Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections. METHODS: We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population. RESULTS: The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24-17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154). CONCLUSIONS: The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity.

English M, Gathara D, Mwinga S, Ayieko P, Opondo C, Aluvaala J, Kihuba E, Mwaniki P, Were F, Irimu G et al. 2014. Adoption of recommended practices and basic technologies in a low-income setting. Arch Dis Child, 99 (5), pp. 452-456. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: In global health considerable attention is focused on the search for innovations; however, reports tracking their adoption in routine hospital settings from low-income countries are absent. DESIGN AND SETTING: We used data collected on a consistent panel of indicators during four separate cross-sectional, hospital surveys in Kenya to track changes over a period of 11 years (2002-2012). MAIN OUTCOME MEASURES: Basic resource availability, use of diagnostics and uptake of recommended practices. RESULTS: There appeared little change in availability of a panel of 28 basic resources (median 71% in 2002 to 82% in 2012) although availability of specific feeds for severe malnutrition and vitamin K improved. Use of blood glucose and HIV testing increased but remained inappropriately low throughout. Commonly (malaria) and uncommonly (lumbar puncture) performed diagnostic tests frequently failed to inform practice while pulse oximetry, a simple and cheap technology, was rarely available even in 2012. However, increasing adherence to prescribing guidance occurred during a period from 2006 to 2012 in which efforts were made to disseminate guidelines. CONCLUSIONS: Findings suggest changes in clinical practices possibly linked to dissemination of guidelines at reasonable scale. However, full availability of basic resources was not attained and major gaps likely exist between the potential and actual impacts of simple diagnostics and technologies representing problems with availability, adoption and successful utilisation. These findings are relevant to debates on scaling up in low-income settings and to those developing novel therapeutic or diagnostic interventions.

Wakaba M, Mbindyo P, Ochieng J, Kiriinya R, Todd J, Waudo A, Noor A, Rakuom C, Rogers M, English M. 2014. The public sector nursing workforce in Kenya: a county-level analysis. Hum Resour Health, 12 (1), pp. 6. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Kenya's human resources for health shortage is well documented, yet in line with the new constitution, responsibility for health service delivery will be devolved to 47 new county administrations. This work describes the public sector nursing workforce likely to be inherited by the counties, and examines the relationships between nursing workforce density and key indicators. METHODS: National nursing deployment data linked to nursing supply data were used and analyzed using statistical and geographical analysis software. Data on nurses deployed in national referral hospitals and on nurses deployed in non-public sector facilities were excluded from main analyses. The densities and characteristics of the public sector nurses across the counties were obtained and examined against an index of county remoteness, and the nursing densities were correlated with five key indicators. RESULTS: Of the 16,371 nurses in the public non-tertiary sector, 76% are women and 53% are registered nurses, with 35% of the nurses aged 40 to 49 years. The nursing densities across counties range from 1.2 to 0.08 per 1,000 population. There are statistically significant associations of the nursing densities with a measure of health spending per capita (P value = 0.0028) and immunization rates (P value = 0.0018). A higher county remoteness index is associated with explaining lower female to male ratio of public sector nurses across counties (P value <0.0001). CONCLUSIONS: An overall shortage of nurses (range of 1.2 to 0.08 per 1,000) in the public sector countrywide is complicated by mal-distribution and varying workforce characteristics (for example, age profile) across counties. All stakeholders should support improvements in human resources information systems and help address personnel shortages and mal-distribution if equitable, quality health-care delivery in the counties is to be achieved.

Gitau EN, Tuju J, Karanja H, Stevenson L, Requena P, Kimani E, Olotu A, Kimani D, Marsh K, Bull P, Urban BC. 2014. CD4+ T cell responses to the Plasmodium falciparum erythrocyte membrane protein 1 in children with mild malaria. J Immunol, 192 (4), pp. 1753-1761. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

The immune response against the variant surface Ag Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a key component of clinical immunity against malaria. We have investigated the development and maintenance of CD4(+) T cell responses to a small semiconserved area of the Duffy binding-like domain (DBL)α-domain of PfEMP1, the DBLα-tag. Young children were followed up longitudinally, and parasites and PBMCs were isolated from 35 patients presenting with an acute case of uncomplicated malaria. The DBLα-tag from the PfEMP1 dominantly expressed by the homologous parasite isolate was cloned and expressed as recombinant protein. The recombinant DBLα-tag was used to activate PBMCs collected from each acute episode and from an annual cross-sectional survey performed after the acute malaria episode. In this article, we report that CD4(+) T cell responses to the homologous DBLα-tag were induced in 75% of the children at the time of the acute episode and in 62% of the children at the following cross-sectional survey on average 235 d later. Furthermore, children who had induced DBLα-tag-specific CD4(+)IL-4(+) T cells at the acute episode remained episode free for longer than children who induced other types of CD4(+) T cell responses. These results suggest that a wide range of DBLα-tag-specific CD4(+) T cell responses were induced in children with mild malaria and, in the case of CD4(+)IL-4(+) T cell responses, were associated with protection from clinical episodes.

Dunning JW, Merson L, Rohde GGU, Gao Z, Semple MG, Tran D, Gordon A, Olliaro PL, Khoo SH, Bruzzone R et al. 2014. Open source clinical science for emerging infections. Lancet Infect Dis, 14 (1), pp. 8-9. | Citations: 11 (Scopus) | Read more

Chantler T, Cheah PY, Miiro G, Hantrakum V, Nanvubya A, Ayuo E, Kivaya E, Kidola J, Kaleebu P, Parker M et al. 2014. International health research monitoring: exploring a scientific and a cooperative approach using participatory action research. BMJ Open, 4 (2), pp. e004104. | Show Abstract | Read more

OBJECTIVES: To evaluate and determine the value of monitoring models developed by the Mahidol Oxford Tropical Research Unit and the East African Consortium for Clinical Research, consider how this can be measured and explore monitors' and investigators' experiences of and views about the nature, purpose and practice of monitoring. RESEARCH DESIGN: A case study approach was used within the context of participatory action research because one of the aims was to guide and improve practice. 34 interviews, five focus groups and observations of monitoring practice were conducted. SETTING AND PARTICIPANTS: Fieldwork occurred in the places where the monitoring models are coordinated and applied in Thailand, Cambodia, Uganda and Kenya. Participants included those coordinating the monitoring schemes, monitors, senior investigators and research staff. ANALYSIS: Transcribed textual data from field notes, interviews and focus groups was imported into a qualitative data software program (NVIVO V. 10) and analysed inductively and thematically by a qualitative researcher. The initial coding framework was reviewed internally and two main categories emerged from the subsequent interrogation of the data. RESULTS: The categories that were identified related to the conceptual framing and nature of monitoring, and the practice of monitoring, including relational factors. Particular emphasis was given to the value of a scientific and cooperative style of monitoring as a means of enhancing data quality, trust and transparency. In terms of practice the primary purpose of monitoring was defined as improving the conduct of health research and increasing the capacity of researchers and trial sites. CONCLUSIONS: The models studied utilise internal and network wide expertise to improve the ethics and quality of clinical research. They demonstrate how monitoring can be a scientific and constructive exercise rather than a threatening process. The value of cooperative relations needs to be given more emphasis in monitoring activities, which seek to ensure that research protects human rights and produces reliable data.

Irimu GW, Greene A, Gathara D, Kihara H, Maina C, Mbori-Ngacha D, Zurovac D, Santau M, Todd J, English M. 2014. Explaining the uptake of paediatric guidelines in a Kenyan tertiary hospital--mixed methods research. BMC Health Serv Res, 14 (1), pp. 119. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Evidence-based standards for management of the seriously sick child have existed for decades, yet their translation in clinical practice is a challenge. The context and organization of institutions are known determinants of successful translation, however, research using adequate methodologies to explain the dynamic nature of these determinants in the quality-of-care improvement process is rarely performed. METHODS: We conducted mixed methods research in a tertiary hospital in a low-income country to explore the uptake of locally adapted paediatric guidelines. The quantitative component was an uncontrolled before and after intervention study that included an exploration of the intervention dose-effect relationship. The qualitative component was an ethnographic research based on the theoretical perspective of participatory action research. Interpretive integration was employed to derive meta-inferences that provided a more complete picture of the overall study results that reflect the complexity and the multifaceted ontology of the phenomenon studied. RESULTS: The improvement in health workers' performance in relation to the intensity of the intervention was not linear and was characterized by improved and occasionally declining performance. Possible root causes of this performance variability included challenges in keeping knowledge and clinical skills updated, inadequate commitment of the staff to continued improvement, limited exposure to positive professional role models, poor teamwork, failure to maintain professional integrity and mal-adaptation to institutional pressures. CONCLUSION: Implementation of best-practices is a complex process that is largely unpredictable, attributed to the complexity of contextual factors operating predominantly at professional and organizational levels. There is no simple solution to implementation of best-practices. Tackling root causes of inadequate knowledge translation in this tertiary care setting will require long-term planning, with emphasis on promotion of professional ethics and values and establishing an organizational framework that enhances positive aspects of professionalism. This study has significant implications for the quality of training in medical institutions and the development of hospital leadership.

Horby PW. 2014. Community studies of influenza: new knowledge, new questions The Lancet Respiratory Medicine, 2 (6), pp. 430-431. | Read more

Tanomsing N, Mayxay M, Newton PN, Nosten F, Dolecek C, Hien TT, White NJ, Day NPJ, Dondorp AM, Imwong M. 2014. Genetic variability of Plasmodium malariae dihydropteroate synthase (dhps) in four Asian countries. PLoS One, 9 (4), pp. e93942. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

The dihydropteroate synthase (dhps) genes of 44 P. malariae strains from four Asian countries were isolated. Only a limited number of polymorphisms were observed. Comparison with homologous mutations in other Plasmodium species showed that these polymorphisms are unlikely to be associated with sulfadoxine resistance.

Brown ST, Tate JP, Kyriakides TC, Kirkwood KA, Holodniy M, Goulet JL, Angus BJ, Cameron DW, Justice AC, OPTIMA Team. 2014. The VACS index accurately predicts mortality and treatment response among multi-drug resistant HIV infected patients participating in the options in management with antiretrovirals (OPTIMA) study. PLoS One, 9 (3), pp. e92606. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. METHODS: Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel's C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. RESULTS: Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14-0.49) and 0.39(95% CI 0.22-0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27-3.38) and 1.51 (95%CI 0.90-2.53) for the 25% least improved scores. CONCLUSIONS: The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research.

Dao TT, Liebenthal D, Tran TK, Ngoc Thi Vu B, Ngoc Thi Nguyen D, Thi Tran HK, Thi Nguyen CK, Thi Vu HL, Fox A, Horby P et al. 2014. Klebsiella pneumoniae oropharyngeal carriage in rural and urban Vietnam and the effect of alcohol consumption. PLoS One, 9 (3), pp. e91999. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Community acquired K. pneumoniae pneumonia is still common in Asia and is reportedly associated with alcohol use. Oropharyngeal carriage of K. pneumoniae could potentially play a role in the pathogenesis of K. pneumoniae pneumonia. However, little is known regarding K. pneumoniae oropharyngeal carriage rates and risk factors. This population-based cross-sectional study explores the association of a variety of demographic and socioeconomic factors, as well as alcohol consumption with oropharyngeal carriage of K. pneumoniae in Vietnam. METHODS AND FINDINGS: 1029 subjects were selected randomly from age, sex, and urban and rural strata. An additional 613 adult men from a rural environment were recruited and analyzed separately to determine the effects of alcohol consumption. Demographic, socioeconomic, and oropharyngeal carriage data was acquired for each subject. The overall carriage rate of K. pneumoniae was 14.1% (145/1029, 95% CI 12.0%-16.2%). By stepwise logistic regression, K. pneumoniae carriage was found to be independently associated with age (OR 1.03, 95% CI 1.02-1.04), smoking (OR 1.9, 95% CI 1.3-2.9), rural living location (OR 1.6, 95% CI 1.1-2.4), and level of weekly alcohol consumption (OR 1.7, 95% CI 1.04-2.8). CONCLUSION: Moderate to heavy weekly alcohol consumption, old age, smoking, and living in a rural location are all found to be associated with an increased risk of K. pneumoniae carriage in Vietnamese communities. Whether K. pneumoniae carriage is a risk factor for pneumonia needs to be elucidated.

Nair M, Ariana P, Webster P. 2014. Impact of mothers' employment on infant feeding and care: a qualitative study of the experiences of mothers employed through the Mahatma Gandhi National Rural Employment Guarantee Act. BMJ Open, 4 (4), pp. e004434. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To explore the experiences of mothers employed through the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA) using focus group discussions (FGDs) to understand the impact of mothers' employment on infant feeding and care. The effects of mothers' employment on nutritional status of children could be variable. It could lead to increased household income, but could also compromise child care and feeding. SETTING: The study was undertaken in the Dungarpur district of Rajasthan, India. PARTICIPANTS: Mothers of infants <12 months of age. Ten FGDs, two in each of the five administrative blocks of the study district were conducted. The groups were composed of a minimum of 5 and maximum of 8 participants, giving a total of 62 mothers. Thematic analysis was conducted to assess patterns and generate emergent themes. RESULTS: Four major themes were identified-'mothers' employment compromises infant feeding and care', 'caregivers' inability to substitute mothers' care', 'compromises related to childcare and feeding outweigh benefits from MGNREGA' and 'employment as disempowering'. Mothers felt that the comprises to infant care and feeding due to long hours of work, lack of alternative adequate care arrangements, low wages and delayed payments outweighed the benefits from the scheme. CONCLUSIONS: This study provides an account of the trade-off between mothers' employment and child care. It provides an understanding of the household power relationships, societal and cultural factors that modulate the effects of mothers' employment. From the perspective of mothers, it helps to understand the benefits and problems related to providing employment to women with infants in the MGNREGA scheme and make a case to pursue policy changes to improve their working conditions.

Wendler JP, Okombo J, Amato R, Miotto O, Kiara SM, Mwai L, Pole L, O'Brien J, Manske M, Alcock D et al. 2014. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya. PLoS One, 9 (5), pp. e96486. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

Opiyo N, Molyneux E, Sinclair D, Garner P, English M. 2014. Immediate fluid management of children with severe febrile illness and signs of impaired circulation in low-income settings: a contextualised systematic review. BMJ Open, 4 (4), pp. e004934. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To evaluate the effects of intravenous fluid bolus compared to maintenance intravenous fluids alone as part of immediate emergency care in children with severe febrile illness and signs of impaired circulation in low-income settings. DESIGN: Systematic review of randomised controlled trials (RCTs), and observational studies, including retrospective analyses, that compare fluid bolus regimens with maintenance fluids alone. The primary outcome measure was predischarge mortality. DATA SOURCES AND SYNTHESIS: We searched PubMed, The Cochrane Library (to January 2014), with complementary earlier searches on, Google Scholar and Clinical Trial Registries (to March 2013). As studies used different clinical signs to define impaired circulation we classified patients into those with signs of severely impaired circulation, or those with any signs of impaired circulation. The quality of evidence for each outcome was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Findings are presented as risk ratios (RRs) with 95% CIs. RESULTS: Six studies were included. Two were RCTs, one large trial (n=3141 children) from a low-income country and a smaller trial from a middle-income country. The remaining studies were from middle-income or high-income settings, observational, and with few participants (34-187 children). SEVERELY IMPAIRED CIRCULATION: The large RCT included a small subgroup with severely impaired circulation. There were more deaths in those receiving bolus fluids (20-40 mL/kg/h, saline or albumin) compared to maintenance fluids (2.5-4 mL/kg/h; RR 2.40, 95% CI 0.84 to 6.88, p=0.054, 65 participants, low quality evidence). Three additional observational studies, all at high risk of confounding, found mixed effects on mortality (very low quality evidence). ANY SIGNS OF IMPAIRED CIRCULATION: The large RCT included children with signs of both severely and non-severely impaired circulation. Overall, bolus fluids increased 48 h mortality compared to maintenance fluids with an additional 3 deaths per 100 children treated (RR 1.45, 95% CI 1.13 to 1.86, 3141 participants, high quality evidence). In a second small RCT from India, no difference in 72 h mortality was detected between children who received 20-40 mL/kg Ringers lactate over 15 min and those who received 20 mL over 20 min up to a maximum of 60 mL/kg over 1 h (147 participants, low quality evidence). In one additional observational study, resuscitation consistent with Advanced Paediatric Life Support (APLS) guidelines, including fluids, was not associated with reduced mortality in the small subgroup with septic shock (very low quality evidence). SIGNS OF IMPAIRED CIRCULATION, BUT NOT SEVERELY IMPAIRED: Only the large RCT allowed an analysis for children with some signs of impaired circulation who would not meet the criteria for severe impairment. Bolus fluids increased 48 h mortality compared to maintenance alone (RR 1.36, 95% CI 1.05 to 1.76, high quality evidence). CONCLUSIONS: Prior to the publication of the large RCT, the global evidence base for bolus fluid therapy in children with severe febrile illness and signs of impaired circulation was of very low quality. This large study provides robust evidence that in low-income settings fluid boluses increase mortality in children with severe febrile illness and impaired circulation, and this increased risk is consistent across children with severe and less severe circulatory impairment.

Dougall D, Johnson A, Goldsmith K, Sharpe M, Angus B, Chalder T, White P. 2014. Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome. J Psychosom Res, 77 (1), pp. 20-26. | Citations: 17 (Scopus) | Show Abstract | Read more

OBJECTIVE: Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them. METHODS: AEs were recorded on three occasions over one year in 641 participants. We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET). We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts. RESULTS: Serious adverse events and reactions were infrequent. Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (P=.47). A greater number of NSAEs were associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder. Physical function deteriorated in 39 (25%) participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (P<.001), with no significant differences in worsening fatigue. CONCLUSIONS: The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT. The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments. Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data.

Kihuba E, Gathara D, Mwinga S, Mulaku M, Kosgei R, Mogoa W, Nyamai R, English M. 2014. Assessing the ability of health information systems in hospitals to support evidence-informed decisions in Kenya. Glob Health Action, 7 (1), pp. 24859. | Citations: 14 (Scopus) | Show Abstract | Read more

BACKGROUND: Hospital management information systems (HMIS) is a key component of national health information systems (HIS), and actions required of hospital management to support information generation in Kenya are articulated in specific policy documents. We conducted an evaluation of core functions of data generation and reporting within hospitals in Kenya to facilitate interpretation of national reports and to provide guidance on key areas requiring improvement to support data use in decision making. DESIGN: The survey was a cross-sectional, cluster sample study conducted in 22 hospitals in Kenya. The statistical analysis was descriptive with adjustment for clustering. RESULTS: Most of the HMIS departments complied with formal guidance to develop departmental plans. However, only a few (3/22) had carried out a data quality audit in the 12 months prior to the survey. On average 3% (range 1-8%) of the total hospital income was allocated to the HMIS departments. About half of the records officer positions were filled and about half (13/22) of hospitals had implemented some form of electronic health record largely focused on improving patient billing and not linked to the district HIS. Completeness of manual patient registers varied, being 90% (95% CI 80.1-99.3%), 75.8% (95% CI 68.7-82.8%), and 58% (95% CI 50.4-65.1%) in maternal child health clinic, maternity, and pediatric wards, respectively. Vital events notification rates were low with 25.7, 42.6, and 71.3% of neonatal deaths, infant deaths, and live births recorded, respectively. Routine hospital reports suggested slight over-reporting of live births and under-reporting of fresh stillbirths and neonatal deaths. CONCLUSIONS: Study findings indicate that the HMIS does not deliver quality data. Significant constraints exist in data quality assurance, supervisory support, data infrastructure in respect to information and communications technology application, human resources, financial resources, and integration.

Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Kabwende AL, Adegnika AA, Mordmueller B, Issifou S, Kremsner PG, Loembe MM et al. 2014. Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites PLOS MEDICINE, 11 (7), pp. e1001685-e1001685. | Citations: 70 (Scopus) | Show Abstract | Read more

Background:A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission.Methods and Findings:6,537 infants aged 6-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine.VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p < 0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT).VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%] , ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol).VE waned over time in both age categories (Schoenfeld residuals p < 0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from -1 to 49, respectively; corresponding ranges among infants were -10 to 1,402 and -13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.Conclusions:RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.Trial registration:http://www.ClinicalTrials.gov NCT00866619. Please see later in the article for the Editors' Summary.

Dunachie S, Teh J, Ejindu V, Bejon P, Pandit H, Byren I. 2014. Radiological features do not predict failure of two-stage arthroplasty for prosthetic joint infection: a retrospective case-control study. BMC Musculoskelet Disord, 15 (1), pp. 300. | Show Abstract | Read more

BACKGROUND: The management of prosthetic joint infection is complex and there is a lack of standardisation of approaches. We evaluated the role of plain film radiography in predicting prosthesis failure after the first stage of a two-stage revision procedure in a retrospective case-control study. METHODS: Plain films for 41 patients aged 46 to 87 years (mean 69) were assessed by two musculoskeletal specialist radiologists for seven features (retained or new metalwork, retained cement or restrictor, new fracture, local antimicrobial delivery system and drain) we hypothesised may predict for failure. Inter-observer agreement was assessed by Kappa score and logistic regression analysis was performed to evaluate the relationship of the seven radiological features adjusting for patient age, gender and number of previous revisions. RESULTS: There was substantial inter-observer agreement, with a Kappa score of 0.73 (95% CI 0.72-0.74) for all data points collected. Concordance was 100% for evaluating the presence or absence of an antimicrobial delivery system or drain, with lower consensus for evaluating cement (Kappa 0.60, 95% CI 0.35-0.84) and fractures (Kappa 0.59, 95% CI 0.31-0.87). None of the variables' conditions significantly predicted failure. CONCLUSIONS: Our findings support the opinion that surgical expertise which maximizes removal of foreign material is sufficient in conjunction with antibiotic therapy.

Kangoye DT, Nebie I, Yaro J-B, Debe S, Traore S, Ouedraogo O, Sanou G, Soulama I, Diarra A, Tiono A et al. 2014. Plasmodium falciparum malaria in children aged 0-2 years: the role of foetal haemoglobin and maternal antibodies to two asexual malaria vaccine candidates (MSP3 and GLURP). PLoS One, 9 (9), pp. e107965. | Citations: 11 (Scopus) | Show Abstract | Read more

BACKGROUND: Children below six months are reported to be less susceptible to clinical malaria. Maternally derived antibodies and foetal haemoglobin are important putative protective factors. We examined antibodies to Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate-rich protein (GLURP), in children in their first two years of life in Burkina Faso and their risk of malaria. METHODS: A cohort of 140 infants aged between four and six weeks was recruited in a stable transmission area of south-western Burkina Faso and monitored for 24 months by active and passive surveillance. Malaria infections were detected by examining blood smears using light microscopy. Enzyme-linked immunosorbent assay was used to quantify total Immunoglobulin G to Plasmodium falciparum antigens MSP3 and two regions of GLURP (R0 and R2) on blood samples collected at baseline, three, six, nine, 12, 18 and 24 months. Foetal haemoglobin and variant haemoglobin fractions were measured at the baseline visit using high pressure liquid chromatography. RESULTS: A total of 79.6% of children experienced one or more episodes of febrile malaria during monitoring. Antibody titres to MSP3 were prospectively associated with an increased risk of malaria while antibody responses to GLURP (R0 and R2) did not alter the risk. Antibody titres to MSP3 were higher among children in areas of high malaria risk. Foetal haemoglobin was associated with delayed first episode of febrile malaria and haemoglobin CC type was associated with reduced incidence of febrile malaria. CONCLUSIONS: We did not find any evidence of association between titres of antibodies to MSP3, GLURP-R0 or GLURP-R2 as measured by enzyme-linked immunosorbent assay and early protection against malaria, although anti-MSP3 antibody titres may reflect increased exposure to malaria and therefore greater risk. Foetal haemoglobin was associated with protection against febrile malaria despite the study limitations and its role is therefore worthy further investigation.

Lubell Y, Dondorp A, Guérin PJ, Drake T, Meek S, Ashley E, Day NPJ, White NJ, White LJ. 2014. Artemisinin resistance--modelling the potential human and economic costs. Malar J, 13 (1), pp. 452. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin combination therapy is recommended as first-line treatment for falciparum malaria across the endemic world and is increasingly relied upon for treating vivax malaria where chloroquine is failing. Artemisinin resistance was first detected in western Cambodia in 2007, and is now confirmed in the Greater Mekong region, raising the spectre of a malaria resurgence that could undo a decade of progress in control, and threaten the feasibility of elimination. The magnitude of this threat has not been quantified. METHODS: This analysis compares the health and economic consequences of two future scenarios occurring once artemisinin-based treatments are available with high coverage. In the first scenario, artemisinin combination therapy (ACT) is largely effective in the management of uncomplicated malaria and severe malaria is treated with artesunate, while in the second scenario ACT are failing at a rate of 30%, and treatment of severe malaria reverts to quinine. The model is applied to all malaria-endemic countries using their specific estimates for malaria incidence, transmission intensity and GDP. The model describes the direct medical costs for repeated diagnosis and retreatment of clinical failures as well as admission costs for severe malaria. For productivity losses, the conservative friction costing method is used, which assumes a limited economic impact for individuals that are no longer economically active until they are replaced from the unemployment pool. RESULTS: Using conservative assumptions and parameter estimates, the model projects an excess of 116,000 deaths annually in the scenario of widespread artemisinin resistance. The predicted medical costs for retreatment of clinical failures and for management of severe malaria exceed US$32 million per year. Productivity losses resulting from excess morbidity and mortality were estimated at US$385 million for each year during which failing ACT remained in use as first-line treatment. CONCLUSIONS: These 'ballpark' figures for the magnitude of the health and economic threat posed by artemisinin resistance add weight to the call for urgent action to detect the emergence of resistance as early as possible and contain its spread from known locations in the Mekong region to elsewhere in the endemic world.

Njue M, Kombe F, Mwalukore S, Molyneux S, Marsh V. 2014. What are fair study benefits in international health research? Consulting community members in Kenya. PLoS One, 9 (12), pp. e113112. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Planning study benefits and payments for participants in international health research in low- income settings can be a difficult and controversial process, with particular challenges in balancing risks of undue inducement and exploitation and understanding how researchers should take account of background inequities. At an international health research programme in Kenya, this study aimed to map local residents' informed and reasoned views on the effects of different levels of study benefits and payments to inform local policy and wider debates in international research. METHODS AND FINDINGS: Using a relatively novel two-stage process community consultation approach, five participatory workshops involving 90 local residents from diverse constituencies were followed by 15 small group discussions, with components of information-sharing, deliberation and reflection to situate normative reasoning within debates. Framework Analysis drew inductively and deductively on voice-recorded discussions and field notes supported by Nvivo 10 software, and the international research ethics literature. Community members' views on study benefits and payments were diverse, with complex contextual influences and interplay between risks of giving 'too many' and 'too few' benefits, including the role of cash. While recognising important risks for free choice, research relationships and community values in giving 'too many', the greatest concerns were risks of unfairness in giving 'too few' benefits, given difficulties in assessing indirect costs of participation and the serious consequences for families of underestimation, related to perceptions of researchers' responsibilities. CONCLUSIONS: Providing benefits and payments to participants in international research in low-income settings is an essential means by which researchers meet individual-level and structural forms of ethical responsibilities, but understanding how this can be achieved requires a careful account of social realities and local judgment. Concerns about undue inducement in low-income communities may often be misplaced; we argue that greater attention should be placed on avoiding unfairness, particularly for the most-poor.

de Jong MD, Reusken C, Horby P, Koopmans M, Bonten M, Chiche J, Giaquinto C, Welte T, Leus F, Schotsman J et al. 2014. Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August-September 2014. Euro Surveill, 19 (48), pp. 20980. | Citations: 14 (Scopus) | Show Abstract | Read more

In response to the Ebola virus disease (EVD) outbreak in West Africa, the World Health Organization has advised all nations to prepare for the detection, investigation and management of confirmed and suspected EVD cases in order to prevent further spread through international travel. To gain insights into the state of preparedness of European hospitals, an electronic survey was circulated in August–September 2014 to 984 medical professionals representing 736 hospitals in 40 countries. The survey addressed the willingness and capacity to admit patients with suspected EVD as well as specific preparedness activities in response to the current Ebola crisis. Evaluable responses were received from representatives of 254 (32%) hospitals in 38 countries, mostly tertiary care centres, of which 46% indicated that they would admit patients with suspected EVD. Patient transfer agreements were in place for the majority of hospitals that would not admit patients. Compared with non-admitting hospitals, admitting hospitals were more frequently engaged in various preparedness activities and more often contained basic infrastructural characteristics such as admission rooms and laboratories considered important for infection control, but some gaps and concerns were also identified. The results of this survey help to provide direction towards further preparedness activities and prioritisation thereof.

Hodgson SH, Juma E, Salim A, Magiri C, Kimani D, Njenga D, Muia A, Cole AO, Ogwang C, Awuondo K et al. 2014. Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection. Front Microbiol, 5 (DEC), pp. 686. | Citations: 30 (Scopus) | Show Abstract | Read more

BACKGROUND: Controlled human malaria infection (CHMI) studies are a vital tool to accelerate vaccine and drug development. As CHMI trials are performed in a controlled environment, they allow unprecedented, detailed evaluation of parasite growth dynamics (PGD) and immunological responses. However, CHMI studies have not been routinely performed in malaria-endemic countries or used to investigate mechanisms of naturally-acquired immunity (NAI) to Plasmodium falciparum. METHODS: We conducted an open-label, randomized CHMI pilot-study using aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) to evaluate safety, infectivity and PGD in Kenyan adults with low to moderate prior exposure to P. falciparum (Pan African Clinical Trial Registry: PACTR20121100033272). RESULTS: All participants developed blood-stage infection confirmed by quantitative polymerase chain reaction (qPCR). However one volunteer (110) remained asymptomatic and blood-film negative until day 21 post-injection of PfSPZ Challenge. This volunteer had a reduced parasite multiplication rate (PMR) (1.3) in comparison to the other 27 volunteers (median 11.1). A significant correlation was seen between PMR and screening anti-schizont Enzyme Linked Immunosorbent Assays (ELISA) OD (p = 0.044, R = -0.384) but not when volunteer 110 was excluded from the analysis (p = 0.112, R = -0.313). CONCLUSIONS: PfSPZ Challenge is safe and infectious in malaria-endemic populations and could be used to assess the efficacy of malaria vaccines and drugs in African populations. Whilst our findings are limited by sample size, our pilot study has demonstrated for the first time that NAI may impact on PMR post-CHMI in a detectable fashion, an important finding that should be evaluated in further CHMI studies.

Dunstan SJ, Hue NT, Han B, Li Z, Tram TTB, Sim KS, Parry CM, Chinh NT, Vinh H, Lan NPH et al. 2014. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet, 46 (12), pp. 1333-1336. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C(1). We conducted a genome-wide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10(-10)), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.

de Jong MD, Reusken C, Horby P, Koopmans M, Bonten M, Chiche J, Giaquinto C, Welte T, Leus F, Schotsman J, Goossens H. 2014. Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August-September 2014 Euro surveillance : bulletin Européen sur les maladies transmissibles = European communicable disease bulletin, 19 (48), pp. 20980. | Citations: 6 (Scopus) | Show Abstract

In response to the Ebola virus disease (EVD) outbreak in West Africa, the World Health Organization has advised all nations to prepare for the detection, investigation and management of confirmed and suspected EVD cases in order to prevent further spread through international travel. To gain insights into the state of preparedness of European hospitals, an electronic survey was circulated in August–September 2014 to 984 medical professionals representing 736 hospitals in 40 countries. The survey addressed the willingness and capacity to admit patients with suspected EVD as well as specific preparedness activities in response to the current Ebola crisis. Evaluable responses were received from representatives of 254 (32%) hospitals in 38 countries, mostly tertiary care centres, of which 46% indicated that they would admit patients with suspected EVD. Patient transfer agreements were in place for the majority of hospitals that would not admit patients. Compared with non-admitting hospitals, admitting hospitals were more frequently engaged in various preparedness activities and more often contained basic infrastructural characteristics such as admission rooms and laboratories considered important for infection control, but some gaps and concerns were also identified. The results of this survey help to provide direction towards further preparedness activities and prioritisation thereof.

Carson GL, Dunning J, Longuere KS, Brooks WA. 2014. Ebola: controlling the nightmare. Trans R Soc Trop Med Hyg, 108 (12), pp. 741-742. | Citations: 1 (Web of Science Lite) | Read more

Ngari MM, Waithira N, Chilengi R, Njuguna P, Lang T, Fegan G. 2014. Experience of using an open source clinical trials data management software system in Kenya. BMC Res Notes, 7 (1), pp. 845. | Citations: 3 (Scopus) | Show Abstract | Read more

BACKGROUND: Clinical trials data management (CTDM) remains one of the many challenges in running state of the art trials in resource-poor settings since most trials do not allocate, or have available, sufficient resources for CTDM and because of poor internet connectivity. Open-source software like OpenClinica could be a solution in such scenarios. FINDINGS: In 2007, the KEMRI-Wellcome Trust Research Programme (KWTRP) adopted OpenClinica (OC) community edition, an open-source software system and we share our experience and lessons learnt since its adoption. We have used OC in three different modes; direct remote data entry from sites through Global System for Mobile Communications (GSM) modems, a centralized data centre approach where all data from paper records were entered at a central location and an off-line approach where data entry was done from a copy of database hosted on a field-site server laptop, then data uploaded to a centralized server later. We have used OC in eleven trials/studies with a cumulative number of participants in excess of 6000. These include large and complex trials, with multiple sites recruiting in different regions of East Africa. In the process, we have developed substantial local capacity through hands-on training and mentorship, which we have now begun to share with other institutions in the region. CONCLUSIONS: Our experience demonstrates that an open source data management system to manage trials' data can be utilized to international industry standards in resource-poor countries.

Horby P. 2014. For some groups traditionally considered to be 'high risk', the evidence of an increased risk of severe influenza-associated illness is poor quality. Evid Based Med, 19 (3), pp. 110. | Read more

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