Tropical Medicine publications 2012

Thriemer K, Ley B, Ame SS, Deen JL, Pak GD, Chang NY, Hashim R, Schmied WH, Busch CJ-L, Nixon S et al. 2012. Clinical and epidemiological features of typhoid fever in Pemba, Zanzibar: assessment of the performance of the WHO case definitions. PLoS One, 7 (12), pp. e51823. | Citations: 18 (Scopus) | Show Abstract | Read more

BACKGROUND: The gold standard for diagnosis of typhoid fever is blood culture (BC). Because blood culture is often not available in impoverished settings it would be helpful to have alternative diagnostic approaches. We therefore investigated the usefulness of clinical signs, WHO case definition and Widal test for the diagnosis of typhoid fever. METHODOLOGY/PRINCIPAL FINDINGS: Participants with a body temperature ≥37.5°C or a history of fever were enrolled over 17 to 22 months in three hospitals on Pemba Island, Tanzania. Clinical signs and symptoms of participants upon presentation as well as blood and serum for BC and Widal testing were collected. Clinical signs and symptoms of typhoid fever cases were compared to other cases of invasive bacterial diseases and BC negative participants. The relationship of typhoid fever cases with rainfall, temperature, and religious festivals was explored. The performance of the WHO case definitions for suspected and probable typhoid fever and a local cut off titre for the Widal test was assessed. 79 of 2209 participants had invasive bacterial disease. 46 isolates were identified as typhoid fever. Apart from a longer duration of fever prior to admission clinical signs and symptoms were not significantly different among patients with typhoid fever than from other febrile patients. We did not detect any significant seasonal patterns nor correlation with rainfall or festivals. The sensitivity and specificity of the WHO case definition for suspected and probable typhoid fever were 82.6% and 41.3% and 36.3 and 99.7% respectively. Sensitivity and specificity of the Widal test was 47.8% and 99.4 both forfor O-agglutinin and H- agglutinin at a cut-off titre of 1:80. CONCLUSIONS/SIGNIFICANCE: Typhoid fever prevalence rates on Pemba are high and its clinical signs and symptoms are non-specific. The sensitivity of the Widal test is low and the WHO case definition performed better than the Widal test.

White AL, Carrara VI, Paw MK, Malika, Dahbu C, Gross MM, Stuetz W, Nosten FH, McGready R. 2012. High initiation and long duration of breastfeeding despite absence of early skin-to-skin contact in Karen refugees on the Thai-Myanmar border: a mixed methods study. Int Breastfeed J, 7 (1), pp. 19. | Citations: 11 (Scopus) | Show Abstract | Read more

UNLABELLED: BACKGROUND: Early skin-to-skin contact (SSC) after birth is recommended as part of the United Nations Children's Fund (UNICEF) baby friendly health initiative to promote optimum breastfeeding. This paper reports rates of breastfeeding initiation and duration in a low resource environment, where early SSC is not practised, and explores views of pregnant women and midwives surrounding breastfeeding and swaddling. METHODS: Data from records from a single hospital on the Thai-Myanmar border where refugee women gave birth during a one-year period (2010) were used to determine breastfeeding initiation rates and the time of the first breastfeed, and duration of breastfeeding of the previous alive child in multigravidae. Focus group discussions (FGD) were conducted to obtain information from pregnant women attending antenatal care about their intended or previous duration of breastfeeding and views on breastfeeding. Interviews with local midwives explored reasons for high rates of breastfeeding in this setting and the practice of newborn swaddling. RESULTS: Of 1404 live births in 2010 in Maela refugee camp there were 982 evaluable mother-newborn pairs, including 80 infants born before 37 weeks gestation. Initiation of breastfeeding within the first hour after birth and exclusive breastfeeding at discharge in term mother-newborn pairs was 91.2% (823/902) and 99.3% (896/902); and before 37 weeks gestation, 48.8% (39/80) and 98.8% (79/80). Reported duration of previous breastfeeding was 19 (range 2 to 72) months.During FGD all primigravidae (n = 17) intended to breastfeed and all multigravidae (n = 33) had previously breastfed; expected or previous duration of feeding was for more than one year or longer. The major theme identified during FGD was breastfeeding is "good". Women stated their intention to breastfeed with certainty. This certainty was echoed during the interviews with midwifery staff. SSC requires a delay in early swaddling that in Karen people, with animistic beliefs, could risk loss of the spirit of the newborn or attract malevolent spirits. CONCLUSIONS: In a population with a strong culture of breastfeeding and robust breastfeeding practices, high rates of initiation and duration of breastfeeding were found despite a lack of early skin-to-skin contact. Local preferences, traditions and practices that protect, support and maintain high rates of breastfeeding should be promoted.

RTS,S Clinical Trials Partnership, Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BGNO, Kabwende AL, Adegnika AA, Mordmüller B, Issifou S et al. 2012. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med, 367 (24), pp. 2284-2295. | Citations: 362 (Scopus) | Show Abstract | Read more

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

Lipsitz R, Garges S, Aurigemma R, Baccam P, Blaney DD, Cheng AC, Currie BJ, Dance D, Gee JE, Larsen J et al. 2012. Workshop on treatment of and postexposure prophylaxis for Burkholderia pseudomallei and B. mallei Infection, 2010. Emerg Infect Dis, 18 (12), pp. e2. | Citations: 50 (Scopus) | Show Abstract | Read more

The US Public Health Emergency Medical Countermeasures Enterprise convened subject matter experts at the 2010 HHS Burkholderia Workshop to develop consensus recommendations for postexposure prophylaxis against and treatment for Burkholderia pseudomallei and B. mallei infections, which cause melioidosis and glanders, respectively. Drugs recommended by consensus of the participants are ceftazidime or meropenem for initial intensive therapy, and trimethoprim/sulfamethoxazole or amoxicillin/clavulanic acid for eradication therapy. For postexposure prophylaxis, recommended drugs are trimethoprim/sulfamethoxazole or co-amoxiclav. To improve the timely diagnosis of melioidosis and glanders, further development and wide distribution of rapid diagnostic assays were also recommended. Standardized animal models and B. pseudomallei strains are needed for further development of therapeutic options. Training for laboratory technicians and physicians would facilitate better diagnosis and treatment options.

Onyango CO, Njeru R, Kazungu S, Achilla R, Bulimo W, Welch SR, Cane PA, Gunson RN, Hammitt LL, Scott JAG et al. 2012. Influenza surveillance among children with pneumonia admitted to a district hospital in coastal Kenya, 2007-2010. J Infect Dis, 206 Suppl 1 (suppl 1), pp. S61-S67. | Citations: 12 (Scopus) | Show Abstract | Read more

BACKGROUND: Influenza data gaps in sub-Saharan Africa include incidence, case fatality, seasonal patterns, and associations with prevalent disorders. METHODS: Nasopharyngeal samples from children aged <12 years who were admitted to Kilifi District Hospital during 2007-2010 with severe or very severe pneumonia and resided in the local demographic surveillance system were screened for influenza A, B, and C viruses by molecular methods. Outpatient children provided comparative data. RESULTS: Of 2002 admissions, influenza A virus infection was diagnosed in 3.5% (71), influenza B virus infection, in 0.9% (19); and influenza C virus infection, in 0.8% (11 of 1404 tested). Four patients with influenza died. Among outpatients, 13 of 331 (3.9%) with acute respiratory infection and 1 of 196 without acute respiratory infection were influenza positive. The annual incidence of severe or very severe pneumonia, of influenza (any type), and of influenza A, was 1321, 60, and 43 cases per 100,000 <5 years of age, respectively. Peak occurrence was in quarters 3-4 each year, and approximately 50% of cases involved infants: temporal association with bacteremia was absent. Hypoxia was more frequent among pneumonia cases involving influenza (odds ratio, 1.78; 95% confidence interval, 1.04-1.96). Influenza A virus subtypes were seasonal H3N2 (57%), seasonal H1N1 (12%), and 2009 pandemic H1N1 (7%). CONCLUSIONS: The burden of influenza was small during 2007-2010 in this pediatric hospital in Kenya. Influenza A virus subtype H3N2 predominated, and 2009 pandemic influenza A virus subtype H1N1 had little impact.

Khanh TH, Sabanathan S, Thanh TT, Thoa LPK, Thuong TC, Hang VTT, Farrar J, Hien TT, Chau NVV, van Doorn HR. 2012. Enterovirus 71-associated hand, foot, and mouth disease, Southern Vietnam, 2011. Emerg Infect Dis, 18 (12), pp. 2002-2005. | Citations: 52 (Scopus) | Show Abstract | Read more

We prospectively studied 3,791 children hospitalized during 2011 during a large outbreak of enterovirus 71-associated hand, foot, and mouth disease in Vietnam. Formal assessment of public health interventions, use of intravenous immunoglobulin and other therapies, and factors predisposing for progression of disease is needed to improve clinical management.

Cauchemez S, Horby P, Fox A, Mai LQ, Thanh LT, Thai PQ, Hoa LNM, Hien NT, Ferguson NM. 2012. Influenza infection rates, measurement errors and the interpretation of paired serology. PLoS Pathog, 8 (12), pp. e1003061. | Citations: 32 (Scopus) | Show Abstract | Read more

Serological studies are the gold standard method to estimate influenza infection attack rates (ARs) in human populations. In a common protocol, blood samples are collected before and after the epidemic in a cohort of individuals; and a rise in haemagglutination-inhibition (HI) antibody titers during the epidemic is considered as a marker of infection. Because of inherent measurement errors, a 2-fold rise is usually considered as insufficient evidence for infection and seroconversion is therefore typically defined as a 4-fold rise or more. Here, we revisit this widely accepted 70-year old criterion. We develop a Markov chain Monte Carlo data augmentation model to quantify measurement errors and reconstruct the distribution of latent true serological status in a Vietnamese 3-year serological cohort, in which replicate measurements were available. We estimate that the 1-sided probability of a 2-fold error is 9.3% (95% Credible Interval, CI: 3.3%, 17.6%) when antibody titer is below 10 but is 20.2% (95% CI: 15.9%, 24.0%) otherwise. After correction for measurement errors, we find that the proportion of individuals with 2-fold rises in antibody titers was too large to be explained by measurement errors alone. Estimates of ARs vary greatly depending on whether those individuals are included in the definition of the infected population. A simulation study shows that our method is unbiased. The 4-fold rise case definition is relevant when aiming at a specific diagnostic for individual cases, but the justification is less obvious when the objective is to estimate ARs. In particular, it may lead to large underestimates of ARs. Determining which biological phenomenon contributes most to 2-fold rises in antibody titers is essential to assess bias with the traditional case definition and offer improved estimates of influenza ARs.

Mwangome MK, Fegan G, Fulford T, Prentice AM, Berkley JA. 2012. Mid-upper arm circumference at age of routine infant vaccination to identify infants at elevated risk of death: a retrospective cohort study in the Gambia. Bull World Health Organ, 90 (12), pp. 887-894. | Citations: 27 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To determine the predictive value for death before 12 months of age of mid-upper arm circumference (MUAC) and weight-for-length Z score (WFLz). METHODS: A retrospective cohort analysis of infants living in Keneba, in rural Gambia, was conducted. Anthropometric measures were obtained from demographic surveillance system records for infants registered between February 1974 and July 2008 who had had MUAC and WFLz recorded at 6-14 weeks of age and vital status recorded at least once more. Hazard ratios (HRs), population attributable fractions and areas under receiver operating characteristic (ROC) curves were estimated to assess the predictive value for death in infancy of MUAC and WFLz. FINDINGS: Of 2876 infants included in the analysis, 40 died before the age of 12 months. The HR for death in this group versus in well-nourished infants was 5.8 (95% confidence interval, CI: 1.6-21) for a WFLz < -3. HRs for MUACs below the thresholds of 115 mm, 110 mm and 105 mm were 4.5 (95% CI: 1.4-15), 9.5 (95% CI: 2.6-35) and 23 (95% CI: 4.2-122), respectively. The attributable fractions for a MUAC < 130 mm and a WFLz < 0 were 51% and 13%, respectively. The areas under the ROC curve for death in infancy were 0.55 (95% CI: 0.46 to 0.64) for WFLz and 0.64 (95% CI: 0.55 to 0.73) for MUAC. CONCLUSION: Among infants aged 6 to 14 weeks, unadjusted MUAC showed good performance in identifying infants at increased risk of death.

van Hasselt JGC, Andrew MA, Hebert MF, Tarning J, Vicini P, Mattison DR. 2012. The status of pharmacometrics in pregnancy: highlights from the 3(rd) American conference on pharmacometrics. Br J Clin Pharmacol, 74 (6), pp. 932-939. | Citations: 20 (Scopus) | Show Abstract | Read more

Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy.

Sobrino-Vegas P, Pérez-Hoyos S, Geskus R, Padilla B, Segura F, Rubio R, Del Romero J, Santos J, Moreno S, Del Amo J. 2012. Imputation of the Date of HIV Seroconversion in a Cohort of Seroprevalent Subjects: Implications for Analysis of Late HIV Diagnosis. AIDS Res Treat, 2012 pp. 725412. | Citations: 6 (Scopus) | Show Abstract | Read more

Objectives. Since subjects may have been diagnosed before cohort entry, analysis of late HIV diagnosis (LD) is usually restricted to the newly diagnosed. We estimate the magnitude and risk factors of LD in a cohort of seroprevalent individuals by imputing seroconversion dates. Methods. Multicenter cohort of HIV-positive subjects who were treatment naive at entry, in Spain, 2004-2008. Multiple-imputation techniques were used. Subjects with times to HIV diagnosis longer than 4.19 years were considered LD. Results. Median time to HIV diagnosis was 2.8 years in the whole cohort of 3,667 subjects. Factors significantly associated with LD were: male sex; Sub-Saharan African, Latin-American origin compared to Spaniards; and older age. In 2,928 newly diagnosed subjects, median time to diagnosis was 3.3 years, and LD was more common in injecting drug users. Conclusions. Estimates of the magnitude and risk factors of LD for the whole cohort differ from those obtained for new HIV diagnoses.

Boender TS, Sigaloff KCE, Kayiwa J, Musiime V, Calis JCJ, Hamers RL, Nakatudde LK, Khauda E, Mukuye A, Ditai J et al. 2012. Barriers to Initiation of Pediatric HIV Treatment in Uganda: A Mixed-Method Study AIDS Research and Treatment, 2012 pp. 1-10. | Citations: 17 (Scopus) | Show Abstract | Read more

Although the advantages of early infant HIV diagnosis and treatment initiation are well established, children often present late to HIV programs in resource-limited settings. We aimed to assess factors related to the timing of treatment initiation among HIV-infected children attending three clinical sites in Uganda. Clinical and demographic determinants associated with early disease (WHO clinical stages 1-2) or late disease (stages 3-4) stage at presentation were assessed using multilevel lo gistic regression. Additionally, semistructured interviews with caregivers and health workers were conducted to qualitatively explore determinants of late disease stage at presentation. Of 306 children initiating first-line regimens, 72% presented late. Risk factors for late presentation were age below 2 years old (OR 2.83, P=0.014), living without parents (OR 3.93, P=0.002), unemployment of the caregiver (OR 4.26, P=0.001), lack of perinatal HIV prophylaxis (OR 5.66, P=0.028), and high transportation costs to the clinic (OR 2.51, P=0.072). Forty-nine interviews were conducted, confirming the identified risk factors and additionally pointing to inconsistent referral from perinatal care, caregivers' unawareness of HIV symptoms, fear, and stigma as important barriers. The problem of late disease at presentation requires a multifactorial approach, addressing both health system and individual-level factors. © 2012 T. Sonia Boender et al.

Hay SI, Price RN, Baird JK. 2012. Advances in Parasitology. Preface. Adv Parasitol, 80 pp. ix-x. | Read more

Barrand MA, Winterberg M, Ng F, Nguyen M, Kirk K, Hladky SB. 2012. Glutathione export from human erythrocytes and Plasmodium falciparum malaria parasites. Biochem J, 448 (3), pp. 389-400. | Citations: 15 (Scopus) | Show Abstract | Read more

Glutathione export from uninfected human erythrocytes was compared with that from cells infected with the malaria parasite Plasmodium falciparum using two separate methods that distinguish between oxidized (GSSG) and reduced (GSH) glutathione. One involved enzymatic recycling with or without thiol-masking; the other involved rapid derivatization followed by HPLC. Glutathione efflux from uninfected erythrocytes under physiological conditions occurred predominantly as GSH. On exposure of the cells to oxidative challenge, efflux of GSSG exceeded that of GSH. Efflux of both species was blocked by MK571, an inhibitor of mammalian multidrug-resistance proteins. Glutathione efflux from parasitized erythrocytes was substantially greater than that from uninfected erythrocytes. Under physiological conditions, the exported species was GSH, whereas under energy-depleted conditions, GSSG efflux occurred. Glutathione export from parasitized cells was inhibited partially by MK571 and more so by furosemide, an inhibitor of the 'new permeability pathways' induced by the parasite in the host erythrocyte membrane. Efflux from isolated parasites occurred as GSH. On exposure to oxidative challenge, this GSH efflux decreased, but no GSSG export was detected. These results are consistent with the view that the parasite supplies its host erythrocyte with GSH, much of which is exported from the infected cell via parasite-induced pathways.

Hoglund RM, Adam I, Hanpithakpong W, Ashton M, Lindegardh N, Day NPJ, White NJ, Nosten F, Tarning J. 2012. A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan. Malar J, 11 (1), pp. 398. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria. METHOD: Symptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power (MCMP) analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study. RESULTS: A three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters (80% power and p=0.05). Pregnancy was, therefore, evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen. CONCLUSIONS: The population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.

Battle KE, Gething PW, Elyazar IRF, Moyes CL, Sinka ME, Howes RE, Guerra CA, Price RN, Baird KJ, Hay SI. 2012. The global public health significance of Plasmodium vivax. Adv Parasitol, 80 pp. 1-111. | Citations: 63 (Scopus) | Show Abstract | Read more

Plasmodium vivax occurs globally and thrives in both temperate and tropical climates. Here, we review the evidence of the biological limits of its contemporary distribution and the global population at risk (PAR) of the disease within endemic countries. We also review the most recent evidence for the endemic level of transmission within its range and discuss the implications for burden of disease assessments. Finally, the evidence-base for defining the contemporary distribution and PAR of P. vivax are discussed alongside a description of the vectors of human malaria within the limits of risk. This information along with recent data documenting the severe morbid and fatal consequences of P. vivax infection indicates that the public health significance of P. vivax is likely to have been seriously underestimated.

Hay SI, Price RN, Baird JK. 2012. Preface Advances in Parasitology, 80 | Read more

Carter JA, Molyneux CS, Mbuba CK, Jenkins J, Newton CRJC, Hartley SD. 2012. The reasons for the epilepsy treatment gap in Kilifi, Kenya: using formative research to identify interventions to improve adherence to antiepileptic drugs. Epilepsy Behav, 25 (4), pp. 614-621. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

Many people with epilepsy (PWE) in resource-poor countries do not receive appropriate treatment, a phenomenon referred to as the epilepsy treatment gap (ETG). We conducted a qualitative study to explore the reasons for this gap and to identify possible interventions in Kilifi, Kenya. Focus group discussions (FGDs) were carried out of PWE and their caregivers. Individual interviews were conducted of PWE, their caregivers, traditional healers, community health workers and leaders, nurses and doctors. In addition, a series of workshops was conducted, and four factors contributing to the ETG were identified: 1) lack of knowledge about the causes, treatment and prognosis of epilepsy; 2) inaccessibility to antiepileptic drugs; 3) misconceptions about epilepsy derived from superstitions about its origin; 4) and dissatisfaction with the communication skills of health providers. These data indicated possible interventions: 1) education and support for PWE and their caregivers; 2) communication skills training for health providers; 3) and improved drug provision.

Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M, Hogg MM, Battle KE, Padilla CD, Baird JK, Hay SI. 2012. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med, 9 (11), pp. e1001339. | Citations: 151 (Scopus) | Show Abstract | Read more

BACKGROUND: Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk. METHODS AND FINDINGS: Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4-8.8) across MECs, and 5.3% (4.4-6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd. CONCLUSIONS: G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit. Please see later in the article for the Editors' Summary.

Ruecker A, Shea M, Hackett F, Suarez C, Hirst EMA, Milutinovic K, Withers-Martinez C, Blackman MJ. 2012. Proteolytic activation of the essential parasitophorous vacuole cysteine protease SERA6 accompanies malaria parasite egress from its host erythrocyte. J Biol Chem, 287 (45), pp. 37949-37963. | Citations: 24 (Scopus) | Show Abstract | Read more

The malaria parasite replicates within an intraerythrocytic parasitophorous vacuole (PV). The PV and host cell membranes eventually rupture, releasing merozoites in a process called egress. Certain inhibitors of serine and cysteine proteases block egress, indicating a crucial role for proteases. The Plasmodium falciparum genome encodes nine serine-repeat antigens (SERAs), each of which contains a central domain homologous to the papain-like (clan CA, family C1) protease family. SERA5 and SERA6 are indispensable in blood-stage parasites, but the function of neither is known. Here we show that SERA6 localizes to the PV where it is precisely cleaved just prior to egress by an essential serine protease called PfSUB1. Mutations that replace the predicted catalytic Cys of SERA6, or that block SERA6 processing by PfSUB1, could not be stably introduced into the parasite genomic sera6 locus, indicating that SERA6 is an essential enzyme and that processing is important for its function. We demonstrate that cleavage of SERA6 by PfSUB1 converts it to an active cysteine protease. Our observations reveal a proteolytic activation step in the malarial PV that may be required for release of the parasite from its host erythrocyte.

Hai LT, Bich VTN, Ngai LK, Diep NTN, Phuc PH, Hung VP, Taylor WR, Horby P, Liem NT, Wertheim HFL. 2012. Fatal respiratory infections associated with rhinovirus outbreak, Vietnam. Emerg Infect Dis, 18 (11), pp. 1886-1888. | Citations: 15 (Scopus) | Show Abstract | Read more

During an outbreak of severe acute respiratory infections in 2 orphanages, Vietnam, 7/12 hospitalized children died. All hospitalized children and 26/43 children from outbreak orphanages tested positive for rhinovirus versus 9/40 control children (p = 0.0005). Outbreak rhinoviruses formed a distinct genetic cluster. Human rhinovirus is an underappreciated cause of severe pneumonia in vulnerable groups.

Talisuna AO, Karema C, Ogutu B, Juma E, Logedi J, Nyandigisi A, Mulenga M, Mbacham WF, Roper C, Guerin PJ et al. 2012. Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems. Lancet Infect Dis, 12 (11), pp. 888-896. | Citations: 37 (Scopus) | Show Abstract | Read more

Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and has been detected in western Thailand. The situation is ominously reminiscent of the emergence of resistance to chloroquine and to sulfadoxine-pyrimethamine several decades ago. Artemisinin resistance is a major threat to global public health, with the most severe potential effects in sub-Saharan Africa, where the disease burden is highest and systems for monitoring and containment of resistance are inadequate. The mechanisms that underlie artemisinin resistance are not fully understood. The main phenotypic trait associated with resistance is a substantial delay in parasite clearance, so far reported in southeast Asia but not in Africa. One of the pillars of the WHO global plan for artemisinin resistance containment is to increase monitoring and surveillance. In this Personal View, we propose strategies that should be adopted by malaria-endemic countries in Africa: resource mobilisation to reactivate regional surveillance networks, establishment of baseline parasite clearance profiles to serve as benchmarks to track emerging artemisinin resistance, improved data sharing to allow pooled analyses to identify rare events, modelling of risk factors for drug resistance, and development and validation of new approaches to monitor resistance.

White NJ. 2012. Counter perspective: artemisinin resistance: facts, fears, and fables. Am J Trop Med Hyg, 87 (5), pp. 785. | Citations: 16 (Scopus) | Read more

Williams AR, Douglas AD, Miura K, Illingworth JJ, Choudhary P, Murungi LM, Furze JM, Diouf A, Miotto O, Crosnier C et al. 2012. Enhancing blockade of Plasmodium falciparum erythrocyte invasion: assessing combinations of antibodies against PfRH5 and other merozoite antigens. PLoS Pathog, 8 (11), pp. e1002991. | Citations: 61 (Scopus) | Show Abstract | Read more

No vaccine has yet proven effective against the blood-stages of Plasmodium falciparum, which cause the symptoms and severe manifestations of malaria. We recently found that PfRH5, a P. falciparum-specific protein expressed in merozoites, is efficiently targeted by broadly-neutralizing, vaccine-induced antibodies. Here we show that antibodies against PfRH5 efficiently inhibit the in vitro growth of short-term-adapted parasite isolates from Cambodia, and that the EC(50) values of antigen-specific antibodies against PfRH5 are lower than those against PfAMA1. Since antibody responses elicited by multiple antigens are speculated to improve the efficacy of blood-stage vaccines, we conducted detailed assessments of parasite growth inhibition by antibodies against PfRH5 in combination with antibodies against seven other merozoite antigens. We found that antibodies against PfRH5 act synergistically with antibodies against certain other merozoite antigens, most notably with antibodies against other erythrocyte-binding antigens such as PfRH4, to inhibit the growth of a homologous P. falciparum clone. A combination of antibodies against PfRH4 and basigin, the erythrocyte receptor for PfRH5, also potently inhibited parasite growth. This methodology provides the first quantitative evidence that polyclonal vaccine-induced antibodies can act synergistically against P. falciparum antigens and should help to guide the rational development of future multi-antigen vaccines.

Wolbers M, Kleinschmidt I, Simmons CP, Donnelly CA. 2012. Considerations in the design of clinical trials to test novel entomological approaches to dengue control. PLoS Negl Trop Dis, 6 (11), pp. e1937. | Citations: 19 (Scopus) | Read more

van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. 2012. Advances in treatment of bacterial meningitis. Lancet, 380 (9854), pp. 1693-1702. | Citations: 122 (Scopus) | Show Abstract | Read more

Bacterial meningitis kills or maims about a fifth of people with the disease. Early antibiotic treatment improves outcomes, but the effectiveness of widely available antibiotics is threatened by global emergence of multidrug-resistant bacteria. New antibiotics, such as fluoroquinolones, could have a role in these circumstances, but clinical data to support this notion are scarce. Additionally, whether or not adjunctive anti-inflammatory therapies (eg, dexamethasone) improve outcomes in patients with bacterial meningitis remains controversial; in resource-poor regions, where the disease burden is highest, dexamethasone is ineffective. Other adjunctive therapeutic strategies, such as glycerol, paracetamol, and induction of hypothermia, are being tested further. Therefore, bacterial meningitis is a substantial and evolving therapeutic challenge. We review this challenge, with a focus on strategies to optimise antibiotic efficacy in view of increasingly drug-resistant bacteria, and discuss the role of current and future adjunctive therapies.

Brouwer MC, Thwaites GE, Tunkel AR, van de Beek D. 2012. Dilemmas in the diagnosis of acute community-acquired bacterial meningitis. Lancet, 380 (9854), pp. 1684-1692. | Citations: 95 (Scopus) | Show Abstract | Read more

Rapid diagnosis and treatment of acute community-acquired bacterial meningitis reduces mortality and neurological sequelae, but can be delayed by atypical presentation, assessment of lumbar puncture safety, and poor sensitivity of standard diagnostic microbiology. Thus, diagnostic dilemmas are common in patients with suspected acute community-acquired bacterial meningitis. History and physical examination alone are sometimes not sufficient to confirm or exclude the diagnosis. Lumbar puncture is an essential investigation, but can be delayed by brain imaging. Results of cerebrospinal fluid (CSF) examination should be interpreted carefully, because CSF abnormalities vary according to the cause, patient's age and immune status, and previous treatment. Diagnostic prediction models that use a combination of clinical findings, with or without test results, can help to distinguish acute bacterial meningitis from other causes, but these models are not infallible. We review the dilemmas in the diagnosis of acute community-acquired bacterial meningitis, and focus on the roles of clinical assessment and CSF examination.

Newton PN, Day NPJ. 2012. Scrub Typhus pp. 542-545. | Read more

Warrell DA. 2012. Pentastomiasis pp. 966-968. | Read more

Warrell DA. 2012. Animals Hazardous to Humans pp. 938-965. | Read more

Warrell DA. 2012. Poisonous Plants and Aquatic Animals: Poisonous Aquatic Animals pp. 923-924. | Read more

Warrell MJ, Warrell DA. 2012. Viral CNS Infections: Rabies and Related Viruses pp. 344-348. | Read more

Warrell DA. 2012. Poisonous Plants and Aquatic Animals: Fish Poisoning: Gastrointestinal and Neurotoxic Syndromes pp. 925-927. | Read more

Warrell DA. 2012. Injurious Arthropods pp. 969-985. | Read more

White NJ. 2012. Melioidosis and Glanders pp. 580-583. | Citations: 1 (Scopus) | Read more

Thwaites GE, Thwaites CL. 2012. Tetanus pp. 508-510. | Read more

Khatib AM, Ali M, von Seidlein L, Kim DR, Hashim R, Reyburn R, Ley B, Thriemer K, Enwere G, Hutubessy R et al. 2012. Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. Lancet Infect Dis, 12 (11), pp. 837-844. | Citations: 50 (Scopus) | Show Abstract | Read more

BACKGROUND: Zanzibar, in east Africa, has been severely and repeatedly affected by cholera since 1978. We assessed the effectiveness of oral cholera vaccination in high-risk populations in the archipelago to estimate the indirect (herd) protection conferred by the vaccine and direct vaccine effectiveness. METHODS: We offered two doses of a killed whole-cell B-subunit cholera vaccine to individuals aged 2 years and older in six rural and urban sites. To estimate vaccine direct protection, we compared the incidence of cholera between recipients and non-recipients using generalised estimating equations with the log link function while controlling for potential confounding variables. To estimate indirect effects, we used a geographic information systems approach and assessed the association between neighbourhood-level vaccine coverage and the risk for cholera in the non-vaccinated residents of that neighbourhood, after controlling for potential confounding variables. This study is registered with ClinicalTrials.gov, number NCT00709410. FINDINGS: Of 48,178 individuals eligible to receive the vaccine, 23,921 (50%) received two doses. Between February, 2009, and May, 2010, there was an outbreak of cholera, enabling us to assess vaccine effectiveness. The vaccine conferred 79% (95% CI 47-92) direct protection against cholera in participants who received two doses. Indirect (herd) protection was shown by a decrease in the risk for cholera of non-vaccinated residents within a household's neighbourhood as the vaccine coverage in that neighbourhood increased. INTERPRETATION: Our findings suggest that the oral cholera vaccine offers both direct and indirect (herd) protection in a sub-Saharan African setting. Mass oral cholera immunisation campaigns have the potential to provide not only protection for vaccinated individuals but also for the unvaccinated members of the community and should be strongly considered for wider use. Because this is an internationally-licensed vaccine, we could not undertake a randomised placebo-controlled trial, but the absence of vaccine effectiveness against non-cholera diarrhoea indicates that the noted protection against cholera could not be explained by bias. FUNDING: Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, and the South Korean Government.

Caillet C, Chauvelot-Moachon L, Montastruc J-L, Bagheri H, French Association of Regional Pharmacovigilance Centers. 2012. Safety profile of enantiomers vs. racemic mixtures: it's the same? Br J Clin Pharmacol, 74 (5), pp. 886-889. | Citations: 5 (Scopus) | Show Abstract | Read more

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The physicochemical properties of racemates and stereoisomers of medicines can differ significantly, and this may affect the side-effect profile in addition to the pharmacokinetics and intended pharmacology. WHAT THIS STUDY ADDS: This is a study to investigate the profile of adverse drug reactions of racemic and enantiomeric forms of drugs. Our data suggest differences in the safety profile for ofloxacin and omeprazole. This area requires more work to investigate this for other compounds. AIMS: The objective was to investigate the safety profile of four drugs marketed as racemic and enantiomeric forms in France. METHODS: Data from the French PharmacoVigilance Data Base (January 2005 to June 2010) were analysed for four pairs of racemic/isomeric drugs. A case-noncase approach was used to measure the disproportionality of combination between adverse drug reaction (ADR) and exposure to drug. RESULTS: No significant difference in the number of ADRs was observed between Rac-cetirizine/(R)-cetirizine or Rac-citalopram/(S)-citalopram pairs. (S)-Omeprazole induced more haematological effects than Rac-omeprazole. Rac-Ofloxacin induced more haematological, renal and neuropsychiatric ADRs than (S)-ofloxacin, whereas levofloxacin was associated with more reports of musculoskeletal ADRs. CONCLUSIONS: The profile of ADRs could differ for some drugs marketed as racemic and enantiomeric forms. Further studies would be necessary to confirm these data.

Ding J-J, Zhang Y-J, Jiao Z, Wang Y. 2012. The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation Acta Pharmacologica Sinica, 33 (11), pp. 1431-1440. | Read more

Emary K, Moore CE, Chanpheaktra N, An KP, Chheng K, Sona S, Duy PT, Nga TVT, Wuthiekanun V, Amornchai P et al. 2012. Enteric fever in Cambodian children is dominated by multidrug-resistant H58 Salmonella enterica serovar Typhi with intermediate susceptibility to ciprofloxacin. Trans R Soc Trop Med Hyg, 106 (12), pp. 718-724. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

Infections with Salmonella enterica serovar Typhi isolates that are multidrug resistant (MDR: resistant to chloramphenicol, ampicillin, trimethoprim-sulphamethoxazole) with intermediate ciprofloxacin susceptibility are widespread in Asia but there is little information from Cambodia. We studied invasive salmonellosis in children at a paediatric hospital in Siem Reap, Cambodia. Between 2007 and 2011 Salmonella was isolated from a blood culture in 162 children. There were 151 children with enteric fever, including 148 serovar Typhi and three serovar Paratyphi A infections, and 11 children with a non-typhoidal Salmonella infection. Of the 148 serovar Typhi isolates 126 (85%) were MDR and 133 (90%) had intermediate ciprofloxacin susceptibility. Inpatient antimicrobial treatment was ceftriaxone alone or initial ceftriaxone followed by a step-down to oral ciprofloxacin or azithromycin. Complications developed in 37/128 (29%) children admitted with enteric fever and two (1.6%) died. There was one confirmed relapse. In a sample of 102 serovar Typhi strains genotyped by investigation of a subset of single nucleotide polymorphisms, 98 (96%) were the H58 haplotype, the majority of which had the common serine to phenylalanine substitution at codon 83 in the DNA gyrase. We conclude that antimicrobial-resistant enteric fever is common in Cambodian children and therapeutic options are limited.

Tran TK, Eriksson B, Nguyen CTK, Horby P, Bondjers G, Petzold M. 2012. DodaLab: an urban health and demographic surveillance site, the first three years in Hanoi, Vietnam. Scand J Public Health, 40 (8), pp. 765-772. | Citations: 12 (Scopus) | Show Abstract | Read more

RATIONALE: Health and demographic surveillance sites (HDSSs) are important sources for health planning and policy in many low and middle income countries. Almost all HDSSs are in rural settings. The article aims to present the experiences and some concrete results for the first three years of operation of an urban HDSS in Hanoi, Vietnam, and discuss advantages and disadvantages of conducting health studies in HDSSs. DESIGN, POPULATION AND SAMPLE SIZE: The DodaLab urban HDSS was established in 2007 in three communes at different economic levels in Dong Da district, Hanoi, Vietnam. Demographic, social and economic information about 10,000 households and their 37,000 persons was obtained through household interviews. Quarterly follow-up was initiated to provide information about vital events, birth, death and migration. A new household survey was undertaken in 2009. The existing rural HDSS FilaBavi, started in 1999, with 12,000 households and 52,000 persons, was used as the blueprint. CONCLUSIONS: It was possible to establish and run an urban HDSS with experiences from the rural site. The urban and rural contexts are different and demographically, economically and socially complex, but the use of HDSSs can facilitate research beyond very simplified models for comparisons. General statements about external validity of results from the HDSS cannot be made. This issue has to be considered specifically in every situation as an integral part of the research so that the results can be made useful outside the researched HDSS and in performing relevant comparisons.

Hien TT, Thuy-Nhien NT, Phu NH, Boni MF, Thanh NV, Nha-Ca NT, Thai LH, Thai CQ, Toi PV, Thuan PD et al. 2012. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J, 11 (1), pp. 355. | Citations: 66 (Scopus) | Show Abstract | Read more

BACKGROUND: By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. METHODS: From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. RESULTS: 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). CONCLUSIONS: This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam. TRIAL REGISTRATION: NTC01165372.

Gitonga CW, Kihara JH, Njenga SM, Awuondo K, Noor AM, Snow RW, Brooker SJ. 2012. Use of rapid diagnostic tests in malaria school surveys in Kenya: does their under-performance matter for planning malaria control? Am J Trop Med Hyg, 87 (6), pp. 1004-1011. | Citations: 9 (Scopus) | Show Abstract | Read more

Malaria rapid diagnostic tests (RDTs) are known to yield false-positive results, and their use in epidemiologic surveys will overestimate infection prevalence and potentially hinder efficient targeting of interventions. To examine the consequences of using RDTs in school surveys, we compared three RDT brands used during a nationwide school survey in Kenya with expert microscopy and investigated the cost implications of using alternative diagnostic approaches in identifying localities with differing levels of infection. Overall, RDT sensitivity was 96.1% and specificity was 70.8%. In terms of classifying districts and schools according to prevalence categories, RDTs were most reliable for the < 1% and > 40% categories and least reliable in the 1-4.9% category. In low-prevalence settings, microscopy was the most expensive approach, and RDT results corrected by either microscopy or polymerase chain reaction were the cheapest. Use of polymerase chain reaction-corrected RDT results is recommended in school malaria surveys, especially in settings with low-to-moderate malaria transmission.

van der Mark LB, Lyklema PHE, Geskus RB, Mohrs J, Bindels PJE, van Aalderen WMC, Ter Riet G. 2012. A systematic review with attempted network meta-analysis of asthma therapy recommended for five to eighteen year olds in GINA steps three and four. BMC Pulm Med, 12 (1), pp. 63. | Citations: 3 (Scopus) | Show Abstract | Read more

BACKGROUND: The recommendations for the treatment of moderate persistent asthma in the Global Initiative for Asthma (GINA) guidelines for paediatric asthma are mainly based on scientific evidence extrapolated from studies in adults or on consensus. Furthermore, clinical decision-making would benefit from formal ranking of treatments in terms of effectiveness.Our objective is to assess all randomized trial-based evidence specifically pertaining to 5-18 year olds with moderate persistent asthma. Rank the different drug treatments of GINA guideline steps 3&4 in terms of effectiveness. METHODS: Systematic review with network meta-analysis. After a comprehensive search in Central, Medline, Embase, CINAHL and the WHO search portal two reviewers selected RCTs performed in 4,129 children from 5-18 year old, with moderate persistent asthma comparing any GINA step 3&4 medication options. Further quality was assessed according the Cochrane Collaboration's tool and data-extracted included papers and built a network of the trials. Attempt at ranking treatments with formal statistical methods employing direct and indirect (e.g. through placebo) connections between all treatments. RESULTS: 8,175 references were screened; 23 randomized trials (RCT), comparing head-to-head (n=17) or against placebo (n=10), met the inclusion criteria. Except for theophylline as add-on therapy in step 4, a closed network allowed all comparisons to be made, either directly or indirectly. Huge variation in, and incomplete reporting of, outcome measurements across RCTs precluded assessment of relative efficacies. CONCLUSION: Evidence-based ranking of effectiveness of drug treatments in GINA steps 3&4 is not possible yet. Existing initiatives for harmonization of outcome measurements in asthma trials need urgent implementation.

Hwang J, Jaroensuk J, Leimanis ML, Russell B, McGready R, Day N, Snounou G, Nosten F, Imwong M. 2012. Long-term storage limits PCR-based analyses of malaria parasites in archival dried blood spots. Malar J, 11 (1), pp. 339. | Citations: 26 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Blood samples collected in epidemiological and clinical investigations and then stored, often at room temperature, as blood spots dried on a filter paper have become one of the most popular source of material for further molecular analyses of malaria parasites. The dried blood spots are often archived so that they can be used for further retrospective investigations of parasite prevalence, or as new genetic markers come to the fore. However, the suitability of the template obtained from dried blood spots that have been stored for long periods for DNA amplification is not known. METHODS: DNA from 267 archived blood spots collected over a period of 12 years from persons with microscopically confirmed Plasmodium falciparum infection was purified by one of two methods, Chelex and Qiagen columns. These templates were subjected to highly sensitive nested PCR amplification targeting three parasite loci that differ in length and/or copy number. RESULTS: When a 1.6 kb fragment of the parasites' small subunit ribosomal RNA was targeted (primary amplification), the efficiency of P. falciparum detection decreased in samples archived for more than six years, reaching very low levels for those stored for more than 10 years. Positive amplification was generally obtained more often with Qiagen-extracted templates. P. falciparum could be detected in 32 of the 40 negative Qiagen-extracted templates when a microsatellite of about 180 bp was targeted. The remaining eight samples gave a positive amplification when a small region of 238 bp of the higher copy number (20 to 200) mitochondrial genome was targeted. CONCLUSIONS: The average length of DNA fragments that can be recovered from dried blood spots decreases with storage time. Recovery of the DNA is somewhat improved, especially in older samples, by the use of a commercial DNA purification column, but targets larger than 1.5 kb are unlikely to be present 10 years after the initial blood collection, when the average length of the DNA fragments present is likely to be around a few hundred bp. In conclusion, the utility of archived dried blood spots for molecular analyses decreases with storage time.

Herbert K, Plugge E, Foster C, Doll H. 2012. Risk factors for non-communicable diseases in prison populations Reply LANCET, 380 (9849), pp. 1227-1228. | Read more

Price RN, Auburn S, Marfurt J, Cheng Q. 2012. Phenotypic and genotypic characterisation of drug-resistant Plasmodium vivax. Trends Parasitol, 28 (11), pp. 522-529. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance.

Noor AM, ElMardi KA, Abdelgader TM, Patil AP, Amine AAA, Bakhiet S, Mukhtar MM, Snow RW. 2012. Malaria risk mapping for control in the republic of Sudan. Am J Trop Med Hyg, 87 (6), pp. 1012-1021. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

Evidence shows that malaria risk maps are rarely tailored to address national control program ambitions. Here, we generate a malaria risk map adapted for malaria control in Sudan. Community Plasmodium falciparum parasite rate (PfPR) data from 2000 to 2010 were assembled and were standardized to 2-10 years of age (PfPR(2-10)). Space-time Bayesian geostatistical methods were used to generate a map of malaria risk for 2010. Surfaces of aridity, urbanization, irrigation schemes, and refugee camps were combined with the PfPR(2-10) map to tailor the epidemiological stratification for appropriate intervention design. In 2010, a majority of the geographical area of the Sudan had risk of < 1% PfPR(2-10). Areas of meso- and hyperendemic risk were located in the south. About 80% of Sudan's population in 2011 was in the areas in the desert, urban centers, or where risk was < 1% PfPR(2-10). Aggregated data suggest reducing risks in some high transmission areas since the 1960s.

Henk DA, Shahar-Golan R, Devi KR, Boyce KJ, Zhan N, Fedorova ND, Nierman WC, Hsueh P-R, Yuen K-Y, Sieu TPM et al. 2012. Clonality despite sex: the evolution of host-associated sexual neighborhoods in the pathogenic fungus Penicillium marneffei. PLoS Pathog, 8 (10), pp. e1002851. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei.

Nair M, Ariana P, Webster P. 2012. What influences the decision to undergo institutional delivery by skilled birth attendants? A cohort study in rural Andhra Pradesh, India. Rural Remote Health, 12 (4), pp. 2311. | Citations: 16 (Scopus) | Show Abstract

INTRODUCTION: Despite continuing efforts to promote skilled institutional delivery, eight women die every hour in India due to causes related to pregnancy and child birth. The objectives of this study were to assess the prevalence and the determinants of institutional delivery by skilled birth attendants in a rural population in Andhra Pradesh, India. METHODS: This cross-sectional study used data from 'Young Lives', a longitudinal study on childhood poverty, and the study population was a cohort of 1419 rural, economically deprived women (from the Young Lives study) in Andhra Pradesh, India. The data are from round-1 of Young Lives younger cohort recruited in 2002 and followed until 2015. The participation rate of households was 99.5%. RESULTS: Prevalence of skilled institutional delivery was 36.8%. Women's education (odds ratio [OR] for secondary education 2.06; 95% confidence interval [95%CI] 1.33-3.19), desire to be pregnant (OR 1.89; 95% CI 1.12-3.22) and adequate prenatal care (OR 1.69; 95% CI 1.30-2.21) were found to be the positive determinants of skilled institutional delivery. High birth order (OR for second birth 0.44; 95% CI 0.32-0.60, OR for third birth 0.47; 95% CI 0.30-0.72 and OR for ≥fourth 0.47; 95% CI 0.27-0.81), schedule caste/schedule tribe social background (OR 0.70; 95% CI 0.53-0.93) and poor economic status of the household (OR for the poorest households 0.67; 95% CI 0.46-0.99) were negatively associated with skilled institutional delivery. CONCLUSIONS: Despite existence of supporting schemes, the utilisation of skilled institutional delivery services was low in the study population. Educated women and women with adequate prenatal care who have a desired pregnancy were more likely to utilise health institutions and skilled delivery care. There is a need for integrated approaches through maternal health, family planning and education programs, and a focus on uneducated, poor women belonging to disadvantaged social groups.

Suraweera W, Morris SK, Kumar R, Warrell DA, Warrell MJ, Jha P, Million Death Study Collaborators. 2012. Deaths from symptomatically identifiable furious rabies in India: a nationally representative mortality survey. PLoS Negl Trop Dis, 6 (10), pp. e1847. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: It is estimated that India has more deaths from rabies than any other country. However, existing estimates are indirect and rely on non-representative studies. METHODS AND PRINCIPAL FINDINGS: We examined rabies deaths in the ongoing Million Death Study (MDS), a representative survey of over 122,000 deaths in India that uses enhanced types of verbal autopsy. We estimated the age-specific mortality rates of symptomatically identifiable furious rabies and its geographic and demographic distributions. A total of 140 deaths in our sample were caused by rabies, suggesting that in 2005 there were 12,700 (99% CI 10,000 to 15,500) symptomatically identifiable furious rabies deaths in India. Most rabies deaths were in males (62%), in rural areas (91%), and in children below the age of 15 years (50%). The overall rabies mortality rate was 1.1 deaths per 100,000 population (99%CI 0.9 to 1.4). One third of the national rabies deaths were found in Uttar Pradesh (4,300) and nearly three quarters (8,900) were in 7 central and south-eastern states: Chhattisgarh, Uttar Pradesh, Odisha, Andhra Pradesh, Bihar, Assam, and Madhya Pradesh. CONCLUSIONS AND SIGNIFICANCE: Rabies remains an avoidable cause of death in India. As verbal autopsy is not likely to identify atypical or paralytic forms of rabies, our figure of 12,700 deaths due to classic and clinically identifiable furious rabies underestimates the total number of deaths due to this virus. The concentrated geographic distribution of rabies in India suggests that a significant reduction in the number of deaths or potentially even elimination of rabies deaths is possible.

Derde L, Cooper B, Buisson CB, Bonten M, Consortium MOSARR. 2012. MASTERING HOSPITAL ANTIBIOTIC RESISTANCE (MOSAR): A EUROPEAN CLUSTER-RANDOMIZED TRIAL ON REDUCING ACQUISITION OF RESISTANT BACTERIA IN INTENSIVE CARE UNITS INTENSIVE CARE MEDICINE, 38 pp. S249-S249.

Khan MI, Soofi SB, Ochiai RL, Khan MJ, Sahito SM, Habib MA, Puri MK, Von Seidlein L, Park JK, You YA et al. 2012. Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan. J Infect Dev Ctries, 6 (10), pp. 704-714. | Citations: 11 (Scopus) | Show Abstract | Read more

INTRODUCTION: Enteric fever remains a major public health problem in Asia. Planning appropriate preventive measures such as immunization requires a clear understanding of disease burden. We conducted a community-based surveillance for Salmonella Typhi infection in children in Karachi, Pakistan. METHODOLOGY: A de jure household census was conducted at baseline in the study setting to enumerate all individuals. A health-care facility-based passive surveillance system was used to capture episodes of fever lasting three or more 3 days in children 2 to 16 years old. RESULTS: A total of 7,401 blood samples were collected for microbiological confirmation, out of which 189 S. Typhi and 32 S. Paratyphi A isolates were identified with estimated annual incidences of 451/100,000 (95% CI: 446 - 457) and 76/100,000 (95% CI: 74 - 78) respectively. At the time of presentation, after adjusting for age, there was an association between the duration of fever and temperature at presentation, and being infected with multidrug-resistant S. Typhi. Of 189 isolates 83 were found to be resistant to first-line antimicrobial therapy. There was no statistically significant difference in clinical presentation of blood culture sensitive and resistant S. Typhi isolates. CONCLUSION: Incidence of S. Typhi in children is high in urban squatter settlements of Karachi, Pakistan. Findings from this study identified duration of fever and temperature at the time of presentation as important symptoms associated with blood culture-confirmed typhoid fever. Preventive strategies such as immunization and improvements in water and sanitation conditions should be the focus of typhoid control in urban settlements of Pakistan.

Taylor SJC, Sohanpal R, Bremner SA, Devine A, McDaid D, Fernández J-L, Griffiths CJ, Eldridge S. 2012. Self-management support for moderate-to-severe chronic obstructive pulmonary disease: a pilot randomised controlled trial. Br J Gen Pract, 62 (603), pp. e687-e695. | Citations: 23 (Scopus) | Show Abstract | Read more

BACKGROUND: Better self management could improve quality of life (QoL) and reduce hospital admissions in chronic obstructive pulmonary disease (COPD), but the best way to promote it remains unclear. AIM: To explore the feasibility, effectiveness and cost effectiveness of a novel, layperson-led, theoretically driven COPD self-management support programme. DESIGN AND SETTING: Pilot randomised controlled trial in one UK primary care trust area. METHOD: Patients with moderate to severe COPD were identified through primary care and randomised 2:1 to the 7-week-long, group intervention or usual care. Outcomes at baseline, 2, and 6 months included self-reported health, St George's Respiratory Questionnaire (SGRQ), EuroQol, and exercise. RESULTS: Forty-four per cent responded to GP invitation, 116 were randomised: mean (standard deviation [SD]) age 69.5 (9.8) years, 46% male, 78% had unscheduled COPD care in the previous year. Forty per cent of intervention patients completed the course; 35% attended no sessions; and 78% participants completed the 6-month follow-up questionnaire. Results suggest that the intervention may increase both QoL (mean EQ-5D change 0.12 (95% confidence interval [CI] = -0.02 to 0.26) higher, intervention versus control) and exercise levels, but not SGRQ score. Economic analyses suggested that with thresholds of £20 000 per quality-adjusted life-year gained, the intervention is likely to be cost-effective. CONCLUSION: This intervention has good potential to meet the UK National Institute for Health and Clinical Excellence criteria for cost effectiveness, and further research is warranted. However, to make a substantial impact on COPD self-management, it will also be necessary to explore other ways to enable patients to access self-management education.

van der Pluijm RW, Lamers MJ, de Boer M, van der Graaf WTA, van Laarhoven HWM. 2012. A female with a leiomyosarcoma presenting with acute thoracic pain and dyspnoea. Neth J Med, 70 (8), pp. 377-380.

Ingabire MC, Mitchell K, Veldhuijzen N, Umulisa MM, Nyinawabega J, Kestelyn E, Van Steijn M, Van De Wijgert J, Pool R. 2012. Joining and leaving sex work: experiences of women in Kigali, Rwanda. Cult Health Sex, 14 (9), pp. 1037-1047. | Citations: 9 (Scopus) | Show Abstract | Read more

Although sex work can bring significant economic benefit there are serious downsides, not least vulnerability to adverse sexual health outcomes. Focus-groups discussions and in-depth interviews were conducted with 70 female sex workers to explore the context in which they started sex work, their motivations to leave, and their experiences of trying to leave. The pathway to becoming a sex worker was underscored by poverty, with disruptive events leading to increasing vulnerability and increasingly difficult life choices. A sizeable minority of women became sex workers while working as house-girls, a position associated with financial, physical and sexual vulnerability. The majority of participants were still working as sex workers, citing financial reasons for not leaving. Motivations to leave sex work included experiencing a frightening incident, peer pressure and concerns about dependent children. Those who left often described a change in their financial circumstances that enabled them to leave. Some had left but had returned to sex work following a financial crisis or because they found their new life too hard. House-girls are particularly vulnerable and therefore an appropriate focus for prevention. Programmes assisting women to leave need to include financial safety nets so that a time of financial difficulty does not necessitate a return to sex work.

Durrieu G, Palmaro A, Pourcel L, Caillet C, Faucher A, Jacquet A, Ouaret S, Perault-Pochat MC, Kreft-Jais C, Castot A et al. 2012. First French experience of ADR reporting by patients after a mass immunization campaign with Influenza A (H1N1) pandemic vaccines: a comparison of reports submitted by patients and healthcare professionals. Drug Saf, 35 (10), pp. 845-854. | Citations: 16 (Scopus) | Show Abstract | Read more

BACKGROUND: Available data concerning the contribution of patient adverse drug reaction (ADR) reporting in practice are scarce. Few studies have compared patients' reports with reports from healthcare professionals (HCPs). During the 2009-10 mass immunization campaign with A (H1N1)v2009 pandemic influenza vaccines, a reinforced pharmacovigilance plan was introduced in France according to European Medicines Agency recommendations. For the first time, patients were offered the opportunity to report suspected ADRs to pandemic vaccines directly to regional pharmacovigilance centres. OBJECTIVE: The aim of the study was to compare the characteristics of patient and HCP ADR reports in order to assess the qualitative and quantitative contribution of patient reporting to the French Pharmacovigilance System. METHODS: All spontaneous ADRs registered into the French Pharmacovigilance Database from 21 October 2009 to 15 June 2010, in which either one of the most frequently administered pandemic vaccines (i.e. Panenza® or Pandemrix®) was involved, were analysed. ADRs were classified as 'serious', 'medically serious' and 'non-serious'. This study focused on 'serious' and 'medically serious' ADRs. An ADR was ranked as 'medically serious' when it required medical intervention or hospitalization within less than 24 hours. In each level of seriousness, frequency of 'unlabelled' ADRs, ADRs of 'special interest', imputability scores and category of ADRs according to Medical Dictionary for Regulatory Activitives (MedDRA®) primary System Organ Class were compared between patient and professional reports. RESULTS: Among the 4746 reports received during the study period, 1006 (21.2%) originated from patients. HCPs reported significantly more 'medically serious' or 'serious' ADRs than patients (15.1% [565/3740] vs 8.4% [85/1006], respectively; p < 0.001). No difference was found in 'unlabelled, serious' ADRs between patients and HCPs (56.5% [n = 13] vs 56.7% [n = 136], respectively). CONCLUSIONS: In this first French experience of formal patient participation to ADR reporting, patient contribution to the total number of ADRs reached 21.2%. This study revealed no major qualitative difference between patient and HCP reports. ADR profiles reported by patients appeared to be consistent with those from professionals. Further investigations are necessary to assess the intrinsic quality of notification forms coming from non-professional reporters. However, this study is of particular interest in the context of publication of the first governmental decree that will formally integrate patient participation to the current French ADR reporting scheme.

van der Gaag NA, Kloek JJ, de Bakker JK, Musters B, Geskus RB, Busch ORC, Bosma A, Gouma DJ, van Gulik TM. 2012. Survival analysis and prognostic nomogram for patients undergoing resection of extrahepatic cholangiocarcinoma. Ann Oncol, 23 (10), pp. 2642-2649. | Citations: 39 (Scopus) | Show Abstract | Read more

BACKGROUND: Tumor location of extrahepatic cholangiocarcinoma (CCA) might influence survival after resection. METHODS: A consecutive series of 175 patients who had undergone a potentially curative resection of extrahepatic CCA was analyzed. We calculated concordance indices of different constructed prognostic models for survival including TNM (tumour-node-metastasis) staging and developed a nomogram of the most sensitive model. RESULTS: Overall cancer-specific survival rates were 83%, 58%, and 26% at 1, 2, and 5 years, respectively. Cancer-specific survival according to location was 42% for proximal, 23% for mid, and 19% for distal CCA after 5 years. Tumor location was not an independent significant predictor (P = 0.06). A prognostic model using all potential prognostic variables predicted survival better compared with TNM staging (concordance index 0.65 versus 0.63). A reduced model containing only lymph node status, microscopically residual tumor status, and tumor differentiation grade, also outperformed TNM staging (concordance index 0.66). CONCLUSIONS: Tumor location of extrahepatic CCA does not independently predict cancer-specific survival after resection. We developed a nomogram, based on a prognostic model with lymph node status, microscopically residual tumor status of resection margins, and tumor differentiation grade, that predicted survival better than TNM staging.

Gupta RK, Jordan MR, Sultan BJ, Hill A, Davis DHJ, Gregson J, Sawyer AW, Hamers RL, Ndembi N, Pillay D, Bertagnolio S. 2012. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet, 380 (9849), pp. 1250-1258. | Citations: 185 (Scopus) | Show Abstract | Read more

BACKGROUND: The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. METHODS: We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. FINDINGS: Study-level data were available for 26,102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (-0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region. INTERPRETATION: Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries--no changes in antiretroviral treatment guidelines are warranted at the moment. FUNDING: Bill & Melinda Gates Foundation and the European Community's Seventh Framework Programme.

Russell B, Suwanarusk R, Malleret B, Costa FTM, Snounou G, Kevin Baird J, Nosten F, Rénia L. 2012. Human ex vivo studies on asexual Plasmodium vivax: the best way forward. Int J Parasitol, 42 (12), pp. 1063-1070. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

The lack of a continuous culture method for Plasmodium vivax has given the impression that investigations on this important species are severely curtailed. However, the use of new or improved ex vivo methods and tools to study fresh and thawed isolates from vivax malaria patients is currently providing useful data on P. vivax, such as sensitivity to antimalarial drugs, invasion mechanisms and pathobiology. This review discusses a practical framework for conducting ex vivo studies on the asexual erythrocytic stages of P. vivax and considers the synergies between ex vivo defined phenotypes, ex vivo derived 'omic' studies and in vivo clinical studies.

Wertheim HFL, Ngoc DM, Wolbers M, Binh TT, Hải NTT, Loan NQ, Tú PT, Sjodin A, Romanoff L, Li Z et al. 2012. Studying the effectiveness of activated carbon R95 respirators in reducing the inhalation of combustion by-products in Hanoi, Vietnam: a demonstration study. Environ Health, 11 (1), pp. 72. | Citations: 6 (Scopus) | Show Abstract | Read more

BACKGROUND: Urban air pollution is an increasing health problem, particularly in Asia, where the combustion of fossil fuels has increased rapidly as a result of industrialization and socio-economic development. The adverse health impacts of urban air pollution are well established, but less is known about effective intervention strategies. In this demonstration study we set out to establish methods to assess whether wearing an R95 activated carbon respirator could reduce intake of polycyclic aromatic hydrocarbons (PAH) in street workers in Hanoi, Vietnam. METHODS: In this demonstration study we performed a cross-over study in which non-smoking participants that worked at least 4 hours per day on the street in Hanoi were randomly allocated to specific respirator wearing sequences for a duration of 2 weeks. Urines were collected after each period, i.e., twice per week, at the end of the working day to measure hydroxy PAHs (OH-PAH) using gas chromatography/high resolution mass spectrometry. The primary endpoint was the urinary concentration of 1-hydroxypyrene (1-OHP). RESULTS: Forty-four participants (54.5% male, median age 40 years) were enrolled with the majority being motorbike taxi drivers (38.6%) or street vendors (34.1%). The baseline creatinine corrected urinary level for 1-OHP was much higher than other international comparisons: 1020 ng/g creatinine (IQR: 604-1551). Wearing a R95 mask had no significant effect on 1-OHP levels: estimated multiplicative effect 1.0 (95% CI: 0.92-1.09) or other OH-PAHs, except 1-hydroxynaphthalene (1-OHN): 0.86 (95% CI: 0.11-0.96). CONCLUSIONS: High levels of urine OH-PAHs were found in Hanoi street workers. No effect was seen on urine OH-PAH levels by wearing R95 particulate respirators in an area of high urban air pollution, except for 1-OHN. A lack of effect may be de to gaseous phase PAHs that were not filtered efficiently by the respirator. The high levels of urinary OH-PAHs found, urges for effective interventions. TRIAL REGISTRATION: ISRCTN74390617 (date of assignation: 04/08/2009).

Baird JK. 2012. Reinventing primaquine for endemic malaria. Expert Opin Emerg Drugs, 17 (4), pp. 439-444. | Citations: 7 (Scopus) | Show Abstract | Read more

After sixty years of continuous use, primaquine remains the only therapy licensed for arresting transmission and relapse of malaria. The US Army developed primaquine for soldiers in a wartime crisis setting. Dosing strategies suited to that narrow population were adopted without modification or validation for the broader population of humans exposed to risk of malaria. The poor suitability of these strategies in populations exhibiting greater vulnerability to hemolytic toxicity among glucose-6-phosphate dehydrogenase deficient patients has not been addressed. Primaquine requires chemotherapeutic reinvention delivering less threatening doses by leveraging unexplored co-drug synergies.

Preston MD, Manske M, Horner N, Assefa S, Campino S, Auburn S, Zongo I, Ouedraogo J-B, Nosten F, Anderson T, Clark TG. 2012. VarB: a variation browsing and analysis tool for variants derived from next-generation sequencing data. Bioinformatics, 28 (22), pp. 2983-2985. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

SUMMARY: There is an immediate need for tools to both analyse and visualize in real-time single-nucleotide polymorphisms, insertions and deletions, and other structural variants from new sequence file formats. We have developed VarB software that can be used to visualize variant call format files in real time, as well as identify regions under balancing selection and informative markers to differentiate user-defined groups (e.g. populations). We demonstrate its utility using sequence data from 50 Plasmodium falciparum isolates comprising two different continents and confirm known signals from genomic regions that contain important antigenic and anti-malarial drug-resistance genes. AVAILABILITY AND IMPLEMENTATION: The C++-based software VarB and user manual are available from www.pathogenseq.org/varb. CONTACT: taane.clark@lshtm.ac.uk

Maude RJ, Hasan MU, Hossain MA, Sayeed AA, Kanti Paul S, Rahman W, Maude RR, Vaid N, Ghose A, Amin R et al. 2012. Temporal trends in severe malaria in Chittagong, Bangladesh. Malar J, 11 (1), pp. 323. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Epidemiological data on malaria in Bangladesh are sparse, particularly on severe and fatal malaria. This hampers the allocation of healthcare provision in this resource-poor setting. Over 85% of the estimated 150,000-250,000 annual malaria cases in Bangladesh occur in Chittagong Division with 80% in the Chittagong Hill Tracts (CHT). Chittagong Medical College Hospital (CMCH) is the major tertiary referral hospital for severe malaria in Chittagong Division. METHODS: Malaria screening data from 22,785 inpatients in CMCH from 1999-2011 were analysed to investigate the patterns of referral, temporal trends and geographical distribution of severe malaria in Chittagong Division, Bangladesh. RESULTS: From 1999 till 2011, 2,394 malaria cases were admitted, of which 96% harboured Plasmodium falciparum and 4% Plasmodium vivax. Infection was commonest in males (67%) between 15 and 34 years of age. Seasonality of malaria incidence was marked with a single peak in P. falciparum transmission from June to August coinciding with peak rainfall, whereas P. vivax showed an additional peak in February-March possibly representing relapse infections. Since 2007 there has been a substantial decrease in the absolute number of admitted malaria cases. Case fatality in severe malaria was 18% from 2008-2011, remaining steady during this period.A travel history obtained in 226 malaria patients revealed only 33% had been to the CHT in the preceding three weeks. Of all admitted malaria patients, only 9% lived in the CHT, and none in the more remote malaria endemic regions near the Indian border. CONCLUSIONS: The overall decline in admitted malaria cases to CMCH suggests recent control measures are successful. However, there are no reliable data on the incidence of severe malaria in the CHT, the most endemic area of Bangladesh, and most of these patients do not reach tertiary health facilities. Improvement of early treatment and simple supportive care for severe malaria in remote areas and implementation of a referral system for cases requiring additional supportive care could be important contributors to further reducing malaria-attributable disease and death in Bangladesh.

Ezard N, Thiptharakun S, Nosten F, Rhodes T, McGready R. 2012. Risky alcohol use among reproductive-age men, not women, in Mae La refugee camp, Thailand, 2009. Confl Health, 6 (1), pp. 7. | Citations: 11 (Scopus) | Show Abstract | Read more

UNLABELLED: BACKGROUND: Globally, alcohol use contributes to close to 4% of all deaths and is a leading cause of ill health and premature death among men of reproductive age. Problem alcohol use is an unaddressed public health issue among populations displaced by conflict. Assessing the magnitude of the problem and identifying affected groups and risk behaviours is difficult in mobile and unstable populations. METHODS: From 15-28 December 2009 we conducted a simple rapid screening test of risky alcohol use using the single item modified Short Assessment Screening Questionnaire (mSASQ) by all women currently enrolled in the antenatal care clinic in Mae La refugee camp, a long standing displaced setting on the Thai Burma border. Women self- reported and gave a secondary report of their male partners. Gender differences in alcohol use were further explored in semi-structured interviews with camp residents on attitudes, behaviours, and beliefs regarding alcohol and analysed thematically. RESULTS: Of 636 women screened in the antenatal clinic, almost none (0.2%, 95CI 0.0-0.9%) reported risky alcohol use prior to pregnancy, whereas around a quarter (24.4%, 95CI 21.2-27.9%) reported risky alcohol use by their male partners. Interviews with 97 camp residents described strong social controls against women's alcohol use and men's drinking to intoxication, despite a dominant perception that the social context of life in displacement promoted alcohol use and that controls are loosening. CONCLUSIONS: As a stigmatised behaviour, alcohol use is difficult to assess, particularly in the context of highly mobile adult male populations: the simple assessment methods here show that it is feasible to obtain adequate data for the purposes of intervention design. The data suggest that risky drinking is common and normalised among men, but that the population may have been partially protected from rapid rises in problem alcohol use observed in nation-wide data from Thailand. The changing social context contains vulnerabilities that might promote problem alcohol use: further investigation, ongoing monitoring, and development of targeted interventions are warranted.

Fowkes FJI, McGready R, Cross NJ, Hommel M, Simpson JA, Elliott SR, Richards JS, Lackovic K, Viladpai-Nguen J, Narum D et al. 2012. New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women. J Infect Dis, 206 (10), pp. 1612-1621. | Citations: 48 (Scopus) | Show Abstract | Read more

BACKGROUND: How antimalarial antibodies are acquired and maintained during pregnancy and boosted after reinfection with Plasmodium falciparum and Plasmodium vivax is unknown. METHODS: A nested case-control study of 467 pregnant women (136 Plasmodium-infected cases and 331 uninfected control subjects) in northwestern Thailand was conducted. Antibody levels to P. falciparum and P. vivax merozoite antigens and the pregnancy-specific PfVAR2CSA antigen were determined at enrollment (median 10 weeks gestation) and throughout pregnancy until delivery. RESULTS: Antibodies to P. falciparum and P. vivax were highly variable over time, and maintenance of high levels of antimalarial antibodies involved highly dynamic responses resulting from intermittent exposure to infection. There was evidence of boosting with each successive infection for P. falciparum responses, suggesting the presence of immunological memory. However, the half-lives of Plasmodium antibody responses were relatively short, compared with measles (457 years), and much shorter for merozoite responses (0.8-7.6 years), compared with PfVAR2CSA responses (36-157 years). The longer half-life of antibodies to PfVAR2CSA suggests that antibodies acquired in one pregnancy may be maintained to protect subsequent pregnancies. CONCLUSIONS: These findings may have important practical implications for predicting the duration of vaccine-induced responses by candidate antigens and supports the development of malaria vaccines to protect pregnant women.

Zugna D, Geskus RB, De Stavola B, Rosinska M, Bartmeyer B, Boufassa F, Chaix M-L, Babiker A, Porter K, CASCADE Collaboration in EuroCoord. 2012. Time to virological failure, treatment change and interruption for individuals treated within 12 months of HIV seroconversion and in chronic infection. Antivir Ther, 17 (6), pp. 1039-1048. | Citations: 3 (Scopus) | Show Abstract | Read more

BACKGROUND: Estimates of treatment failure, change and interruption are lacking for individuals treated in early HIV infection. METHODS: Using CASCADE data, we compared the effect of treatment in early infection (within 12 months of seroconversion) with that seen in chronic infection on risk of virological failure, change and interruption. Failure was defined as two subsequent measures of HIV RNA>1,000 copies/ml following suppression (<500 copies/ml), or >500 copies/ml 6 months following initiation. Treatment change and interruption were defined as modification or interruption lasting >1 week. In multivariable competing risks proportional subdistribution hazards models, we adjusted for combination antiretroviral therapy (cART) class, sex, risk group, age, CD4(+) T-cell count, HIV RNA and calendar period at treatment initiation. RESULTS: Of 1,627 individuals initiating cART early (median 1.8 months from seroconversion), 159, 395 and 692 failed, changed and interrupted therapy, respectively. For 2,710 individuals initiating cART in chronic infection (median 35.9 months from seroconversion), the corresponding values were 266, 569 and 597. Adjusted hazard ratios (HRs; 95% CIs) for treatment failure and change were similar between the two treatment groups (0.93 [0.72, 1.20] and 1.06 [0.91, 1.24], respectively). There was an increasing trend in rates of interruption over calendar time for those treated early, and a decreasing trend for those starting treatment in chronic infection. Consequently, compared with chronic infection, treatment interruption was similar for early starters in the early cART period, but the relative hazard increased over calendar time (1.54 [1.33, 1.79] in 2000). CONCLUSIONS: Individuals initiating treatment in early HIV infection are more likely to interrupt treatment than those initiating later. However, rates of failure and treatment change were similar between the two groups.

Gething PW, Elyazar IRF, Moyes CL, Smith DL, Battle KE, Guerra CA, Patil AP, Tatem AJ, Howes RE, Myers MF et al. 2012. A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis, 6 (9), pp. e1814. | Citations: 283 (Scopus) | Show Abstract | Read more

BACKGROUND: Current understanding of the spatial epidemiology and geographical distribution of Plasmodium vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination. Here we present the first systematic effort to map the global endemicity of this hitherto neglected parasite. METHODOLOGY AND FINDINGS: We first updated to the year 2010 our earlier estimate of the geographical limits of P. vivax transmission. Within areas of stable transmission, an assembly of 9,970 geopositioned P. vivax parasite rate (PvPR) surveys collected from 1985 to 2010 were used with a spatiotemporal Bayesian model-based geostatistical approach to estimate endemicity age-standardised to the 1-99 year age range (PvPR(1-99)) within every 5×5 km resolution grid square. The model incorporated data on Duffy negative phenotype frequency to suppress endemicity predictions, particularly in Africa. Endemicity was predicted within a relatively narrow range throughout the endemic world, with the point estimate rarely exceeding 7% PvPR(1-99). The Americas contributed 22% of the global area at risk of P. vivax transmission, but high endemic areas were generally sparsely populated and the region contributed only 6% of the 2.5 billion people at risk (PAR) globally. In Africa, Duffy negativity meant stable transmission was constrained to Madagascar and parts of the Horn, contributing 3.5% of global PAR. Central Asia was home to 82% of global PAR with important high endemic areas coinciding with dense populations particularly in India and Myanmar. South East Asia contained areas of the highest endemicity in Indonesia and Papua New Guinea and contributed 9% of global PAR. CONCLUSIONS AND SIGNIFICANCE: This detailed depiction of spatially varying endemicity is intended to contribute to a much-needed paradigm shift towards geographically stratified and evidence-based planning for P. vivax control and elimination.

Lee SJ, Newton PN. 2012. Use of the correlation coefficient to compare a point-of-care antigen test against a quantitative sandwich enzyme-linked immunosorbent assay for the detection of cryptococcal meningitis. Clin Infect Dis, 55 (12), pp. 1744-1745. | Citations: 2 (Scopus) | Read more

Turner P, Willemse C, Phakaudom K, Zin TW, Nosten F, McGready R. 2012. Aeromonas spp. bacteremia in pregnant women, Thailand-Myanmar border, 2011. Emerg Infect Dis, 18 (9), pp. 1522-1523. | Citations: 3 (Scopus) | Read more

Simmons CP, Wolbers M, Nguyen MN, Whitehorn J, Shi PY, Young P, Petric R, Nguyen VVC, Farrar J, Wills B. 2012. Therapeutics for dengue: recommendations for design and conduct of early-phase clinical trials. PLoS Negl Trop Dis, 6 (9), pp. e1752. | Citations: 21 (Scopus) | Read more

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection (vol 42, pg 535, 2012) INTERNATIONAL JOURNAL FOR PARASITOLOGY, 42 (10), pp. 961-961. | Read more

Basnyat B. 2012. Acclimatizing with acetazolamide. J Travel Med, 19 (5), pp. 281-283. | Citations: 3 (Web of Science Lite) | Read more

Cushing TA, McIntosh SE, Keyes LE, Rodway GW, Schoene RB, Basnyat B, Freer L. 2012. Performance-enhancing drugs-commentaries. Wilderness Environ Med, 23 (3), pp. 207-211. | Citations: 5 (Scopus) | Read more

Thomas S, Thomson G, Dowall S, Bruce C, Cook N, Easterbrook L, O'Donoghue L, Summers S, Ajazaj L, Hewson R et al. 2012. Review of Crimean Congo hemorrhagic fever infection in Kosova in 2008 and 2009: prolonged viremias and virus detected in urine by PCR. Vector Borne Zoonotic Dis, 12 (9), pp. 800-804. | Show Abstract | Read more

Crimean-Congo hemorrhagic fever (CCHF) is a virus transmitted predominantly by ticks. However, contact with infected body fluids or tissues can result in animal-to-human or human-to-human transmission. Numbers of CCHF cases appear to be increasing, especially in Europe. We reviewed cases admitted to a tertiary referral unit in Kosova with suspected CCHF in 2008 and 2009, and looked at a smaller number of specimens which were sent to the Health Protection Agency, Porton Down, U.K., in further detail. The clinical features of cases admitted with suspected CCHF infection were assessed in more detail, and these are the focus of this article. Between 2008 and 2009, the numbers of patients admitted for suspected CCHF infection increased. Of the samples received in Porton Down, CCHF virus was detected in urine samples, and these patients were found to have prolonged viremia. The detection of CCHF in urine, as well as the prolonged viremias seen, are important for clinicians to know, as they may have public health implications with regard to the risk of infection, as well as provide insights into the biology and pathophysiology of infection. Further studies are required regarding the pathogenesis of this virus.

Thomson G, Glaser V. 2012. Gail Thomson, M.D. Health Protection Agency (HPA), Porton, United Kingdom. Vector Borne Zoonotic Dis, 12 (9), pp. 715-717. | Read more

Sigaloff KCE, Mandaliya K, Hamers RL, Otieno F, Jao IM, Lyagoba F, Magambo B, Kapaata A, Ndembi N, Rinke de Wit TF. 2012. Short communication: High prevalence of transmitted antiretroviral drug resistance among newly HIV type 1 diagnosed adults in Mombasa, Kenya. AIDS Res Hum Retroviruses, 28 (9), pp. 1033-1037. | Citations: 12 (Scopus) | Show Abstract | Read more

Abstract In view of the recent antiretroviral therapy (ART) scale-up in Kenya, surveillance of transmitted HIV drug resistance (TDR) is important. A cross-sectional survey was conducted among newly HIV-1 diagnosed, antiretroviral-naive adults in Mombasa, Kenya. Surveillance drug resistance mutations (SDRMs) were identified according to the 2009 WHO list. HIV-1 subtypes were determined using REGA and SCUEAL subtyping tools. Genotypic test results were obtained for 68 of 81 participants, and SDRMs were identified in 9 samples. Resistance to nonnucleoside reverse transcriptase inhibitors (K103N) occurred in five participants, yielding a TDR prevalence of 7.4% (95% confidence interval 2.4-16.3%). Frequencies of HIV-1 subtypes were A (70.6%), C (5.9%), D (2.9%), and unique recombinant forms (20.6%). The TDR prevalence found in this survey is higher than previously reported in different regions in Kenya. These findings justify increased vigilance with respect to TDR surveillance in African regions where ART programs are scaled-up in order to inform treatment guidelines.

Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, Zhou C, Mao S, Anderson JM, Lindegardh N et al. 2012. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis, 12 (11), pp. 851-858. | Citations: 176 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. METHODS: Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10,000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD, which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum: age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. FINDINGS: We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54-6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean parasite heritability of half-life was 0·40 (SD 0·17). INTERPRETATION: Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. FUNDING: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Tarning J, Chotsiri P, Jullien V, Rijken MJ, Bergstrand M, Cammas M, McGready R, Singhasivanon P, Day NPJ, White NJ et al. 2012. Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy. Antimicrob Agents Chemother, 56 (11), pp. 5764-5773. | Citations: 20 (Scopus) | Show Abstract | Read more

Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.

Vithana EN, Khor C-C, Qiao C, Nongpiur ME, George R, Chen L-J, Do T, Abu-Amero K, Huang CK, Low S et al. 2012. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. Nat Genet, 44 (10), pp. 1142-1146. | Citations: 73 (Web of Science Lite) | Show Abstract | Read more

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33×10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22×10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29×10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Hamers RL, Sawyer AW, Tuohy M, Stevens WS, Rinke de Wit TF, Hill AM, ART-A Consortium. 2012. Cost-effectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis. AIDS, 26 (13), pp. 1663-1672. | Citations: 38 (Scopus) | Show Abstract | Read more

OBJECTIVE: To compare the cost-effectiveness of three different strategies for long-term monitoring of antiretroviral therapy (ART) failure and regimen switching in sub-Saharan Africa: a symptom-based approach, or monitoring of either CD4 cell counts or plasma viral load (pVL). DESIGN: Markov model. SETTING AND PARTICIPANTS: Hypothetical HIV-infected adult population who began first-line ART and subsequently had up to 6 years of follow-up. MAIN OUTCOME MEASURES: Total cost, life expectancy and incremental cost-effectiveness ratio (ICER). RESULTS: A symptom-based approach yielded a life expectancy of 64.0 months at a total cost of US$ 4028 per person. All laboratory-based strategies, at testing intervals of 6 or 12 months, were cost-saving and improved life expectancy, compared with a symptom-based approach. The life-expectancy gain was larger for pVL than for CD4 strategies at 6-monthly (2.3 and 0.9 months, respectively) and 12-monthly testing (2.0 and 0.8 months, respectively). Cost-savings of 6-monthly pVL or CD4 testing were similar (US$ 630 and 621, respectively), whereas 12-monthly CD4 cell counts were more cost-saving than 12-monthly pVL (US$ 1132 and 880, respectively). Testing every 12 months - rather than every 6 months - decreased the ICER by 102% for CD4 cell count and 67% for pVL. These findings were robust to a wide range of deterministic sensitivity analyses, but were sensitive to the specificity and costs of diagnostic tests. CONCLUSION: Additional diagnostic costs are balanced by cost-savings from avoiding unnecessary switching due to misdiagnosis of ART failure. Routine pVL monitoring may be preferred as a replacement for CD4 cell counts because of its additional public-health advantages in preventing drug-resistance, supporting adherence and reducing HIV transmission.

Tarning J, Kloprogge F, Piola P, Dhorda M, Muwanga S, Turyakira E, Nuengchamnong N, Nosten F, Day NPJ, White NJ et al. 2012. Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda. Malar J, 11 (1), pp. 293. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. METHODS: Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. RESULTS: The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. CONCLUSION: The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

Hamers RL, Kityo C, Lange JMA, de Wit TFR, Mugyenyi P. 2012. Global threat from drug resistant HIV in sub-Saharan Africa. BMJ, 344 (jun18 1), pp. e4159. | Citations: 24 (Scopus) | Read more

Joshi VS, Maude RJ, Reinhardt JM, Tang L, Garvin MK, Abu Sayeed A, Ghose A, Hassan MU, Abràmoff MD. 2012. Automated detection of malarial retinopathy-associated retinal hemorrhages. Invest Ophthalmol Vis Sci, 53 (10), pp. 6582-6588. | Citations: 8 (Scopus) | Show Abstract | Read more

PURPOSE: To develop an automated method for the detection of retinal hemorrhages on color fundus images to characterize malarial retinopathy, which may help in the assessment of patients with cerebral malaria. METHODS: A fundus image dataset from 14 patients (200 fundus images, with an average of 14 images per patient) previously diagnosed with malarial retinopathy was examined. We developed a pattern recognition-based algorithm, which extracted features from image watershed regions called splats (tobogganing). A reference standard was obtained by manual segmentation of hemorrhages, which assigned a label to each splat. The splat features with the associated splat label were used to train a linear k-nearest neighbor classifier that learnt the color properties of hemorrhages and identified the splats belonging to hemorrhages in a test dataset. In a crossover design experiment, data from 12 patients were used for training and data from two patients were used for testing, with 14 different permutations; and the derived sensitivity and specificity values were averaged. RESULTS: The experiment resulted in hemorrhage detection sensitivities in terms of splats as 80.83%, and in terms of lesions as 84.84%. The splat-based specificity was 96.67%, whereas for the lesion-based analysis, an average of three false positives was obtained per image. The area under the receiver operating characteristic curve was reported as 0.9148 for splat-based, and as 0.9030 for lesion-based analysis. CONCLUSIONS: The method provides an automated means of detecting retinal hemorrhages associated with malarial retinopathy. The results matched well with the reference standard. With further development, this technique may provide automated assistance for screening and quantification of malarial retinopathy.

John GK, Douglas NM, von Seidlein L, Nosten F, Baird JK, White NJ, Price RN. 2012. Primaquine radical cure of Plasmodium vivax: a critical review of the literature. Malar J, 11 (1), pp. 280. | Citations: 83 (Scopus) | Show Abstract | Read more

BACKGROUND: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. METHODS: Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. RESULTS: Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001). CONCLUSIONS: Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.

Larsson M, Nguyen LHT, Wertheim HF, Dao TT, Taylor W, Horby P, Nguyen TV, Nguyen MHT, Le T, Nguyen KV. 2012. Clinical characteristics and outcome of Penicillium marneffei infection among HIV-infected patients in northern Vietnam. AIDS Res Ther, 9 (1), pp. 24. | Citations: 18 (Scopus) | Show Abstract | Read more

OBJECTIVE: This study reports the clinical characteristics and outcome of HIV-associated Penicilliummarneffei infection in northern Vietnam. METHODS: We conducted a retrospective chart review of all patients with laboratory confirmed Penicilliummarneffei infection admitted to the National Hospital for Tropical Diseases in Hanoi, Vietnam, between July 2006 and September 2009. RESULTS: 127 patients with P. marneffei infection were identified. All were HIV-infected; median CD4+ T-cell count was 24 cells/μl (IQR:12-48); 76% were men. Common clinical features were fever (92.9%), skin lesions (82.6%), hepatomegaly (61.4%), lymphadenopathy (40.2%), weight loss (59.1%) and cough (49.6%). Concurrent opportunistic infections were present in 22.0%; half of those had tuberculosis. Initial treatment regimens were: itraconazole or ketoconazole capsule (77.2%), amphotericin B (20.5%), and fluconazole (1.6%). In-hospital mortality was 12.6% and showed no significant difference in patients treated with itraconazole (or ketoconazole) and amphotericin B (p = 0.43). Dyspnea, ascites, and increased LDH level were independent predictors of mortality. No seasonality was observed. CONCLUSION: The clinical features, treatments and outcomes of HIV-associated P. marneffei infection in northern Vietnam are similar to those reported in other endemic regions. Dyspnea was an important predictor of mortality. More patients were treated with itraconazole than amphotericin B and no significant difference in treatment outcome was observed. It would be of clinical value to compare the efficacy of oral itraconazole and amphotericin B in a clinical trial.

Ramutton T, Hendriksen ICE, Mwanga-Amumpaire J, Mtove G, Olaosebikan R, Tshefu AK, Onyamboko MA, Karema C, Maitland K, Gomes E et al. 2012. Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria. Malar J, 11 (1), pp. 276. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements. METHODS: Studies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania. RESULTS: There was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration. CONCLUSIONS: These findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.

Jonker FAM, Calis JCJ, van Hensbroek MB, Phiri K, Geskus RB, Brabin BJ, Leenstra T. 2012. Iron status predicts malaria risk in Malawian preschool children. PLoS One, 7 (8), pp. e42670. | Citations: 35 (Scopus) | Show Abstract | Read more

INTRODUCTION: Iron deficiency is highly prevalent in pre-school children in developing countries and an important health problem in sub-Saharan Africa. A debate exists on the possible protective effect of iron deficiency against malaria and other infections; yet consensus is lacking due to limited data. Recent studies have focused on the risks of iron supplementation but the effect of an individual's iron status on malaria risk remains unclear. Studies of iron status in areas with a high burden of infections often are exposed to bias. The aim of this study was to assess the predictive value of baseline iron status for malaria risk explicitly taking potential biases into account. METHODS AND MATERIALS: We prospectively assessed the relationship between baseline iron deficiency (serum ferritin <30 µg/L) and malaria risk in a cohort of 727 Malawian preschool children during a year of follow-up. Data were analyzed using marginal structural Cox regression models and confounders were selected using causal graph theory. Sensitivity of results to bias resulting from misclassification of iron status by concurrent inflammation and to bias from unmeasured confounding were assessed using modern causal inference methods. RESULTS AND CONCLUSIONS: The overall incidence of malaria parasitemia and clinical malaria was 1.9 (95% CI 1.8-2.0) and 0.7 (95% CI 0.6-0.8) events per person-year, respectively. Children with iron deficiency at baseline had a lower incidence of malaria parasitemia and clinical malaria during a year of follow-up; adjusted hazard ratio's 0.55 (95%-CI:0.41-0.74) and 0.49 (95%-CI:0.33-0.73), respectively. Our results suggest that iron deficiency protects against malaria parasitemia and clinical malaria in young children. Therefore the clinical importance of treating iron deficiency in a pre-school child should be weighed carefully against potential harms. In malaria endemic areas treatment of iron deficiency in children requires sustained prevention of malaria.

Heymans R, A Matser A, Bruisten SM, Heijman T, Geskus RB, Speksnijder AGCL, Davidovich U, de Vries HJC, Coutinho RA, Schim van der Loeff MF. 2012. Distinct Neisseria gonorrhoeae transmission networks among men who have sex with men in Amsterdam, The Netherlands. J Infect Dis, 206 (4), pp. 596-605. | Citations: 15 (Scopus) | Show Abstract | Read more

BACKGROUND: Molecular typing was used to elucidate Neisseria gonorrhoeae transmission networks among men who have sex with men (MSM) in Amsterdam, the Netherlands. We determined whether clusters of patients infected with specific N. gonorrhoeae genotypes were related to various epidemiological characteristics. METHODS: MSM (age ≥18 years) visiting the sexually transmitted infections (STI) clinic between July 2008 and August 2009 were eligible. After STI screening, participants completed a behavioral questionnaire concerning the previous 6 months. N. gonorrhoeae cultures were genotyped using multiple-locus variable-number tandem repeat analysis typing. RESULTS: We obtained 278 N. gonorrhoeae-positive isolates from 240 MSM. Five large clusters (≥10 isolates), a unique sixth cluster (n = 9), and 8 smaller clusters (5-9 isolates) were identified. Prevalence of human immunodeficiency virus differed between clusters I and VI (P = .003), ranging from 27.8% to 100%. Receptive unprotected anal intercourse was frequently reported by MSM (51.8%) but did not differ significantly among clusters. Significant differences were identified concerning the participant's history of syphilis (P = .030), having met partners at a popular sex venue in Amsterdam (P = .048), and meeting partners outside Amsterdam (P = .036). CONCLUSIONS: Distinct N. gonorrhoeae transmission networks were present in a mixed high-risk MSM population; concordance between clusters and epidemiological characteristics was present but not marked.

White NJ, Dondorp AM, Faiz A, Mishra S, Hien TT. 2012. New global estimates of malaria deaths. Lancet, 380 (9841), pp. 559-560. | Citations: 11 (Web of Science Lite) | Read more

Devine A, Spencer A, Eldridge S, Norman R, Feder G. 2012. Cost-effectiveness of Identification and Referral to Improve Safety (IRIS), a domestic violence training and support programme for primary care: a modelling study based on a randomised controlled trial. BMJ Open, 2 (3), pp. e001008-e001008. | Citations: 10 (Scopus) | Show Abstract | Read more

OBJECTIVE: The Identification and Referral to Improve Safety (IRIS) cluster randomised controlled trial tested the effectiveness of a training and support intervention to improve the response of primary care to women experiencing domestic violence (DV). The aim of this study is to estimate the cost-effectiveness of this intervention. DESIGN: Markov model-based cost-effectiveness analysis. SETTING: General practices in two urban areas in the UK. PARTICIPANTS: Simulated female individuals from the general UK population who were registered at general practices, aged 16 years and older. INTERVENTION: General practices received staff training, prompts to ask women about DV embedded in the electronic medical record, a care pathway including referral to a specialist DV agency and continuing contact from that agency. The trial compared the rate of referrals of women with specialist DV agencies from 24 general practices that received the IRIS programme with 24 general practices not receiving the programme. The trial did not measure outcomes for women beyond the intermediate outcome of referral to specialist agencies. The Markov model extrapolated the trial results to estimate the long-term healthcare and societal costs and benefits using data from other trials and epidemiological studies. RESULTS: The intervention would produce societal cost savings per woman registered in the general practice of UK£37 (95% CI £178 saved to a cost of £136) over 1 year. The incremental quality-adjusted life-year was estimated to be 0.0010 (95% CI -0.0157 to 0.0101) per woman. Probabilistic sensitivity analysis found 78% of model replications under a willingness to pay threshold of £20 000 per quality-adjusted life-year. CONCLUSIONS: The IRIS programme is likely to be cost-effective and possibly cost saving from a societal perspective. Better data on the trajectory of abuse and the effect of advocacy are needed for a more robust model. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN74012786.

Weerasuriya CK, Tan SO, Alexakis LC, Set AK, Rijken MJ, Martyn P, Nosten F, McGready R. 2012. Evaluation of a surgical service in the chronic phase of a refugee camp: an example from the Thai-Myanmar border. Confl Health, 6 (1), pp. 5. | Citations: 7 (Scopus) | Show Abstract | Read more

UNLABELLED: BACKGROUND: Published literature on surgical care in refugees tends to focus on the acute ('emergent') phase of crisis situations. Here we posit that there is a substantial burden of non-acute morbidity amenable to surgical intervention among refugees in the 'chronic' phase of crisis situations. We describe surgery for non-acute conditions undertaken at Mae La Refugee Camp, Thailand over a two year period. METHODS: Surgery was performed by a general surgeon in a dedicated room of Mae La Refugee Camp over May 2005 to April 2007 with minimal instruments and staff. We obtained the equivalent costs for these procedures if they were done at the local Thai District General Hospital. We also acquired the list (and costs) of acute surgical referrals to the District General Hospital over September 2006 to December 2007. RESULTS: 855 operations were performed on 847 patients in Mae La Refugee Camp (60.1% sterilizations, 13.3% 'general surgery', 5.6% 'gynaecological surgery', 17.4% 'mass excisions', 3.5% 'other'). These procedures were worth 2,207,500 THB (75,683.33 USD) at costs quoted by the District General Hospital. Total cost encountered for these operations (including staff costs, consumables, anaesthesia and capital costs such as construction) equaled 1,280,000 THB (42,666 USD). Pertaining to acute surgical referrals to District General hospital: we estimate that 356,411.96 THB (11,880.40 USD) worth of operations over 14 months were potentially preventable if these cases had been operated at an earlier, non-acute state in Mae La Refugee Camp. CONCLUSIONS: A considerable burden of non-acute surgical morbidity exists in 'chronic' refugee situations. An in-house general surgical service is found to be cost-effective in relieving some of this burden and should be considered by policy makers as a viable intervention.

Tam DTH, Ngoc TV, Tien NTH, Kieu NTT, Thuy TTT, Thanh LTC, Tam CT, Truong NT, Dung NT, Qui PT et al. 2012. Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial. Clin Infect Dis, 55 (9), pp. 1216-1224. | Citations: 76 (Scopus) | Show Abstract | Read more

BACKGROUND: Patients with dengue can experience a variety of serious complications including hypovolemic shock, thrombocytopenia, and bleeding. These problems occur as plasma viremia is resolving and are thought to be immunologically mediated. Early corticosteroid therapy may prevent the development of such complications but could also prolong viral clearance. METHODS: We performed a randomized, placebo-controlled, blinded trial of low-dose (0.5 mg/kg) or high-dose (2 mg/kg) oral prednisolone therapy for 3 days in Vietnamese patients aged 5-20 years admitted with dengue and fever for ≤72 hours, aiming to assess potential harms from steroid use during the viremic phase. Intention-to-treat analysis was performed using linear trend tests with a range of clinical and virological endpoints specified in advance. In addition to recognized complications of dengue, we focused on the are under the curve for serial plasma viremia measurements and the number of days after enrollment to negative viremia and dengue nonstructural protein 1 status. RESULTS: Between August 2009 and January 2011, 225 participants were randomized to 1 of the 3 treatment arms. Baseline characteristics were similar across the groups. All patients recovered fully and adverse events were infrequent. Aside from a trend toward hyperglycemia in the steroid recipients, we found no association between treatment allocation and any of the predefined clinical, hematological, or virological endpoints. CONCLUSIONS: Use of oral prednisolone during the early acute phase of dengue infection was not associated with prolongation of viremia or other adverse effects. Although not powered to assess efficacy, we found no reduction in the development of shock or other recognized complications of dengue virus infection in this study.

Chan J-A, Howell KB, Reiling L, Ataide R, Mackintosh CL, Fowkes FJI, Petter M, Chesson JM, Langer C, Warimwe GM et al. 2012. Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity. J Clin Invest, 122 (9), pp. 3227-3238. | Citations: 78 (Scopus) | Show Abstract | Read more

Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

Fairhurst RM, Nayyar GML, Breman JG, Hallett R, Vennerstrom JL, Duong S, Ringwald P, Wellems TE, Plowe CV, Dondorp AM. 2012. Artemisinin-resistant malaria: research challenges, opportunities, and public health implications. Am J Trop Med Hyg, 87 (2), pp. 231-241. | Citations: 89 (Scopus) | Show Abstract | Read more

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance.

Gharbi M, Pillai DR, Lau R, Hubert V, Khairnar K, Existe A, Kendjo E, Dahlström S, Guérin PJ, Le Bras J, French National Reference Center for Imported Malaria Study. 2012. Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake. Emerg Infect Dis, 18 (8), pp. 1346-1349. | Citations: 14 (Scopus) | Show Abstract | Read more

We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance.

Conlan JV, Vongxay K, Khamlome B, Dorny P, Sripa B, Elliot A, Blacksell SD, Fenwick S, Thompson RCA. 2012. A cross-sectional study of Taenia solium in a multiple taeniid-endemic region reveals competition may be protective. Am J Trop Med Hyg, 87 (2), pp. 281-291. | Citations: 20 (Scopus) | Show Abstract | Read more

We conducted cross-sectional surveys for taeniasis and cysticercosis in humans, pigs, and dogs in four northern provinces of Laos. Human cysticercosis and taeniasis prevalence was 2.2% (95% confidence interval [CI] = 1.4-3.0%) and 8.4% (95% CI = 6.9-9.9%), respectively. Eating uncooked beef, being male, province of residence, age, and ethnicity were significant risk factors for taeniasis and only province of residence was a significant risk factor for cystiercosis. Thirty-five human tapeworms were recovered during the survey and 33 (94.3%) and 2 (5.7%) were identified as Taenia saginata and T. solium, respectively. Maximum-likelihood adjusted prevalence of T. solium and T. hydatigena in pigs was 4.2% (95% CI = 0.5-7.9%) and 55.9% (95% CI = 47.5-64.3%), respectively, and T. hydatigena taeniasis in dogs was 4.8% (95% CI = 0.0-11.3%). Taenia hydatigena and T. saginata were the most prevalent taeniids in the respective pig and human populations and together may suppress T. solium transmission.

Hendriksen ICE, Mwanga-Amumpaire J, von Seidlein L, Mtove G, White LJ, Olaosebikan R, Lee SJ, Tshefu AK, Woodrow C, Amos B et al. 2012. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med, 9 (8), pp. e1001297. | Citations: 59 (Scopus) | Show Abstract | Read more

BACKGROUND: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. METHODS AND FINDINGS: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. CONCLUSIONS: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.

Duenser MW, Festic E, Dondorp A, Kissoon N, Ganbat T, Kwizera A, Haniffa R, Baker T, Schultz MJ, Med ESIC. 2012. Point of care ultrasound for sepsis management in resource-limited settings: response to Via et al. INTENSIVE CARE MEDICINE, 38 (8), pp. 1408-1409. | Read more

Read RC, Carson G. 2012. Using the NIHR Comprehensive Clinical Research Network for infectious diseases and microbiology research. J Infect, 65 (2), pp. 99-101. | Read more

Heuker J, Sonder G, Stolte I, Geskus R, van den Hoek A. 2012. HIV incidence among men who have sex with men prescribed postexposure prophylaxis AIDS, 26 (12), pp. 1583-1584. | Read more

Blacksell SD, Lee SJ, Chanthongthip A, Taojaikong T, Thongpaseuth S, Hübscher T, Newton PN. 2012. Comparison of performance of serum and plasma in panbio dengue and Japanese encephalitis virus enzyme-linked immunosorbent assays. Am J Trop Med Hyg, 87 (3), pp. 573-575. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

We examined the comparative performance of serum and plasma (in dipotassium EDTA) in Panbio Dengue enzyme-linked immunosorbent assays (ELISAs) for detection of non-structural protein 1 (NS1), IgM, and IgG, and a dengue/Japanese encephalitis virus (JEV) combination IgM ELISA in a prospective series of 201 patients with suspected dengue in Laos. Paired comparisons of medians from serum and plasma samples were not significantly different for Dengue IgM, and NS1 which had the highest number of discordant pairs (both 2%; P = 0.13 and P = 0.25, respectively). Comparison of qualitative final diagnostic interpretations for serum and plasma samples were not significantly different: only 1.5% (3 of 201 for Dengue/JEV IgM and Dengue IgG) and 2.0% (4 of 201; IgM and NS1) showed discordant pairs. These results demonstrate that plasma containing EDTA is suitable for use in these ELISAs.

Manske M, Miotto O, Campino S, Auburn S, Almagro-Garcia J, Maslen G, O'Brien J, Djimde A, Doumbo O, Zongo I et al. 2012. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature, 487 (7407), pp. 375-379. | Citations: 199 (Web of Science Lite) | Show Abstract | Read more

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

Tanganuchitcharnchai A, Smythe L, Dohnt M, Hartskeerl R, Vongsouvath M, Davong V, Lattana O, Newton PN, Blacksell SD. 2012. Evaluation of the Standard Diagnostics Leptospira IgM ELISA for diagnosis of acute leptospirosis in Lao PDR. Trans R Soc Trop Med Hyg, 106 (9), pp. 563-566. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

The diagnostic utility of the Standard Diagnostics Leptospira IgM ELISA for detection of acute leptospirosis was assessed in febrile adults admitted in Vientiane, Laos. Using the cut-off suggested by the manufacturer [optical density (OD) ≥0.75], the assay demonstrated limited diagnostic capacity with a sensitivity of 95% and a specificity of 41% compared with the Leptospira microscopic agglutination test, which is the serological gold standard. However, re-evaluation of the diagnostic cut-off to an OD of 1.7 demonstrated improved diagnostic accuracy overall (sensitivity 70%; specificity 78%).

Chue AL, Moore RL, Cavey A, Ashley EA, Stepniewska K, Nosten F, McGready R. 2012. Comparability of tympanic and oral mercury thermometers at high ambient temperatures. BMC Res Notes, 5 (1), pp. 356. | Citations: 5 (Scopus) | Show Abstract | Read more

BACKGROUND: Body temperature can be measured in seconds with tympanic thermometers as opposed to minutes with mercury ones. The aim of this study was to compare tympanic and oral mercury thermometer measurements under high ambient field temperatures. RESULTS: Tympanic temperature (measured thrice by 3 operators) was compared to oral temperature measured once with a mercury-in-glass thermometer in 201 patients (aged ≥5 years), on the Thai-Myanmar border. Ambient temperature was measured with an electronic thermo-hygrometer. Participants had a mean [min-max] age of 27 [5-60] years and 42% (84) were febrile by oral thermometer. The mean difference in the mercury and tympanic temperature measurement for all observers/devices was 0.09 (95%CI 0.07-0.12)°C and intra-class correlation for repeat tympanic measurements was high (≥0.97) for each observer. Deviations in tympanic temperatures were not related to ambient temperature. CONCLUSION: Clinically significant differences were not observed between oral and tympanic temperature measurements at high ambient temperatures in a rural tropical setting.

Chan XH, Wynn-Jones W, Lobban C. 2012. Time for an open access secure online data collection tool. BMJ, 345 (jul16 2), pp. e4805. | Citations: 1 (Scopus) | Read more

Tigoi CC, Gatakaa H, Karani A, Mugo D, Kungu S, Wanjiru E, Jomo J, Musyimi R, Ojal J, Glass NE et al. 2012. Rates of acquisition of pneumococcal colonization and transmission probabilities, by serotype, among newborn infants in Kilifi District, Kenya. Clin Infect Dis, 55 (2), pp. 180-188. | Citations: 26 (Scopus) | Show Abstract | Read more

BACKGROUND: Herd protection and serotype replacement disease following introduction of pneumococcal conjugate vaccine (PCV) are attributable to the vaccine's impact on colonization. Prior to vaccine introduction in Kenya, we did an epidemiological study to estimate the rate of pneumococcal acquisition, by serotype, in an uncolonized population. METHODS: Nasopharyngeal swab specimens were taken from newborns aged ≤ 7 days and weekly thereafter for 13 weeks. Parents, and siblings aged <10 years, were swabbed at monthly intervals. Swabs were transported in skim milk-tryptone-glucose-glycerin and cultured on gentamicin blood agar. Pneumococci were serotyped by the Quellung reaction. We used survival analysis and Cox regression analysis to examine serotype-specific acquisition rates and risk factors and calculated transmission probabilities from the pattern of acquisitions within the family. RESULTS: Of 1404 infants recruited, 887 were colonized by 3 months of age, with the earliest acquisition detected on the first day of life. The median time to acquisition was 38.5 days. The pneumococcal acquisition rate was 0.0189 acquisitions/day (95% confidence interval, .0177-.0202 acquisitions/day). Serotype-specific acquisition rates varied from 0.00002-0.0025 acquisitions/day among 49 different serotypes. Season, coryza, and exposure to cigarettes, cooking fumes, and other children in the home were each significant risk factors for acquisition. The transmission probability per 30-day duration of contact with a carrier was 0.23 (95% CI, .20-.26). CONCLUSIONS: Newborn infants in Kilifi have high rates of nasopharyngeal acquisition of pneumococci. Half of these acquisitions involve serotypes not included in any current vaccine. Several risk factors are modifiable through intervention. Newborns represent a consistent population of pneumococcus-naive individuals in which to estimate the impact of PCV on transmission.

Maude RR, Maude RJ, Ghose A, Amin MR, Islam MB, Ali M, Bari MS, Majumder MI, Wuthiekanan V, Dondorp AM et al. 2012. Seroepidemiological surveillance of Burkholderia pseudomallei in Bangladesh. Trans R Soc Trop Med Hyg, 106 (9), pp. 576-578. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

Melioidosis (Burkholderia pseudomallei infection) has yet to be demonstrated systematically in Bangladesh. A prospective, cross-sectional serological survey was conducted in 2010 at six Bangladeshi hospitals. Age, gender, occupation and residential address were recorded. Of 1244 patients, 359 (28.9%) were positive for B. pseudomallei by indirect haemagglutination assay. Farmers had an increased risk of seropositivity (risk ratio=1.4, 95% CI 1.0-1.8; p=0.03). There was no clear geographic clustering of seropositives. Melioidosis should be considered as a possible cause of febrile illness in Bangladesh. Further studies are needed to establish the incidence of clinical disease and distribution of environmental risk.

Chau NVV, Simmons CP, Wills B. 2012. Dengue REPLY NEW ENGLAND JOURNAL OF MEDICINE, 367 (2), pp. 181-181.

Siritantikorn S, Jintaworn S, Noisakran S, Suputtamongkol Y, Paris DH, Blacksell SD. 2012. Application of ImageJ program to the enumeration of Orientia tsutsugamushi organisms cultured in vitro. Trans R Soc Trop Med Hyg, 106 (10), pp. 632-635. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

The ImageJ program was applied to the enumeration of Orientia tsutsugamushi organisms in cell culture using indirect immunofluorescence assay (IFA). The highest correlation (r=0.984) was observed between manual counting methods and the ImageJ program (MaxEntropy threshold algorithm). This software-based methodology is cheaper, more standardised and better reproducible than a manual-based approach.

Tham NT, Hang VTT, Khanh TH, Viet DC, Hien TT, Farrar J, Chau NVV, van Doorn HR. 2012. Comparison of the Roche RealTime ready Influenza A/H1N1 Detection Set with CDC A/H1N1pdm09 RT-PCR on samples from three hospitals in Ho Chi Minh City, Vietnam. Diagn Microbiol Infect Dis, 74 (2), pp. 131-136. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Real-time polymerase chain reaction (PCR) can be considered the gold standard for detection of influenza viruses due to its high sensitivity and specificity. Roche has developed the RealTime ready Influenza A/H1N1 Detection Set, consisting of a generic influenza virus A PCR targeting the M2 gene (M2 PCR) and a specific PCR targeting the hemagglutinin (HA) of A/H1N1-pdm09 (HA PCR, 2009 H1N1), with the intention to make a reliable, rapid, and simple test to detect and quantify 2009 H1N1 in clinical samples. We evaluated this kit against the US Centers for Disease Control and Prevention (USCDC)/World Health Organization real-time PCR for influenza virus using 419 nose and throat swabs from 210 patients collected in 3 large hospitals in Ho Chi Minh City, Vietnam. In the per-patient analysis, when compared to CDC PCR, the sensitivity and specificity of the M2 PCR were 85.8% and 97.6%, respectively; the sensitivity and specificity of HA PCR were 88.2% and 100%, respectively. In the per-sample analysis, the sensitivity and specificity in nose swabs were higher than those in throat swabs for both M2 and HA PCRs. The viral loads as determined with the M2 and HA PCRs correlated well with the Ct values of the CDC PCR. Compared with the CDC PCR, the kit has a reasonable sensitivity and very good specificity for the detection and quantification of influenza A virus and A/H1N1-pdm09. However, given the current status of 2009 H1N1, a kit that can detect all circulating seasonal influenza viruses would be preferable.

Maude RR, Vatcharapreechasakul T, Ariyaprasert P, Maude RJ, Hongsuwan M, Yuentrakul P, Limmathurotsakul D, Koh GCKW, Chaowagul W, Day NPJ, Peacock SJ. 2012. Prospective observational study of the frequency and features of intra-abdominal abscesses in patients with melioidosis in northeast Thailand. Trans R Soc Trop Med Hyg, 106 (10), pp. 629-631. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

Retrospective case series from Thailand have reported the presence of intra-abdominal abscesses in around half of patients with melioidosis, a much higher rate than our clinical experience would suggest. We performed a prospective, observational study of 230 adult patients with culture-confirmed melioidosis in which all patients underwent abdominal ultrasound. One or more abscesses were detected in the liver and/or spleen in 77 (33%) cases. These were often multiple (70%, 31/44 in hepatic abscesses and 88%, 50/57 in splenic abscesses) and clinically silent (27% of cases with abscesses presenting with abdominal pain). The mortality rate at 4 weeks post-discharge was lower in patients who were abscess-positive vs abscess-negative (10%, 8/77 vs 20%, 31/153).

Hendriksen ICE, Ferro J, Montoya P, Chhaganlal KD, Seni A, Gomes E, Silamut K, Lee SJ, Lucas M, Chotivanich K et al. 2012. Diagnosis, clinical presentation, and in-hospital mortality of severe malaria in HIV-coinfected children and adults in Mozambique. Clin Infect Dis, 55 (8), pp. 1144-1153. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria. METHODS: HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status. RESULTS: HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P < .001). In an age- and antimalarial treatment-adjusted logistic regression model, significant, independent predictors for death were renal impairment, acidosis, parasitemia, and plasma PfHRP2 concentration. CONCLUSIONS: Severe malaria in HIV-coinfected patients presents with higher parasite burden, more complications, and comorbidity, and carries a higher case fatality rate. Early identification of HIV coinfection is important for the clinical management of severe malaria.

Rijken MJ, de Wit MC, Mulder EJH, Kiricharoen S, Karunkonkowit N, Paw T, Visser GHA, McGready R, Nosten FH, Pistorius LR. 2012. Effect of malaria in pregnancy on foetal cortical brain development: a longitudinal observational study. Malar J, 11 (1), pp. 222. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria in pregnancy has a negative impact on foetal growth, but it is not known whether this also affects the foetal nervous system. The aim of this study was to examine the effects of malaria on foetal cortex development by three-dimensional ultrasound. METHODS: Brain images were acquired using a portable ultrasound machine and a 3D ultrasound transducer. All recordings were analysed, blinded to clinical data, using the 4D view software package. The foetal supra-tentorial brain volume was determined and cortical development was qualitatively followed by scoring the appearance and development of six sulci. Multilevel analysis was used to study brain volume and cortical development in individual foetuses. RESULTS: Cortical grading was possible in 161 out of 223 (72%) serial foetal brain images in pregnant women living in a malaria endemic area. There was no difference between foetal cortical development or brain volumes at any time in pregnancy between women with immediately treated malaria infections and non-infected pregnancies. CONCLUSION: The percentage of images that could be graded was similar to other neuro-sonographic studies. Maternal malaria does not have a gross effect on foetal brain development, at least in this population, which had access to early detection and effective treatment of malaria.

Adam I, Tarning J, Lindegardh N, Mahgoub H, McGready R, Nosten F. 2012. Pharmacokinetics of piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg, 87 (1), pp. 35-40. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

The pharmacokinetic properties of piperaquine were investigated in 12 pregnant and 12 well-matched, non-pregnant women receiving a three-day oral fixed dose combination regimen of dihydroartemisinin and piperaquine for treatment of uncomplicated Plasmodium falciparum at New Halfa Hospital in eastern Sudan. Frequent venous plasma samples were drawn from the patients over a 63-day period and a complete concentration-time profile was collected for 7 pregnant and 11 non-pregnant patients. Piperaquine was quantified using a liquid chromatography-mass spectrometry/mass spectrometry method. Pregnant women had a significantly higher total drug exposure (median area under the curve [range] = 1,770 [1,200-5,600] hr × ng/mL versus 858 [325-2,370] hr × ng/mL; P = 0.018) and longer time to maximal concentration (4.00 [1.50-4.03] hr versus 1.50 [0.500-8.00] hr; P = 0.02) after the first dose compared with non-pregnant women. There was no other significant difference observed in piperaquine pharmacokinetics between pregnant and non-pregnant women, including no difference in total drug exposure or maximum concentration. The overall pharmacokinetic properties of piperaquine in this study were consistent with previously published reports in non-pregnant patients.

Moore CE, Blacksell SD, Taojaikong T, Jarman RG, Gibbons RV, Lee SJ, Chansamouth V, Thongpaseuth S, Mayxay M, Newton PN. 2012. A prospective assessment of the accuracy of commercial IgM ELISAs in diagnosis of Japanese encephalitis virus infections in patients with suspected central nervous system infections in Laos. Am J Trop Med Hyg, 87 (1), pp. 171-178. | Citations: 12 (Scopus) | Show Abstract | Read more

Japanese encephalitis virus (JEV) is a major cause of encephalitis in Asia. We estimated the diagnostic accuracy of two anti-JEV immunoglobulin M (IgM) enzyme-linked immunosorbent assays (ELISAs) (Panbio and XCyton JEVCheX) compared with a reference standard (AFRIMS JEV MAC ELISA) in a prospective study of the causes of central nervous system infections in Laos. Cerebrospinal fluid (CSF; 515 patients) and serum samples (182 patients) from those admitted to Mahosot Hospital, Vientiane, were tested. The CSF from 14.5% of acute encephalitis syndrome (AES) patients and 10.1% from those with AES and meningitis were positive for anti-JEV IgM in the reference ELISA. The sensitivities for CSF were 65.4% (95% confidence interval [CI] = 51-78) (Xcyton), 69.2% (95% CI = 55-81) (Panbio), however 96.2% (95% CI = 87-100) with Panbio Ravi criteria. Specificities were 89-100%. For admission sera from AES patients, sensitivities and specificities of the Panbio ELISA were 85.7% (95% CI = 42-100%) and 92.9% (95% CI = 83-98%), respectively.

Nurleila S, Syafruddin D, Elyazar IRF, Baird JK. 2012. Serious and fatal illness associated with falciparum and vivax malaria among patients admitted to hospital at West Sumba in eastern Indonesia. Am J Trop Med Hyg, 87 (1), pp. 41-49. | Citations: 19 (Web of Science Lite) | Show Abstract | Read more

Records of 3,449 patients admitted to Karitas Hospital at Waitabula in eastern Indonesia with microscopy-confirmed malaria through 2008 and 2009 were systematically reviewed. Falciparum, vivax, and mixed species malaria occurred among 1,541, 1,837, and 71 admissions, respectively. Among these, 400 (26%), 199 (11%), and 15 (21%) had serious illness. Fatalities occurred in 46 (12%), 18 (9%), and 2 (13%) of these patients, respectively. Although patients with a diagnosis of falciparum malaria were more likely to have serious illness compared with those with vivax malaria (odds ratio [OR] = 2.9; 95% confidence interval [CI]: 2.4-3.5), this diagnosis nonetheless was associated with 32% of serious illness and 27% of fatalities. Among the seriously ill with a diagnosis of falciparum or vivax malaria, no significant difference in risk of death occurred (OR = 1.3; 95% CI: 0.7-2.5). Serious and fatal illness was predominantly anemia or altered mental state syndromes among patients with either of the species diagnoses. Plasmodium vivax was associated with a substantial share of the burden of morbidity and mortality caused by malaria in this hypo- to meso-endemic community.

Anders KL, Nguyet NM, Quyen NTH, Ngoc TV, Tram TV, Gan TT, Tung NT, Dung NT, Chau NVV, Wills B, Simmons CP. 2012. An evaluation of dried blood spots and oral swabs as alternative specimens for the diagnosis of dengue and screening for past dengue virus exposure. Am J Trop Med Hyg, 87 (1), pp. 165-170. | Citations: 29 (Scopus) | Show Abstract | Read more

Non-invasive specimens for dengue diagnosis may be preferable where venous blood is difficult to collect and/or process, such as community-based or remote settings or when sampling from young children. We evaluated the performance of oral swabs and dried blood spots (DBS), compared with plasma, in diagnosing acute dengue and screening for past dengue virus (DENV) exposure. DENV-specific immunoglobulin (Ig) M, IgG, and NS1 antigen were detected both in oral swabs and DBS from acute patients. Oral swabs were less sensitive (IgM: 68.7%, IgG: 91.9%, NS1: 64.7%), but retained good specificity (100%, 92.3%, 95.8%, respectively) compared with plasma. DBS displayed high sensitivity (IgM: 100%, IgG: 96%, NS1: 100%) and specificity (IgM: 75%, IgG: 93%). DENV RNA was amplified from DBS (sensitivity 95.6%) but not from oral swabs. DENV-IgG (indicative of past flavivirus exposure) were detected with moderate sensitivity (61.1%) but poor specificity (50%) in oral swabs from healthy volunteers. Dried blood spots allow sensitive and specific diagnosis of acute dengue by serological, molecular, and antigen detection methods. Oral swabs may be an adequate alternative where blood cannot be collected.

Ke L, An KP, Heng S, Riley M, Sona S, Moore CE, Parry CM, Stoesser N, Chanpheaktra N. 2012. Paediatric Chromobacterium violaceum in Cambodia: the first documented case. Trop Doct, 42 (3), pp. 178-179. | Citations: 6 (Scopus) | Show Abstract | Read more

Chromobacterium violaceum infection is rarely described in Southeast Asian children, which may be due partly to the lack of access to adequate microbiology facilities in many areas. This case report describes the first documented case to occur in a Cambodian child. An awareness of the disease and its manifestations is important as treatment can be difficult and may require prolonged courses of antimicrobials and surgery.

Hashim R, Khatib AM, Enwere G, Park JK, Reyburn R, Ali M, Chang NY, Kim DR, Ley B, Thriemer K et al. 2012. Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy. PLoS Negl Trop Dis, 6 (7), pp. e1743. | Citations: 20 (Scopus) | Show Abstract | Read more

INTRODUCTION: Mass vaccinations are a main strategy in the deployment of oral cholera vaccines. Campaigns avoid giving vaccine to pregnant women because of the absence of safety data of the killed whole-cell oral cholera (rBS-WC) vaccine. Balancing this concern is the known higher risk of cholera and of complications of pregnancy should cholera occur in these women, as well as the lack of expected adverse events from a killed oral bacterial vaccine. METHODOLOGY/PRINCIPAL FINDINGS: From January to February 2009, a mass rBS-WC vaccination campaign of persons over two years of age was conducted in an urban and a rural area (population 51,151) in Zanzibar. Pregnant women were advised not to participate in the campaign. More than nine months after the last dose of the vaccine was administered, we visited all women between 15 and 50 years of age living in the study area. The outcome of pregnancies that were inadvertently exposed to at least one oral cholera vaccine dose and those that were not exposed was evaluated. 13,736 (94%) of the target women in the study site were interviewed. 1,151 (79%) of the 1,453 deliveries in 2009 occurred during the period when foetal exposure to the vaccine could have occurred. 955 (83%) out of these 1,151 mothers had not been vaccinated; the remaining 196 (17%) mothers had received at least one dose of the oral cholera vaccine. There were no statistically significant differences in the odds ratios for birth outcomes among the exposed and unexposed pregnancies. CONCLUSIONS/SIGNIFICANCE: We found no statistically significant evidence of a harmful effect of gestational exposure to the rBS-WC vaccine. These findings, along with the absence of a rational basis for expecting a risk from this killed oral bacterial vaccine, are reassuring but the study had insufficient power to detect infrequent events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00709410.

von Seidlein L, Deen JL. 2012. Considerations for oral cholera vaccine use during outbreak after earthquake in Haiti, 2010-2011. Emerg Infect Dis, 18 (7), pp. 1211-1214. | Citations: 5 (Scopus) | Read more

Maltezou HC, Fusco FM, Schilling S, De Iaco G, Gottschalk R, Brodt H-R, Bannister B, Brouqui P, Thomson G, Puro V et al. 2012. Infection control practices in facilities for highly infectious diseases across Europe. J Hosp Infect, 81 (3), pp. 184-191. | Show Abstract | Read more

BACKGROUND: The management of patients with highly infectious diseases (HIDs) is a challenge for healthcare provision requiring a high level of care without compromising the safety of other patients and healthcare workers. AIM: To study the infection control practice in isolation facilities participating in the European Network for Highly Infectious Diseases (EuroNHID) project. METHODS: A survey was conducted during 2009 of 48 isolation facilities caring for patients with HIDs in 16 European countries. Checklists and standard evaluation forms were used to collect and interpret data on hand hygiene, routine hygiene and disinfection, and waste management. FINDINGS: Forty percent of HIDs had no non-hand-operated sinks or alcohol-based antiseptic distributors, while 27% did not have procedures for routine hygiene, final disinfection, or safe discarding of non-disposable objects or equipment. There was considerable variation in the management of waste and in the training of housekeeping personnel. EuroNHID has developed recommendations for hand hygiene, disinfection, routine hygiene, and waste management. CONCLUSIONS: Most aspects of hand hygiene, routine hygiene and disinfection, and waste management were considered at least partially adequate in the majority of European isolation facilities dedicated for the care of patients with HIDs. But considerable variability was observed, with management of waste and training of housekeeping personnel being generally less satisfactory.

Dondorp AM, Maude RJ, Hendriksen ICE, Day NP, White NJ. 2012. Artesunate dosing in severe falciparum malaria. J Infect Dis, 206 (4), pp. 618-619. | Citations: 6 (Scopus) | Read more

Molyneux S, Mulupi S, Mbaabu L, Marsh V. 2012. Benefits and payments for research participants: experiences and views from a research centre on the Kenyan coast. BMC Med Ethics, 13 (1), pp. 13. | Citations: 33 (Scopus) | Show Abstract | Read more

BACKGROUND: There is general consensus internationally that unfair distribution of the benefits of research is exploitative and should be avoided or reduced. However, what constitutes fair benefits, and the exact nature of the benefits and their mode of provision can be strongly contested. Empirical studies have the potential to contribute viewpoints and experiences to debates and guidelines, but few have been conducted. We conducted a study to support the development of guidelines on benefits and payments for studies conducted by the KEMRI-Wellcome Trust programme in Kilifi, Kenya. METHODS: Following an initial broad based survey of cash, health services and other items being offered during research by all programme studies (n = 38 studies), interviews were held with research managers (n = 9), and with research staff involved in 8 purposively selected case studies (n = 30 interviewees). Interviews explored how these 'benefits' were selected and communicated, experiences with their administration, and recommendations for future guidelines. Data fed into a consultative workshop attended by 48 research staff and health managers, which was facilitated by an external ethicist. FINDINGS: The most commonly provided benefits were medical care (for example free care, and strengthened quality of care), and lunch or snacks. Most cash given to participants was reimbursement of transport costs (for example to meet appointments or facilitate use of services when unexpectedly sick), but these payments were often described by research participants as benefits. Challenges included: tensions within households and communities resulting from lack of clarity and agreement on who is eligible for benefits; suspicion regarding motivation for their provision; and confusion caused by differences between studies in types and levels of benefits. CONCLUSIONS: Research staff differed in their views on how benefits should be approached. Echoing elements of international benefit sharing and ancillary care debates, some research staff saw research as based on goodwill and partnership, and aimed to avoid costs to participants and a commercial relationship; while others sought to maximise participant benefits given the relative wealth of the institution and the multiple community needs. An emerging middle position was to strengthen collateral or indirect medical benefits to communities through collaborations with the Ministry of Health to support sustainability.

Gomes MGM, Aguas R, Lopes JS, Nunes MC, Rebelo C, Rodrigues P, Struchiner CJ. 2012. How host heterogeneity governs tuberculosis reinfection? Proc Biol Sci, 279 (1737), pp. 2473-2478. | Citations: 22 (Scopus) | Show Abstract | Read more

Recurrent episodes of tuberculosis (TB) can be due to relapse of latent infection or exogenous reinfection, and discrimination is crucial for control planning. Molecular genotyping of Mycobacterium tuberculosis isolates offers concrete opportunities to measure the relative contribution of reinfection in recurrent disease. Here, a mathematical model of TB transmission is fitted to data from 14 molecular epidemiology studies, enabling the estimation of relevant epidemiological parameters. Meta-analysis reveals that rates of reinfection after successful treatment are higher than rates of new TB, raising an important question about the underlying mechanism. We formulate two alternative mechanisms within our model framework: (i) infection increases susceptibility to reinfection or (ii) infection affects individuals differentially, thereby recruiting high-risk individuals to the group at risk for reinfection. The second mechanism is better supported by the fittings to the data, suggesting that reinfection rates are inflated through a population phenomenon that occurs in the presence of heterogeneity in individual risk of infection. As a result, rates of reinfection are higher when measured at the population level even though they might be lower at the individual level. Finally, differential host recruitment is modulated by transmission intensity, being less pronounced when incidence is high.

Barasa EW, Ayieko P, Cleary S, English M. 2012. Out-of-pocket costs for paediatric admissions in district hospitals in Kenya. Trop Med Int Health, 17 (8), pp. 958-961. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To describe out-of-pocket costs of inpatient care for children under 5 years of age in district hospitals in Kenya. METHODS: A total of 256 caretakers of admitted children were interviewed in 2-week surveys conducted in eight hospitals in four provinces in Kenya. Caretakers were asked to report care seeking behaviour and expenditure related to accessing inpatient care. Family socio-economic status was assessed through reported expenditure in the previous month. RESULTS: Seventy eight percent of caretakers were required to pay user charges to access inpatient care for children. User charges (mean, US$ 8.1; 95% CI, 6.4-9.7) were 59% of total out-of-pocket costs, while transport costs (mean, US$ 4.9; 95% CI, 3.9-6.0) and medicine costs (mean, US$ 0.7; 95% CI, 0.5-1.0) were 36% and 5%, respectively. The mean total out-of-pocket cost per paediatric admission was US$ 14.1 (95% CI, 11.9-16.2). Out-of-pocket expenditures on health were catastrophic for 25.4% (95% CI, 18.4-33.3) of caretakers interviewed. Out-of-pocket expenditures were regressive, with a greater burden being experienced by households with lower socio-economic status. CONCLUSION: Despite a policy of user fee exemption for children under 5 years of age in Kenya, our findings show that high unofficial user fees are still charged in district hospitals. Financing mechanisms that will offer financial risk protection to children seeking care need to be developed to remove barriers to child survival.

Moore CE, Hor PC, Soeng S, Sun S, Lee SJ, Parry CM, Day NPJ, Stoesser N. 2012. Changing patterns of gastrointestinal parasite infections in Cambodian children: 2006-2011. J Trop Pediatr, 58 (6), pp. 509-512. | Citations: 12 (Scopus) | Show Abstract | Read more

We studied gastrointestinal parasites in symptomatic Cambodian children attending a provincial hospital in Siem Reap, Cambodia between 2006 and 2011. A total of 16 372 faecal samples were examined by direct microscopy. Parasites were detected in 3121 (19.1%) samples and most common were Giardia lamblia (8.0% of samples; 47.6% disease episodes), hookworm (5.1%; 30.3%) and Strongyloides stercoralis (2.6%; 15.6%). The proportion of infected children increased, and the number of disease episodes effectively treated with a single dose of mebendazole decreased, over the 5-year period.

Harrington W, McGready R, Muehlenbachs A, Fried M, Nosten F, Duffy P. 2012. Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. Clin Infect Dis, 55 (7), pp. 1025-1026. | Citations: 6 (Scopus) | Read more

Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, Yan H, Huang X, Angus B, Kuldanek K et al. 2012. Antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ T-cell decline in HIV-1 infection. J Infect Dis, 206 (4), pp. 552-561. | Citations: 53 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Rare human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain control of viremia without therapy show potent CD8+ T-cell-mediated suppression of viral replication in vitro. Whether this is a determinant of the rate of disease progression in viremic individuals is unknown. METHODS: We measured CD8+ T-cell-mediated inhibition of a heterologous HIV-1 isolate in 50 HIV-1-seropositive adults with diverse progression rates. Linear mixed models were used to determine whether CD8+ T-cell function could explain variation in the rate of CD4+ T-cell decline. RESULTS: There was a significant interaction between CD8+ T-cell antiviral activity in vitro and the rate of CD4+ T-cell decline in chronically infected individuals (P < .0001). In a second prospective analysis of recently infected subjects followed for up to 3 years, CD8+ T-cell antiviral activity strongly predicted subsequent CD4+ T-cell decline (P < .0001) and explained up to 73% of the interindividual variation in the CD4+ T-cell slope. In addition, it was inversely associated with viral load set point (r = -0.68 and P = .002). CONCLUSIONS: The antiviral inhibitory capacity of CD8+ T cells is highly predictive of CD4+ T-cell loss in early HIV-1 infection. It has potential as a benchmark of effective immunity in vaccine evaluation.

Thwaites GE. 2012. The management of suspected encephalitis. BMJ, 344 (jun06 2), pp. e3489. | Citations: 3 (Scopus) | Read more

Webb C, Ngama M, Ngatia A, Shebbe M, Morpeth S, Mwarumba S, Bett A, Nokes DJ, Seale AC, Kazungu S et al. 2012. Treatment failure among Kenyan children with severe pneumonia--a cohort study. Pediatr Infect Dis J, 31 (9), pp. e152-e157. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Pneumonia is the leading cause of childhood mortality worldwide. The World Health Organization recommends presumptive treatment based on clinical syndromes. Recent studies raise concerns over the frequency of treatment failure in Africa. METHODS: We applied a definition of treatment failure to data prospectively collected from children who were 2-59 months of age with severe, or very severe, pneumonia admitted to Kilifi District Hospital, Kenya, from May 2007 through May 2008 and treated using World Health Organization guidelines. The primary outcome was treatment failure at 48 hours. RESULTS: Of 568 children, median age 11 months, 165 (29%) had very severe pneumonia, 30 (5.3%) a positive HIV test and 62 (11%) severe malnutrition. One hundred eleven (20%; 95% confidence interval: 17-23%) children failed treatment at 48 hours and 34 (6.0%) died; 22 (65%) deaths occurred before 48 hours. Of 353 children with severe pneumonia, without HIV or severe malnutrition, 42 (12%) failed to respond at 48 hours, 15 (4.3%) failed at 5 days and 1 child (0.3%) died. Among 215 children with either severe pneumonia complicated by HIV or severe malnutrition, or very severe pneumonia, 69 (32%) failed to treatment at 48 hours, 47 (22%) failed at 5 days and 33 (16%) died. Treatment failure at 48 hours was associated with shock, bacteremia, very severe pneumonia, oxygen saturation in hemoglobin <95%, severe malnutrition, HIV and age <1 year in multivariable models. CONCLUSIONS: In this setting, few children with uncomplicated severe pneumonia fail treatment or die under current guidelines. Deaths mainly occurred early and may be reduced by improving prevention, prehospital care and treatment of sepsis.

Hanson J, Lam SWK, Mahanta KC, Pattnaik R, Alam S, Mohanty S, Hasan MU, Hossain A, Charunwatthana P, Chotivanich K et al. 2012. Relative contributions of macrovascular and microvascular dysfunction to disease severity in falciparum malaria. J Infect Dis, 206 (4), pp. 571-579. | Citations: 34 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Sequestration of parasitized erythrocytes in the microcirculation is considered the central pathophysiological process in severe falciparum malaria. Hypovolemia with reduced oxygen delivery and microvascular obstruction have different implications for patient management; however, their relative contributions to disease severity are uncertain. METHODS: Adult patients (n = 28) with severe Plasmodium falciparum malaria were enrolled in a prospective hemodynamic study. Volume status and oxygen delivery were assessed using transpulmonary thermodilution. Microvascular sequestration was measured using orthogonal polarized spectroscopy. FINDINGS: Duration of therapy before study enrollment was correlated with the amount of directly visualized and quantitated microvascular sequestration (P = .03). The amount of sequestration correlated with plasma lactate (r(s )= 0.55; P = .003) and disease severity (r(s )= 0.41; P = .04). In patients who had received artesunate for <10 hours, sequestration was higher in fatal cases than in survivors: median (range) 45% (32-50) vs 15% (0-40); P = .03). Parasite biomass estimated from plasma P. falciparum histidine-rich protein 2 correlated positively with disease severity (r(s )= 0.48; P = .01) and was significantly higher in patients who died (P = .046). There was no relationship between oxygen delivery and disease severity (P = .64) or outcome (P = .74). INTERPRETATION: Vital organ dysfunction in severe malaria results primarily from sequestration of parasitized erythrocytes in the microvasculature rather than reduction in circulating blood volume and oxygen delivery.

Byakika-Kibwika P, Lamorde M, Mayito J, Nabukeera L, Namakula R, Mayanja-Kizza H, Katabira E, Ntale M, Pakker N, Ryan M et al. 2012. Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother, 67 (9), pp. 2213-2221. | Citations: 36 (Scopus) | Show Abstract | Read more

OBJECTIVES: Co-administration of artemether/lumefantrine with antiretroviral therapy has potential for pharmacokinetic drug interactions. We investigated drug-drug interactions between artemether/lumefantrine and efavirenz or nevirapine. METHODS: We performed a cross-over study in which HIV-infected adults received standard six-dose artemether/lumefantrine 80/480 mg before and at efavirenz or nevirapine steady state. Artemether, dihydroartemisinin, lumefantrine, efavirenz and nevirapine plasma concentrations were measured and compared. RESULTS: Efavirenz significantly reduced artemether maximum concentration (C(max)) and plasma AUC (median 29 versus 12 ng/mL, P < 0.01, and 119 versus 25 ng · h/mL, P < 0.01), dihydroartemisinin C(max) and AUC (median 120 versus 26 ng/mL, P < 0.01, and 341 versus 84 ng · h/mL, P < 0.01), and lumefantrine C(max) and AUC (median 8737 versus 6331 ng/mL, P = 0.03, and 280 370 versus 124 381 ng · h/mL, P < 0.01). Nevirapine significantly reduced artemether C(max) and AUC (median 28 versus 11 ng/mL, P < 0.01, and 123 versus 34 ng · h/mL, P < 0.01) and dihydroartemisinin C(max) and AUC (median 107 versus 59 ng/mL, P < 0.01, and 364 versus 228 ng · h/mL, P < 0.01). Lumefantrine C(max) and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced nevirapine C(max) and AUC (median 8620 versus 4958 ng/mL, P < 0.01, and 66 329 versus 35 728 ng · h/mL, P < 0.01), but did not affect efavirenz exposure. CONCLUSIONS: Co-administration of artemether/lumefantrine with efavirenz or nevirapine resulted in a reduction in artemether, dihydroartemisinin, lumefantrine and nevirapine exposure. These drug interactions may increase the risk of malaria treatment failure and development of resistance to artemether/lumefantrine and nevirapine. Clinical data from population pharmacokinetic and pharmacodynamic trials evaluating the impact of these drug interactions are urgently needed.

Mayxay M, Khanthavong M, Chanthongthip O, Imwong M, Pongvongsa T, Hongvanthong B, Phompida S, Vanisaveth V, White NJ, Newton PN. 2012. Efficacy of artemether-lumefantrine, the nationally-recommended artemisinin combination for the treatment of uncomplicated falciparum malaria, in southern Laos. Malar J, 11 (1), pp. 184. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The Lao Government changed the national policy for uncomplicated Plasmodium falciparum malaria from chloroquine to artemether-lumefantrine (AL) in 2005. Since then, no information on AL efficacy has been reported. With evidence of resistance to artemisinin derivatives in adjacent Cambodia, there has been a concern as to AL efficacy. Monitoring of AL efficacy would help the Lao Government to make decisions on appropriate malaria treatment. METHODS: The efficacy of a three-day, twice daily oral artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Xepon District, Savannakhet Province, southern Laos was studied over 42 days follow-up. This was part of a trial of thiamin supplementation in falciparum malaria. RESULTS: Of 630 patients with P. falciparum enrolled in the trial of thiamin treatment, 549 (87%, 357 children ≤15 years and 192 adults) were included in this study. The per protocol 42-day cure rates were 97% (524/541) [96% (337/352) for children and 99% (187/189) for adults, p = 0.042]. By conventional intention-to-treat analysis, the 42-day cure rates adjusted for re-infection, were 97% (532/549) [96% (342/357) in children and 99% (190/192) in adults, p = 0.042]. The proportion of patients who remained parasitaemic at day 1 after treatment was significantly higher in children [33% (116/356)] compared to adults [15% (28/192)] (p < 0.001) and only one adult patient had detectable parasitaemia on day 2. There were no serious adverse events. Potential side effects after treatment were reported more commonly in adults (32%) compared to children (15%) (p < 0.001). Patients with recrudescent infections were significantly younger, had longer mean time to fever clearance, and had longer median time to parasite clearance compared to those who were cured. CONCLUSIONS: The current nationally-recommended anti-malarial treatment (artemether-lumefantrine) remains highly efficacious for the treatment of uncomplicated falciparum malaria five years after introduction in Laos. Regular monitoring is required in case artemisinin-resistant P. falciparum parasites should appear. TRIAL REGISTRATION: ISRCTN85411059.

Dunstan SJ, Rockett KA, Quyen NTN, Teo YY, Thai CQ, Hang NT, Jeffreys A, Clark TG, Small KS, Simmons CP et al. 2012. Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese. Genes Immun, 13 (6), pp. 503-508. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

The genetic basis for susceptibility to malaria has been studied widely in African populations but less is known of the contribution of specific genetic variants in Asian populations. We genotyped 67 single-nucleotide polymorphisms (SNPs) in 1030 severe malaria cases and 2840 controls from Vietnam. After data quality control, genotyping data of 956 cases and 2350 controls were analysed for 65 SNPs (3 gender confirmation, 62 positioned in/near 42 malarial candidate genes). A total of 14 SNPs were monomorphic and 2 (rs8078340 and rs33950507) were not in Hardy-Weinberg equilibrium in controls (P<0.01). In all, 7/46 SNPs in 6 genes (ICAM1, IL1A, IL17RC, IL13, LTA and TNF) were associated with severe malaria, with 3/7 SNPs in the TNF/LTA region. Genotype-phenotype correlations between SNPs and clinical parameters revealed that genotypes of rs708567 (IL17RC) correlate with parasitemia (P=0.028, r(2)=0.0086), with GG homozygotes having the lowest parasite burden. Additionally, rs708567 GG homozygotes had a decreased risk of severe malaria (P=0.007, OR=0.78 (95% CI; 0.65-0.93)) and death (P=0.028, OR=0.58 (95% CI; 0.37-0.93)) than those with AA and AG genotypes. In summary, variants in six genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese. Further replicative studies in independent populations will be necessary to confirm these findings.

Dunstan SJ, Rockett KA, Quyen NTN, Teo YY, Thai CQ, Hang NT, Jeffreys A, Clark TG, Small KS, Simmons CP et al. 2012. Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese Genes and Immunity, 13 (6), pp. 503-508. | Citations: 9 (Scopus) | Show Abstract | Read more

The genetic basis for susceptibility to malaria has been studied widely in African populations but less is known of the contribution of specific genetic variants in Asian populations. We genotyped 67 single-nucleotide polymorphisms (SNPs) in 1030 severe malaria cases and 2840 controls from Vietnam. After data quality control, genotyping data of 956 cases and 2350 controls were analysed for 65 SNPs (3 gender confirmation, 62 positioned in/near 42 malarial candidate genes). A total of 14 SNPs were monomorphic and 2 (rs8078340 and rs33950507) were not in Hardy-Weinberg equilibrium in controls (P < 0.01). In all, 7/46 SNPs in 6 genes (ICAM1, IL1A, IL17RC, IL13, LTA and TNF) were associated with severe malaria, with 3/7 SNPs in the TNF/LTA region. Genotype-phenotype correlations between SNPs and clinical parameters revealed that genotypes of rs708567 (IL17RC) correlate with parasitemia (P=0.028, r 2 =0.0086), with GG homozygotes having the lowest parasite burden. Additionally, rs708567 GG homozygotes had a decreased risk of severe malaria (P=0.007, OR=0.78 (95% CI; 0.65-0.93)) and death (P=0.028, OR=0.58 (95% CI; 0.37-0.93)) than those with AA and AG genotypes. In summary, variants in six genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese. Further replicative studies in independent populations will be necessary to confirm these findings. © 2012 Macmillan Publishers Limited. All rights reserved.

Warrell DA. 2012. Venomous bites, stings, and poisoning. Infect Dis Clin North Am, 26 (2), pp. 207-223. | Citations: 13 (Scopus) | Show Abstract | Read more

This article discusses the epidemiology, prevention, clinical features, first aid and medical treatment of venomous bites by snakes, lizards, and spiders; stings by fish, jellyfish, echinoderms, and insects; and poisoning by fish and molluscs, in all parts of the world. Of these envenoming and poisonings, snake bite causes the greatest burden of human suffering, killing 46,000 people each year in India alone and more than 100,000 worldwide and resulting in physical handicap in many survivors. Specific antidotes (antivenoms/antivenins) are available to treat envenoming by many of these taxa but supply and distribution is inadequate in many tropical developing countries.

Conlan JV, Vongxay K, Jarman RG, Gibbons RV, Lunt RA, Fenwick S, Thompson RCA, Blacksell SD. 2012. Serologic study of pig-associated viral zoonoses in Laos. Am J Trop Med Hyg, 86 (6), pp. 1077-1084. | Citations: 7 (Scopus) | Show Abstract | Read more

We conducted a serologic survey of four high-priority pig-associated viral zoonoses, Japanese encephalitis virus (JEV), hepatitis E virus (HEV), Nipah virus (NiV), and swine influenza virus (SIV), in Laos. We collected blood from pigs at slaughter during May 2008-January 2009 in four northern provinces. Japanese encephalitis virus hemagglutination inhibition seroprevalence was 74.7% (95% confidence interval [CI] = 71.5-77.9%), JEV IgM seroprevalence was 2.3% (95% CI = 1.2-3.2%), and HEV seroprevalence was 21.1% (95% CI = 18.1-24.0%). Antibodies to SIV were detected in 1.8% (95% CI = 0.8-2.8%) of pigs by screening enzyme-linked immunosorbent assay, and only subtype H3N2 was detected by hemagglutination inhibition in two animals with an inconclusive enzyme-linked immunosorbent assay result. No NiV antibody-positive pigs were detected. Our evidence indicates that peak JEV and HEV transmission coincides with the start of the monsoonal wet season and poses the greatest risk for human infection.

Deen J, von Seidlein L, Andersen F, Elle N, White NJ, Lubell Y. 2012. Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect Dis, 12 (6), pp. 480-487. | Citations: 55 (Web of Science Lite) | Show Abstract | Read more

Information about community-acquired bacteraemia in developing countries in south and southeast Asia is scarce. We aimed to establish the case fraction of bacteraemia in febrile patients admitted to hospital. We searched four databases and identified studies of south and southeast Asia published between 1990 and 2010 that prospectively assessed patients admitted to hospital and from whom a blood culture was taken. We reviewed 17 eligible studies describing 40,644 patients. Pathogenic organisms were isolated from 3506 patients (9%; range 1-51%); 1784 (12%) of 14,386 adults and 1722 (7%) of 26,258 children. Salmonella enterica serotype Typhi was the most common bacterial pathogen, accounting for 532 of 1798 (30%) isolates in adults and 432 of 1723 (25%) in children. Other commonly isolated organisms in adults were Staphylococcus aureus, Escherichia coli, and other gram-negative organisms, and in children were Streptococcus pneumoniae and Haemophilus influenzae. A substantial case fraction of bacteraemia occurs in patients admitted to hospital with fever in this region. Management could be improved if diagnostic microbiology facilities were more widely available. The prevailing organisms causing bacteraemia and their susceptibility patterns could inform empirical treatment regimens and prevention strategies.

Lang T, Siribaddana S. 2012. Clinical trials have gone global: is this a good thing? PLoS Med, 9 (6), pp. e1001228. | Citations: 45 (Scopus) | Read more

Lang T. 2012. Using digital technology to support and enhance clinical trials in resource-limited settings TROPICAL MEDICINE & INTERNATIONAL HEALTH, 17 pp. 49-49.

Whitehorn J, Rodriguez Roche R, Guzman MG, Martinez E, Gomez WV, Nainggolan L, Laksono IS, Mishra A, Lum L, Faiz A et al. 2012. Prophylactic platelets in dengue: survey responses highlight lack of an evidence base. PLoS Negl Trop Dis, 6 (6), pp. e1716. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

Dengue is the most important arboviral infection of humans. Thrombocytopenia is frequently observed in the course of infection and haemorrhage may occur in severe disease. The degree of thrombocytopenia correlates with the severity of infection, and may contribute to the risk of haemorrhage. As a result of this prophylactic platelet transfusions are sometimes advocated for the prevention of haemorrhage. There is currently no evidence to support this practice, and platelet transfusions are costly and sometimes harmful. We conducted a global survey to assess the different approaches to the use of platelets in dengue. Respondents were all physicians involved with the treatment of patients with dengue. Respondents were asked that their answers reflected what they would do if they were the treating physician. We received responses from 306 physicians from 20 different countries. The heterogeneity of the responses highlights the variation in clinical practice and lack of an evidence base in this area and underscores the importance of prospective clinical trials to address this key question in the clinical management of patients with dengue.

Trung DT, Thao LTT, Dung NM, Ngoc TV, Hien TT, Chau NVV, Wolbers M, Tam DTH, Farrar J, Simmons C, Wills B. 2012. Clinical features of dengue in a large Vietnamese cohort: intrinsically lower platelet counts and greater risk for bleeding in adults than children. PLoS Negl Trop Dis, 6 (6), pp. e1679. | Citations: 51 (Scopus) | Show Abstract | Read more

BACKGROUND: As dengue spreads to new geographical regions and the force of infection changes in existing endemic areas, a greater breadth of clinical presentations is being recognised. Clinical experience suggests that adults manifest a pattern of complications different from those observed in children, but few reports have described the age-related spectrum of disease in contemporaneous groups of patients recruited at the same geographical location. METHODOLOGY/PRINCIPAL FINDINGS: Using detailed prospectively collected information from ongoing studies that encompass the full spectrum of hospitalised dengue cases admitted to a single hospital in southern Vietnam, we compared clinical and laboratory features, management, and outcome for 647 adults and 881 children with confirmed dengue. Signs of vascular leakage and shock were more frequent and more severe in children than adults, while bleeding manifestations and organ involvement were more common in adults. Additionally, adults experienced significantly more severe thrombocytopenia. Secondary infection but not serotype was independently associated with greater thrombocytopenia, although with a smaller effect than age-group. The effect of age-group on platelet count was also apparent in the values obtained several weeks after recovery, indicating that healthy adults have intrinsically lower counts compared to children. CONCLUSIONS/SIGNIFICANCE: There are clear distinctions between adults and children in the pattern of complications seen in association with dengue infection, and these depend partly on intrinsic age-dependent physiological differences. Knowledge of such differences is important to inform research on disease pathogenesis, as well as to encourage development of management guidelines that are appropriate to the age-groups at risk.

Barasa EW, Ayieko P, Cleary S, English M. 2012. A multifaceted intervention to improve the quality of care of children in district hospitals in Kenya: a cost-effectiveness analysis. PLoS Med, 9 (6), pp. e1001238. | Citations: 14 (Scopus) | Show Abstract | Read more

BACKGROUND: To improve care for children in district hospitals in Kenya, a multifaceted approach employing guidelines, training, supervision, feedback, and facilitation was developed, for brevity called the Emergency Triage and Treatment Plus (ETAT+) strategy. We assessed the cost effectiveness of the ETAT+ strategy, in Kenyan hospitals. Further, we estimate the costs of scaling up the intervention to Kenya nationally and potential cost effectiveness at scale. METHODS AND FINDINGS: Our cost-effectiveness analysis from the provider's perspective used data from a previously reported cluster randomized trial comparing the full ETAT+ strategy (n = 4 hospitals) with a partial intervention (n = 4 hospitals). Effectiveness was measured using 14 process measures that capture improvements in quality of care; their average was used as a summary measure of quality. Economic costs of the development and implementation of the intervention were determined (2009 US$). Incremental cost-effectiveness ratios were defined as the incremental cost per percentage improvement in (average) quality of care. Probabilistic sensitivity analysis was used to assess uncertainty. The cost per child admission was US$50.74 (95% CI 49.26-67.06) in intervention hospitals compared to US$31.1 (95% CI 30.67-47.18) in control hospitals. Each percentage improvement in average quality of care cost an additional US$0.79 (95% CI 0.19-2.31) per admitted child. The estimated annual cost of nationally scaling up the full intervention was US$3.6 million, approximately 0.6% of the annual child health budget in Kenya. A "what-if" analysis assuming conservative reductions in mortality suggests the incremental cost per disability adjusted life year (DALY) averted by scaling up would vary between US$39.8 and US$398.3. CONCLUSION: Improving quality of care at scale nationally with the full ETAT+ strategy may be affordable for low income countries such as Kenya. Resultant plausible reductions in hospital mortality suggest the intervention could be cost-effective when compared to incremental cost-effectiveness ratios of other priority child health interventions.

Turner C, Turner P, Cararra V, Htoo STL, Watthanaworawit W, Day N, White N, Goldblatt D, Nosten F. 2012. The epidemiology of pneumonia in a birth cohort of children living on the Thai-Myanmar border INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E13-E13. | Read more

Limmathurotsakul D, Thammasart S, Warrasuth N, Thapanagulsak P, Jatapai A, Pengreungrojanachai V, Anun S, Joraka W, Thongkamkoon P, Saiyen P et al. 2012. Animal melioidosis in Thailand INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E453-E453. | Read more

Khun PA, Seng S, Emary K, Moore C, Soeng S, Ngoun C, Kumar V, Day N, Parry C, Stoesser N. 2012. Surveillance of healthcare-associated infection at Angkor Hospital for Children, Siem Reap, Cambodia INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E375-E375. | Read more

Limmathurotsakul D, Turner E, Lim C, Day N, Cooper B, Peacock S. 2012. Defining the true accuracy of diagnostic tests when the gold standard is imperfect using web-based application INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E398-E398. | Read more

Blacksell S, Richards A, Paris DH, Tanganuchitcharnchai A, Day N. 2012. Validation of a semi-quantitative IgM ELISA for the detection of Orientia tsutsugamushi IgM antibodies for use in seroepidemiology studies in Thailand INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E390-E390. | Read more

Limmathurotsakul D, Wuthiekanun V, Kanoksil M, deStavola B, Day N, Peacock S. 2012. A matched case-control study identifies activities of daily living associated with acquisition of melioidosis in northeast Thailand INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E350-E351. | Read more

Luangxay K, Sisouk K, Vorlasan L, Soumphonphakdy B, Sengmouang V, Anderson M, Chansamouth V, Phommasone K, Begue R, Newton P. 2012. High hospital incidence of Staphylococcus aureus bacteremia in young infants in the Lao PDR INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E202-E203. | Read more

Moore C, Pan-ngum W, Wijedoru L, Ngoun C, Pastoor R, Tran N, Soeng S, Kheng C, Kumar V, Emary K et al. 2012. Evaluation of a Typhoid IgM flow assay for the diagnosis of typhoid fever in Cambodian children using a Bayesian modelling approach assuming an imperfect gold standard INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E400-E401. | Read more

Hongsuwan M, Srisamang P, Luangasanatip N, Kanoksil M, Day N, Limmathurotsakul D, Cooper B. 2012. A qualitative exploration into infection control practices and obstacles to improvements amongst health care workers at a regional hospital INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E373-E373. | Read more

Ngoun C, Emary K, Khun PA, Moore C, Soeng S, Duy PT, Tranh NTV, Wuthiekanum V, Amonrnchai P, Kheng C et al. 2012. Enteric fever in Cambodian children is dominated by multidrug resistant H58 Salmonella enterica serovar Typhi with decreased susceptibility to ciprofloxacin INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E427-E427. | Read more

Hongsuwan M, Srisamang P, Luangasanatip N, Kanoksil M, Day N, Cooper B, Limmathurotsakul D. 2012. A retrospective study to define the incidence and associated mortality of hospital-acquired bacteraemia at a regional hospital in northeast Thailand INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E385-E385. | Read more

Waddington C, Darton T, Jones C, Haworth K, Peters A, Kerridge S, Crook D, Lockhart S, Farrar J, Dougan G et al. 2012. Variations in attack rate in a single-blind, dose escalation challenge study of Salmonella Typhi in healthy adult volunteers INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E244-E244. | Read more

Khanh TH, Sabanathan S, Thoa LPK, Thuong TC, Farrar J, Hien TT, van Doorn HR. 2012. A large epidemic of enterovirus 71 associated hand, foot and mouth disease in southern Vietnam, 2011 INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E274-E274. | Read more

Jones C, Waddington C, Darton T, Bowman J, Farrar J, Dougan G, Levine M, Lockhart S, Sztein M, Crook D et al. 2012. Quantification of antibody secreting cell responses in a human challenge model of Salmonella Typhi infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E224-E224. | Read more

Yacoub S, Grifiths A, Chau TTH, Simmons C, Wills B, Hien TT, Henein M, Farrar J. 2012. Cardiac function and haemodynamics in Vietnemese patients with different dengue severity grades INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E119-E119. | Read more

Darton T, Jones C, Waddington C, Dougan G, Sztein M, Levine M, Angus B, Farrar J, Lockhart S, Crook D et al. 2012. Demonstration of primary and asymptomatic DNAaemia in participants challenged with Salmonella Typhi (Quailes strain) during the development of a human model of typhoid infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E215-E215. | Citations: 1 (Web of Science Lite) | Read more

Cuong HQ, Thai K, Boni M, Rabaa M, Vu NT, Quang LC, Huu TN, Cazelles B, Simmons C, Anders K. 2012. Spatial and temporal dynamics of dengue in southern Vietnam INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E13-E14. | Read more

Baker S. 2012. Solving the typhoid diagnostics conundrum INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E29-E29. | Read more

Phan VTM, Ha ML, Thompson C, Nguyen VMH, Pham VM, Nguyen TV, Cao TT, Nguyen TTN, Tang CT, Hoang LP et al. 2012. Risk factors of norovirus infection and the spatiotemporal dynamics of GII.4 strain replacement in Ho Chi Minh City, Vietnam INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E101-E101. | Read more

Witkowski B, Sokunmalis K, Kim S, Pheaktra C, Sopheakvatey K, Kloeung N, Khim N, Duong S, Leang R, Ringwald P et al. 2012. In vitro phenotype of reduced susceptibility to artemisinin in Plasmodium falciparum isolates from western Cambodia INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E178-E178. | Read more

Kanoksil M, Jatapai A, Peacock S, Limmathurotsakul D. 2012. Epidemiology, microbiology and mortality of community-acquired bacteremia in northeast Thailand: a multicenter population-based study INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E132-E132. | Read more

Luangasanatip N, Hongsuwan M, Lubell Y, Srisamang P, Limmathurotsakul D, Cooper B. 2012. Excess length of stay due to hospital-associated infections in Thailand: 8 years retrospective data INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E378-E379. | Read more

Cooper B. 2012. Transmission dynamics of MRSA in Asia INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E53-E53. | Read more

Hien TT. 2012. Clinical features and pathogenesis of H5N1 influenza in humans INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E41-E41. | Read more

Meeyai A, Cooper B, Coker R, Pan W, Akarasewie P, Iamsirithaworn S. 2012. The effective reproduction number of Pandemic 2009 H1N1 influenza in Thailand: a spatiotemporal analysis INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E353-E354. | Read more

Dondorp A. 2012. Artemisinin resistance in falciparum malaria INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E43-E43. | Read more

Sabapathy K, Ford N, Chan KN, Kyaw MK, Elema R, Smithuis F, Floyd S. 2012. Treatment outcomes from the largest antiretroviral treatment program in Myanmar (Burma): a cohort analysis of retention after scale-up. J Acquir Immune Defic Syndr, 60 (2), pp. e53-e62. | Citations: 15 (Scopus) | Show Abstract | Read more

BACKGROUND: Antiretroviral treatment (ART) coverage in Myanmar is well below average. This study describes retention and baseline predictors of prognosis from the largest ART program in the country. METHODS: A cohort analysis of adult patients who initiated ART during 2003-2007 was conducted, with follow-up until the end of 2009. The primary outcome was attrition [death plus losses to follow-up (LTF)]. Baseline variables were assessed as potential risk factors. The cumulative probabilities of death, LTF, and attrition up to 5 years were described using Kaplan-Meier estimates. Cox regression was used to calculate hazard ratios of attrition, overall and separately for 2 time periods on ART: 1-6 and 7-36 months. RESULTS: A total of 5963 adults enrolled in the program, providing 17,581 person-years of follow-up. Median age at baseline was 33 years [interquartile range (IQR): 28-38], 61% were men, 45% were in World Health Organization stage IV, and the median CD4 count was 71 cells per cubic millimeter (IQR: 29-164). There were 821 (13.8%) deaths and 389 (6.5%) LTF over the study period, with a 72% probability of being retained in care in the 5-year cohort. Double the rate of loss was contributed by death compared with LTF, and attrition was almost 4 times higher in the period 1-6 months compared with 7-36 months. In the multivariable analyses of the program overall, older age [adjusted hazard ratio (aHR): 1.56, 95% confidence interval (CI): 1.25 to 1.94], being male (aHR: 1.52, 95% CI: 1.25 to 1.85), World Health Organization stage IV (aHR: 1.44, 95% CI: 1.19 to 1.74), and body mass index <16 kg/m² (aHR: 2.13, 95% CI: 1.71 to 2.66) were independently predictive of attrition. CONCLUSIONS: The excellent retention over >6 years in this large cohort demonstrates that ART delivery at the primary care level in Myanmar is feasible and should encourage support for further ART expansion in the country.

Nyberg J, Höglund R, Bergstrand M, Karlsson MO, Hooker AC. 2012. Serial correlation in optimal design for nonlinear mixed effects models. J Pharmacokinet Pharmacodyn, 39 (3), pp. 239-249. | Citations: 2 (Scopus) | Show Abstract | Read more

In population modeling two sources of variability are commonly included; inter individual variability and residual variability. Rich sampling optimal design (more samples than model parameters) using these models will often result in a sampling schedule where some measurements are taken at exactly the same time point, thereby maximizing the signal-to-noise ratio. This behavior is a result of not appropriately taking into account error generation mechanisms and is often clinically unappealing and may be avoided by including intrinsic variability, i.e. serially correlated residual errors. In this paper we extend previous work that investigated optimal designs of population models including serial correlation using stochastic differential equations to optimal design with the more robust, and analytic, AR(1) autocorrelation model. Further, we investigate the importance of correlation strength, design criteria and robust designs. Finally, we explore the optimal design properties when estimating parameters with and without serial correlation. In the investigated examples the designs and estimation performance differs significantly when handling serial correlation.

Puro V, Fusco FM, Schilling S, Thomson G, De Iaco G, Brouqui P, Maltezou HC, Bannister B, Gottschalk R, Brodt H-R et al. 2012. Biosecurity measures in 48 isolation facilities managing highly infectious diseases. Biosecur Bioterror, 10 (2), pp. 208-214. | Show Abstract | Read more

Biosecurity measures are traditionally applied to laboratories, but they may also be usefully applied in highly specialized clinical settings, such as the isolation facilities for the management of patients with highly infectious diseases (eg, viral hemorrhagic fevers, SARS, smallpox, potentially severe pandemic flu, and MDR- and XDR-tuberculosis). In 2009 the European Network for Highly Infectious Diseases conducted a survey in 48 isolation facilities in 16 European countries to determine biosecurity measures for access control to the facility. Security personnel are present in 39 facilities (81%). In 35 facilities (73%), entrance to the isolation area is restricted; control methods include electronic keys, a PIN system, closed-circuit TV, and guards at the doors. In 25 facilities (52%), identification and registration of all staff entering and exiting the isolation area are required. Access control is used in most surveyed centers, but specific lacks exist in some facilities. Further data are needed to assess other biosecurity aspects, such as the security measures during the transportation of potentially contaminated materials and measures to address the risk of an "insider attack."

Andersen PK, Geskus RB, de Witte T, Putter H. 2012. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol, 41 (3), pp. 861-870. | Citations: 255 (Scopus) | Show Abstract | Read more

BACKGROUND: In studies of all-cause mortality, the fundamental epidemiological concepts of rate and risk are connected through a well-defined one-to-one relation. An important consequence of this relation is that regression models such as the proportional hazards model that are defined through the hazard (the rate) immediately dictate how the covariates relate to the survival function (the risk). METHODS: This introductory paper reviews the concepts of rate and risk and their one-to-one relation in all-cause mortality studies and introduces the analogous concepts of rate and risk in the context of competing risks, the cause-specific hazard and the cause-specific cumulative incidence function. RESULTS: The key feature of competing risks is that the one-to-one correspondence between cause-specific hazard and cumulative incidence, between rate and risk, is lost. This fact has two important implications. First, the naïve Kaplan-Meier that takes the competing events as censored observations, is biased. Secondly, the way in which covariates are associated with the cause-specific hazards may not coincide with the way these covariates are associated with the cumulative incidence. An example with relapse and non-relapse mortality as competing risks in a stem cell transplantation study is used for illustration. CONCLUSION: The two implications of the loss of one-to-one correspondence between cause-specific hazard and cumulative incidence should be kept in mind when deciding on how to make inference in a competing risks situation.

Castro-Sánchez A, Shkedy Z, Hens N, Aerts M, Geskus R, Prins M, Wiessing L, Kretzschmar M. 2012. Estimating the force of infection for HCV in injecting drug users using interval-censored data. Epidemiol Infect, 140 (6), pp. 1064-1074. | Citations: 8 (Scopus) | Show Abstract | Read more

Injecting drug users (IDUs) account for most new HCV infections. The objectives of this study were: to estimate the force of infection for hepatitis C virus in IDUs within the interval-censoring framework and to determine the impact of risk factors such as frequency of injection, drug injected, sharing of syringes and time of first injection on the time to HCV infection. We used data from the Amsterdam Cohort Study collected in The Netherlands and focused on those individuals who were HCV negative upon entry into the study. Based on the results, the force of infection was found to vary with time of first injection. The risk of infection was higher in the first 3 years of an IDU's career, implying estimates based on single cross-sectional studies could be biased. Frequency of injection and type of drug injected were found to be highly significant predictors, whereas sharing syringes was not.

Hamers RL, Sigaloff KCE, Wensing AM, Wallis CL, Kityo C, Siwale M, Mandaliya K, Ive P, Botes ME, Wellington M et al. 2012. Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies. Clin Infect Dis, 54 (11), pp. 1660-1669. | Citations: 96 (Scopus) | Show Abstract | Read more

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility. METHODS: A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was >1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility. RESULTS: HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried ≥1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with ≥1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine. CONCLUSIONS: Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priority.

Sigaloff KCE, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, Botes ME, Mandaliya K, Wellington M, Osibogun A et al. 2012. Second-line antiretroviral treatment successfully resuppresses drug-resistant HIV-1 after first-line failure: prospective cohort in Sub-Saharan Africa. J Infect Dis, 205 (11), pp. 1739-1744. | Citations: 40 (Scopus) | Show Abstract | Read more

Little is known about the effect of human immunodeficiency virus type 1 (HIV-1) resistance mutations present at time of regimen switch on the response to second-line antiretroviral therapy in Africa. In adults who switched to boosted protease inhibitor-based regimens after first-line failure, HIV-RNA and genotypic resistance testing was performed at switch and after 12 months. Factors associated with treatment failure were assessed using logistic regression. Of 243 participants, 53% were predicted to receive partially active second-line regimens due to drug resistance. The risk of treatment failure was, however, not increased in these participants. In this African cohort, boosted protease inhibitors successfully resuppressed drug-resistant HIV after first-line failure.

Vongxay K, Conlan JV, Khounsy S, Dorny P, Fenwick S, Thompson RCA, Blacksell SD. 2012. Seroprevalence of major bovine-associated zoonotic infectious diseases in the Lao People's Democratic Republic. Vector Borne Zoonotic Dis, 12 (10), pp. 861-866. | Citations: 9 (Scopus) | Show Abstract | Read more

Bovine-associated zoonotic infectious diseases pose a significant threat to human health in the Lao People's Democratic Republic (Lao PDR). In all, 905 cattle and buffalo serum samples collected in northern Lao PDR in 2006 were used to determine seroprevalence of five major bovine zoonotic infectious diseases that included Taenia saginata cysticercosis, bovine tuberculosis, Q-fever, bovine brucellosis, and bovine leptospirosis. Five enzyme-linked immunosorbent assays (ELISAs) were used to test for the presence of antibodies to the diseases, except Taenia saginata, for which we tested for the presence of Taenia metacestode circulating antigens. The overall highest prevalence was for T. saginata (46.4%), with lower prevalence for Q-fever (4%), leptospirosis (3%), tuberculosis (1%), and brucellosis (0.2%). Although there were no significant differences in the proportion of seroprevalence between sex and age of the animals sampled, there were significant differences between the provincial distributions. Further studies are required to determine the seroprevalence of these infections in other locations in Lao PDR, as well as other animal species including humans, in order to develop effective prevention and control strategies. This is the first study to investigate the prevalence of bovine zoonotic infectious agents in the Lao PDR. Positivity was demonstrated for all diseases investigated, with the highest prevalence for T. saginata antigen and Coxiella burnetti antibodies. For T. saginata, there were significant differences in the provincial distribution. Approximately 16% seroprevalence of Coxiella burnetti was noted in Xayabuly Province; however, there are no clear reasons why this was the case, and further studies are required to determine risk factors associated with this observation.

Chotivanich K, Mungthin M, Ruengweerayuth R, Udomsangpetch R, Dondorp AM, Singhasivanon P, Pukrittayakamee S, White NJ. 2012. The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against Plasmodium falciparum. Malar J, 11 (1), pp. 177. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Lumefantrine and atovaquone are highly lipophilic anti-malarial drugs. As a consequence absorption is increased when the drugs are taken together with a fatty meal, but the free fraction of active drug decreases in the presence of triglyceride-rich plasma lipoproteins. In this study, the consequences of lipidaemia on anti-malarial drug efficacy were assessed in vitro. METHODS: Serum was obtained from non-immune volunteers under fasting conditions and after ingestion of a high fat meal and used in standard Plasmodium falciparum in-vitro susceptibility assays. Anti-malarial drugs, including lumefantrine, atovaquone and chloroquine in five-fold dilutions (range 0.05 ng/ml-1 ug/mL) were diluted in culture medium supplemented with fasting or post-prandial 10% donor serum. The in-vitro drug susceptibility of parasite isolates was determined using the ³H-hypoxanthine uptake inhibition method and expressed as the concentration which gave 50% inhibition of hypoxanthine uptake (IC₅₀). RESULTS: Doubling plasma triglyceride concentrations (from 160 mg/dL to 320 mg/dL), resulted in an approximate doubling of the IC₅₀ for lumefantrine (191 ng/mL to 465 ng/mL, P < 0.01) and a 20-fold increase in the IC₅₀ for atovaquone (0.5 ng/mL to 12 ng/ml; P < 0.01). In contrast, susceptibility to the hydrophilic anti-malarial chloroquine did not change in relation to triglyceride content of the medium. CONCLUSIONS: Lipidaemia reduces the anti-malarial activity of lipophilic anti-malarial drugs. This is an important confounder in laboratory in vitro testing and it could have therapeutic relevance.

Espié E, Lima A, Atua B, Dhorda M, Flévaud L, Sompwe EM, Palma Urrutia PP, Guerin PJ. 2012. Efficacy of fixed-dose combination artesunate-amodiaquine versus artemether-lumefantrine for uncomplicated childhood Plasmodium falciparum malaria in Democratic Republic of Congo: a randomized non-inferiority trial. Malar J, 11 (1), pp. 174. | Citations: 19 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In 2005, the Democratic Republic of Congo (DRC) adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment. In order to compare the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL), a randomized, non-inferiority open-label trial was conducted in Katanga. METHODS: Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed. RESULTS: Between April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference -0.7%, one sided 95% CI -3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated. CONCLUSION: Both ASAQ and AL are highly effective and currently adequate as the first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces. TRIAL REGISTRATION: The protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.

Ley B, Khatib AM, Thriemer K, von Seidlein L, Deen J, Mukhopadyay A, Chang N-Y, Hashim R, Schmied W, Busch CJ-L et al. 2012. Evaluation of a rapid dipstick (Crystal VC) for the diagnosis of cholera in Zanzibar and a comparison with previous studies. PLoS One, 7 (5), pp. e36930. | Citations: 15 (Scopus) | Show Abstract | Read more

BACKGROUND: The gold standard for the diagnosis of cholera is stool culture, but this requires laboratory facilities and takes at least 24 hours. A rapid diagnostic test (RDT) that can be used by minimally trained staff at treatment centers could potentially improve the reporting and management of cholera outbreaks. METHODS: We evaluated the Crystal VC™ RDT under field conditions in Zanzibar in 2009. Patients presenting to treatment centers with watery diarrhea provided a stool sample for rapid diagnostic testing. Results were compared to stool culture performed in a reference laboratory. We assessed the overall performance of the RDT and evaluated whether previous intake of antibiotics, intravenous fluids, location of testing, and skill level of the technician affected the RDT results. RESULTS: We included stool samples from 624 patients. Compared to culture, the overall sensitivity of the RDT was 93.1% (95%CI: 88.7 to 96.2%), specificity was 49.2% (95%CI: 44.3 to 54.1%), the positive predictive value was 47.0% (95%CI: 42.1 to 52.0%) and the negative predictive value was 93.6% (95%CI: 89.6 to 96.5%). The overall false positivity rate was 50.8% (213/419); fieldworkers frequently misread very faint test lines as positive. CONCLUSION: The observed sensitivity of the Crystal VC RDT evaluated was similar compared to earlier versions, while specificity was poorer. The current version of the RDT could potentially be used as a screening tool in the field. Because of the high proportion of false positive results when field workers test stool specimens, positive results will need to be confirmed with stool culture.

Elyazar IRF, Gething PW, Patil AP, Rogayah H, Sariwati E, Palupi NW, Tarmizi SN, Kusriastuti R, Baird JK, Hay SI. 2012. Plasmodium vivax malaria endemicity in Indonesia in 2010. PLoS One, 7 (5), pp. e37325. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones. Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it. We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010. METHODS: Plasmodium vivax Annual Parasite Incidence data (2006-2008) and temperature masks were used to map P. vivax transmission limits. A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985-2010) for mapping quantitative estimates of contemporary endemicity within those limits. After error-checking a total of 4,457 points were included into a national database of age-standardized 1-99 year old PvPR data. A Bayesian MBG procedure created a predicted PvPR(1-99) endemicity surface with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population surface. RESULTS: We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010. Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas. In western Indonesia, the predicted P. vivax prevalence was uniformly low. Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs. High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua. In general, prediction uncertainty was relatively low in the west and high in the east. CONCLUSION: Most Indonesians living with endemic P. vivax experience relatively low risk of infection. However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection. The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy practices and manageability of P. vivax importation risk, especially in Java and Bali.

Sigaloff KCE, Hamers RL, Menke J, Labib M, Siwale M, Ive P, Botes ME, Kityo C, Mandaliya K, Wellington M et al. 2012. Early warning indicators for population-based monitoring of HIV drug resistance in 6 African countries. Clin Infect Dis, 54 Suppl 4 (suppl_4), pp. S294-S299. | Citations: 18 (Scopus) | Show Abstract | Read more

Human immunodeficiency virus (HIV) RNA testing and HIV drug resistance (HIVDR) testing are not routinely available for therapeutic monitoring of patients receiving antiretroviral therapy (ART) in resource-limited settings. World Health Organization HIVDR early warning indicators (EWIs) assess ART site factors known to favor the emergence of HIVDR. HIV drug resistance EWI monitoring was performed within the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) study, comprising 13 ART sites in 6 African countries. Early warning indicator assessment in the PASER network identified vulnerable aspects of ART programs and triggered interventions aimed at minimizing HIVDR emergence. Additionally, data suggest an advantage of medication possession ratio over on-time antiretroviral drug pickup in identifying patients at risk for HIVDR development.

Hamers RL, Straatsma E, Kityo C, Wallis CL, Stevens WS, Sigaloff KCE, Siwale M, Conradie F, Botes ME, Mandaliya K et al. 2012. Building capacity for the assessment of HIV drug resistance: experiences from the PharmAccess African Studies to Evaluate Resistance network. Clin Infect Dis, 54 Suppl 4 (suppl 4), pp. S261-S265. | Citations: 7 (Scopus) | Show Abstract | Read more

The PharmAccess African Studies to Evaluate Resistance (PASER) network was established as a collaborative partnership of clinical sites, laboratories, and research groups in 6 African countries; its purpose is to build research and laboratory capacity in support of a coordinated effort to assess population-level acquired and transmitted human immunodeficiency virus type-1 drug resistance (HIVDR), thus contributing to the goals of the World Health Organization Global HIV Drug Resistance Network. PASER disseminates information to medical professionals and policy makers and conducts observational research related to HIVDR. The sustainability of the network is challenged by funding limitations, constraints in human resources, a vulnerable general health infrastructure, and high cost and complexity of molecular diagnostic testing. This report highlights experiences and challenges in the PASER network from 2006 to 2010.

Gitonga CW, Edwards T, Karanja PN, Noor AM, Snow RW, Brooker SJ. 2012. Plasmodium infection, anaemia and mosquito net use among school children across different settings in Kenya. Trop Med Int Health, 17 (7), pp. 858-870. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To investigate risk factors, including reported net use, for Plasmodium infection and anaemia among school children and to explore variations in effects across different malaria ecologies occurring in Kenya. METHODS: This study analysed data for 49 975 school children in 480 schools surveyed during a national school malaria survey, 2008-2010. Mixed effects logistic regression was used to investigate factors associated with Plasmodium infection and anaemia within different malaria transmission zones. RESULTS: Insecticide-treated net (ITN) use was associated with reduction in the odds of Plasmodium infection in coastal and western highlands epidemic zones and among boys in the lakeside high transmission zone. Other risk factors for Plasmodium infection and for anaemia also varied by zone. Plasmodium infection was negatively associated with increasing socio-economic status in all transmission settings, except in the semi-arid north-east zone. Plasmodium infection was a risk factor for anaemia in lakeside high transmission, western highlands epidemic and central low-risk zones, whereas ITN use was only associated with lower levels of anaemia in coastal and central zones and among boys in the lakeside high transmission zone. CONCLUSIONS: The risk factors for Plasmodium infection and anaemia, including the protective associations with ITN use, vary according to malaria transmission settings in Kenya, and future efforts to control malaria and anaemia should take into account such heterogeneities among school children.

Jung K-O, Khan AM, Tan BYL, Hu Y, Simon GG, Nascimento EJM, Lemonnier F, Brusic V, Miotto O, Tan TW et al. 2012. West Nile virus T-cell ligand sequences shared with other flaviviruses: a multitude of variant sequences as potential altered peptide ligands. J Virol, 86 (14), pp. 7616-7624. | Citations: 11 (Scopus) | Show Abstract | Read more

Phylogenetic relatedness and cocirculation of several major human pathogen flaviviruses are recognized as a possible cause of deleterious immune responses to mixed infection or immunization and call for a greater understanding of the inter-Flavivirus protein homologies. This study focused on the identification of human leukocyte antigen (HLA)-restricted West Nile virus (WNV) T-cell ligands and characterization of their distribution in reported sequence data of WNV and other flaviviruses. H-2-deficient mice transgenic for either A2, A24, B7, DR2, DR3, or DR4 HLA alleles were immunized with overlapping peptides of the WNV proteome, and peptide-specific T-cell activation was measured by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays. Approximately 30% (137) of the WNV proteome peptides were identified as HLA-restricted T-cell ligands. The majority of these ligands were conserved in ∼≥88% of analyzed WNV sequences. Notably, only 51 were WNV specific, and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amino acids with sequences of 64 other flaviviruses, including several major human pathogens. Many of the shared ligands had an incidence of >50% in the analyzed sequences of one or more of six major flaviviruses. The multitude of WNV sequences shared with other flaviviruses as interspecies variants highlights the possible hazard of defective T-cell activation by altered peptide ligands in the event of dual exposure to WNV and other flaviviruses, by either infection or immunization. The data suggest the possible preferred use of sequences that are pathogen specific with minimum interspecies sequence homology for the design of Flavivirus vaccines.

Ndungu FM, Olotu A, Mwacharo J, Nyonda M, Apfeld J, Mramba LK, Fegan GW, Bejon P, Marsh K. 2012. Memory B cells are a more reliable archive for historical antimalarial responses than plasma antibodies in no-longer exposed children. Proc Natl Acad Sci U S A, 109 (21), pp. 8247-8252. | Citations: 42 (Scopus) | Show Abstract | Read more

Humans respond to foreign antigen by generating plasma Abs and memory B cells (MBCs). The Ab response then declines, sometimes to below the limit of detection. In contrast, MBCs are generally thought to be long-lived. We tested and compared Plasmodium falciparum (Pf)-specific Ab and MBC responses in two populations of children: (i) previously exposed children who had documented Pf infections several years ago, but minimal exposure since then; and (ii) persistently exposed children living in a separate but nearby endemic area. We found that although Pf-specific plasma Abs were lower in previously exposed children compared with persistently exposed children, their cognate MBCs were maintained at similar frequencies. We conclude that serological analysis by itself would greatly underestimate the true memory of Pf-specific Ab responses in previously exposed children living in areas where Pf transmission has been reduced or eliminated.

Muehlenbachs A, Nabasumba C, McGready R, Turyakira E, Tumwebaze B, Dhorda M, Nyehangane D, Nalusaji A, Nosten F, Guerin PJ, Piola P. 2012. Artemether-lumefantrine to treat malaria in pregnancy is associated with reduced placental haemozoin deposition compared to quinine in a randomized controlled trial. Malar J, 11 (1), pp. 150. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance. METHODS: Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data. RESULTS: Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria. CONCLUSIONS: Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy. TRIAL REGISTRATION: REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508.

Jamsen KM, Duffull SB, Tarning J, Lindegardh N, White NJ, Simpson JA. 2012. Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria. Malar J, 11 (1), pp. 143. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin-based combination therapy (ACT) is currently recommended as first-line treatment for uncomplicated malaria, but of concern, it has been observed that the effectiveness of the main artemisinin derivative, artesunate, has been diminished due to parasite resistance. This reduction in effect highlights the importance of the partner drugs in ACT and provides motivation to gain more knowledge of their pharmacokinetic (PK) properties via population PK studies. Optimal design methodology has been developed for population PK studies, which analytically determines a sampling schedule that is clinically feasible and yields precise estimation of model parameters. In this work, optimal design methodology was used to determine sampling designs for typical future population PK studies of the partner drugs (mefloquine, lumefantrine, piperaquine and amodiaquine) co-administered with artemisinin derivatives. METHODS: The optimal designs were determined using freely available software and were based on structural PK models from the literature and the key specifications of 100 patients with five samples per patient, with one sample taken on the seventh day of treatment. The derived optimal designs were then evaluated via a simulation-estimation procedure. RESULTS: For all partner drugs, designs consisting of two sampling schedules (50 patients per schedule) with five samples per patient resulted in acceptable precision of the model parameter estimates. CONCLUSIONS: The sampling schedules proposed in this paper should be considered in future population pharmacokinetic studies where intensive sampling over many days or weeks of follow-up is not possible due to either ethical, logistic or economical reasons.

Lagace-Wiens PRS, Duncan S, Kimani J, Thiong'o A, Shafi J, McClelland S, Sanders EJ, Zhanel G, Muraguri N, Mehta SD. 2012. Emergence of fluoroquinolone resistance in Neisseria gonorrhoeae isolates from four clinics in three regions of Kenya. Sex Transm Dis, 39 (5), pp. 332-334. | Citations: 8 (Scopus) | Show Abstract | Read more

We have recently reported high levels of fluoroquinolone resistance in a single region of Kenya. In this article, we report high prevalence of fluoroquinolone resistance (53.2%) in Neisseria gonorrhoeae isolates from 4 clinics in 3 additional regions of Kenya. These findings highlight the need to change first-line treatment in these settings and the need to evaluate empirical management guidelines for treatment of gonococcal infection in Kenya.

Vongphayloth K, Rattanavong S, Moore CE, Phetsouvanh R, Wuthiekanun V, Sengdouangphachanh A, Phouminh P, Newton PN, Buisson Y. 2012. Burkholderia pseudomallei detection in surface water in southern Laos using Moore's swabs. Am J Trop Med Hyg, 86 (5), pp. 872-877. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

The causal agent of melioidosis, Burkholderia pseudomallei, has been cultured from paddy fields in the Lao PDR. We carried out a pilot study to examine the relationship between bacterial soil contamination and that of nearby surface waters in Saravane Province. Soil sampling was conducted at a depth of 30 cm (100 holes in a 45 × 45 m grid) at two sites, East and West Saravane. Moore's swabs were used for water sampling of paddy fields, lakes, rivers, boreholes, and storage tanks within 2 km of the two soil sampling sites. B. pseudomallei from soil and water were cultured on Ashdown's agar. Thirty-six percent and 6% of water samples collected around East and West Saravane, respectively, were culture positive for B. pseudomallei. Low pH and high turbidity were independently associated with culture of B. pseudomallei. Most positive water samples were from the Sedone River, downstream of the East Saravane site. Moore's swabs are simple and inexpensive tools for detecting B. pseudomallei in surface waters.

Weehuizen TAF, Wieland CW, van der Windt GJW, Duitman J-W, Boon L, Day NPJ, Peacock SJ, van der Poll T, Wiersinga WJ. 2012. Expression and function of transforming growth factor β in melioidosis. Infect Immun, 80 (5), pp. 1853-1857. | Citations: 5 (Scopus) | Show Abstract | Read more

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast Asia and northern Australia. An important controller of the immune system is the pleiotropic cytokine transforming growth factor β (TGF-β), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-β expression and function in experimental melioidosis. TGF-β expression was determined in 33 patients with culture-proven infection with B. pseudomallei and 30 healthy controls. We found that plasma TGF-β concentrations were strongly elevated during melioidosis. In line with this finding, TGF-β expression in C57BL/6 mice intranasally inoculated with B. pseudomallei was enhanced as well. To assess the role of TGF-β, we inhibited TGF-β using a selective murine TGF-β antibody. Treatment of mice with anti-TGF-β antibody resulted in decreased lung Smad2 phosphorylation. TGF-β blockade appeared to be protective: mice treated with anti-TGF-β antibody and subsequently infected with B. pseudomallei showed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-β treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-β treatment did not have an effect on survival. In conclusion, TGF-β is upregulated during B. pseudomallei infection and plays a limited but proinflammatory role during experimental melioidosis.

Newton P. 2012. Interview. Pathog Glob Health, 106 (2), pp. 69-71. | Read more

Tabernero P, Newton PN. 2012. The WWARN antimalarial quality surveyor. Pathog Glob Health, 106 (2), pp. 77-78. | Citations: 10 (Web of Science Lite) | Read more

van der Pal HJ, van Dalen EC, van Delden E, van Dijk IW, Kok WE, Geskus RB, Sieswerda E, Oldenburger F, Koning CC, van Leeuwen FE et al. 2012. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol, 30 (13), pp. 1429-1437. | Citations: 129 (Scopus) | Show Abstract | Read more

PURPOSE: To evaluate the long-term risk for validated symptomatic cardiac events (CEs) and associated risk factors in childhood cancer survivors (CCSs). PATIENTS AND METHODS: We determined CEs grade 3 or higher: congestive heart failure (CHF), cardiac ischemia, valvular disease, arrhythmia and/or pericarditis (according to Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) in a hospital-based cohort of 1,362 5-year CCSs diagnosed between 1966 and 1996. We calculated both marginal and cause-specific cumulative incidence of CEs and cause-specific cumulative incidence of separate events. We analyzed different risk factors in multivariable Cox regression models. RESULTS: Overall, 50 CEs, including 27 cases of CHF, were observed in 42 survivors (at a median attained age of 27.1 years). The 30-year cause-specific cumulative incidence of CEs was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3% to 20.3%), after anthracyclines (7.3%; 95% CI, 3.8% to 10.7%), and after cardiac irradiation (4.0%; 95% CI, 0.5% to 7.4%) compared with other treatments. In the proportional hazards analyses, anthracycline (dose), cardiac irradiation (dose), combination of these treatments, and congenital heart disease were significantly associated with developing a CE. We demonstrated an exponential relationship between the cumulative anthracycline dose, cardiac irradiation dose, and risk of CE. CONCLUSION: CCSs have a high risk of developing symptomatic CEs at an early age. The most common CE was CHF. Survivors treated with both anthracyclines and radiotherapy have the highest risk; after 30 years, one in eight will develop severe heart disease. The use of potentially cardiotoxic treatments should be reconsidered for high-risk groups, and frequent follow-up for high-risk survivors is needed.

Kramer A, Stel VS, Geskus RB, Tizard EJ, Verrina E, Schaefer F, Heaf JG, Kramar R, Krischock L, Leivestad T et al. 2012. The effect of timing of the first kidney transplantation on survival in children initiating renal replacement therapy. Nephrol Dial Transplant, 27 (3), pp. 1256-1264. | Citations: 7 (Scopus) | Show Abstract | Read more

BACKGROUND: Controversy exists concerning the timing of the first kidney transplantation for children who need to start renal replacement therapy (RRT). Our aim was to estimate the effect of timing of the first transplantation on patient survival in children, for the first time also taking into account the mortality on dialysis before transplantation. METHODS: We included 2091 patients who started RRT between the age of 3 and 18 years in the period 1988-2007, from 13 European renal registries. A multistate model was used to simulate patient survival assuming (i) pre-emptive transplantation, (ii) transplantation after 1 or 2 years on dialysis and (iii) remaining on dialysis. RESULTS: Over the 20-year period, the highest 8-year survival probabilities were achieved in children transplanted pre-emptively {living donor (LD): 95.9% [95% confidence interval (CI): 93.1-98.8], deceased donor (DD): 95.3% (95% CI: 90.9-99.9)} rather than after 2 years of dialysis [LD: 94.2% (95% CI: 91.6-96.8), DD: 93.4% (95% CI: 91.0-95.9)], although these differences were not statistically significant. CONCLUSIONS: Even after taking mortality on dialysis into account, the potentially negative effect of postponing transplantation for 1 or 2 years was relatively small and not statistically significant. Therefore, if pre-emptive transplantation is not possible, starting RRT with a short period of dialysis and receiving a transplant thereafter seems an acceptable alternative from the perspective of patient survival.

Abdulla S, Alonso P, Binka F, Graves P, Greenwood B, Leke R, Malik E, Marsh K, Meek S, Mendis K et al. 2012. Inaugural meeting of the malaria policy advisory committee to the WHO: conclusions and recommendations MALARIA JOURNAL, 11 (1), pp. 137-137. | Read more

Scott JAG, Bauni E, Moisi JC, Ojal J, Gatakaa H, Nyundo C, Molyneux CS, Kombe F, Tsofa B, Marsh K et al. 2012. Profile: The Kilifi Health and Demographic Surveillance System (KHDSS). Int J Epidemiol, 41 (3), pp. 650-657. | Citations: 92 (Scopus) | Show Abstract | Read more

The Kilifi Health and Demographic Surveillance System (KHDSS), located on the Indian Ocean coast of Kenya, was established in 2000 as a record of births, pregnancies, migration events and deaths and is maintained by 4-monthly household visits. The study area was selected to capture the majority of patients admitted to Kilifi District Hospital. The KHDSS has 260 000 residents and the hospital admits 4400 paediatric patients and 3400 adult patients per year. At the hospital, morbidity events are linked in real time by a computer search of the population register. Linked surveillance was extended to KHDSS vaccine clinics in 2008. KHDSS data have been used to define the incidence of hospital presentation with childhood infectious diseases (e.g. rotavirus diarrhoea, pneumococcal disease), to test the association between genetic risk factors (e.g. thalassaemia and sickle cell disease) and infectious diseases, to define the community prevalence of chronic diseases (e.g. epilepsy), to evaluate access to health care and to calculate the operational effectiveness of major public health interventions (e.g. conjugate Haemophilus influenzae type b vaccine). Rapport with residents is maintained through an active programme of community engagement. A system of collaborative engagement exists for sharing data on survival, morbidity, socio-economic status and vaccine coverage.

Byakika-Kibwika P, Lamorde M, Mayito J, Nabukeera L, Mayanja-Kizza H, Katabira E, Hanpithakpong W, Obua C, Pakker N, Lindegardh N et al. 2012. Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults. Malar J, 11 (1), pp. 132. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria. METHODS: Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134). RESULTS: All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8-24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020-164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8) hours and total artesunate exposure (AUC) was 727 (290-111256) ng·h/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670-9530) ng/mL, with Tmax of 0.14 (0.6 - 6.07) hours and T1/2 of 1.31 (0.8-2.8) hours. Dihydroartemisinin AUC was 3492 (2183-6338) ng·h/mL. None of the participants reported adverse events. CONCLUSIONS: Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.

Wesolowski A, Eagle N, Noor AM, Snow RW, Buckee CO. 2012. Heterogeneous mobile phone ownership and usage patterns in Kenya. PLoS One, 7 (4), pp. e35319. | Citations: 64 (Web of Science Lite) | Show Abstract | Read more

The rapid adoption of mobile phone technologies in Africa is offering exciting opportunities for engaging with high-risk populations through mHealth programs, and the vast volumes of behavioral data being generated as people use their phones provide valuable data about human behavioral dynamics in these regions. Taking advantage of these opportunities requires an understanding of the penetration of mobile phones and phone usage patterns across the continent, but very little is known about the social and geographical heterogeneities in mobile phone ownership among African populations. Here, we analyze a survey of mobile phone ownership and usage across Kenya in 2009 and show that distinct regional, gender-related, and socioeconomic variations exist, with particularly low ownership among rural communities and poor people. We also examine patterns of phone sharing and highlight the contrasting relationships between ownership and sharing in different parts of the country. This heterogeneous penetration of mobile phones has important implications for the use of mobile technologies as a source of population data and as a public health tool in sub-Saharan Africa.

Stoesser N, Pocock J, Moore CE, Soeng S, Chhat HP, Sar P, Limmathurotsakul D, Day N, Thy V, Sar V, Parry CM. 2012. Pediatric suppurative parotitis in Cambodia between 2007 and 2011. Pediatr Infect Dis J, 31 (8), pp. 865-868. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

The causes of suppurative parotitis in Cambodian children are not known. We describe 39 cases at the Angkor Hospital for Children, Siem Reap, between January 2007 and July 2011 (0.07/1000 hospital attendances). The median age was 5.7 years with no neonates affected. Burkholderia pseudomallei was cultured in 29 (74%) cases. No deaths occurred; 1 child developed facial nerve palsy.

Aiken AM, Mturi N, Morpeth SC, Seale AC, Scott JAG. 2012. Paediatric hospital-acquired bacteraemia in developing countries reply LANCET, 379 (9825), pp. 1484-1485. | Read more

Limmathurotsakul D, Turner EL, Wuthiekanun V, Thaipadungpanit J, Suputtamongkol Y, Chierakul W, Smythe LD, Day NPJ, Cooper B, Peacock SJ. 2012. Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. Clin Infect Dis, 55 (3), pp. 322-331. | Citations: 83 (Scopus) | Show Abstract | Read more

BACKGROUND: We observed that some patients with clinical leptospirosis supported by positive results of rapid tests were negative for leptospirosis on the basis of our diagnostic gold standard, which involves isolation of Leptospira species from blood culture and/or a positive result of a microscopic agglutination test (MAT). We hypothesized that our reference standard was imperfect and used statistical modeling to investigate this hypothesis. METHODS: Data for 1652 patients with suspected leptospirosis recruited during three observational studies and one randomized control trial that described the application of culture, MAT, immunofluorescence assay (IFA), lateral flow (LF) and/or PCR targeting the 16S rRNA gene were reevaluated using Bayesian latent class models and random-effects meta-analysis. RESULTS: The estimated sensitivities of culture alone, MAT alone, and culture plus MAT (for which the result was considered positive if one or both tests had a positive result) were 10.5% (95% credible interval [CrI], 2.7%-27.5%), 49.8% (95% CrI, 37.6%-60.8%), and 55.5% (95% CrI, 42.9%-67.7%), respectively. These low sensitivities were present across all 4 studies. The estimated specificity of MAT alone (and of culture plus MAT) was 98.8% (95% CrI, 92.8%-100.0%). The estimated sensitivities and specificities of PCR (52.7% [95% CrI, 45.2%-60.6%] and 97.2% [95% CrI, 92.0%-99.8%], respectively), lateral flow test (85.6% [95% CrI, 77.5%-93.2%] and 96.2% [95% CrI, 87.7%-99.8%], respectively), and immunofluorescence assay (45.5% [95% CrI, 33.3%-60.9%] and 96.8% [95% CrI, 92.8%-99.8%], respectively) were considerably different from estimates in which culture plus MAT was considered a perfect gold standard test. CONCLUSIONS: Our findings show that culture plus MAT is an imperfect gold standard against which to compare alterative tests for the diagnosis of leptospirosis. Rapid point-of-care tests for this infection would bring an important improvement in patient care, but their future evaluation will require careful consideration of the reference test(s) used and the inclusion of appropriate statistical models.

Fischer J, Butt C, Dawes H, Foster C, Neale J, Plugge E, Wheeler C, Wright N. 2012. Fitness levels and physical activity among class A drug users entering prison. Br J Sports Med, 46 (16), pp. 1142-1144. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Physical activity could benefit drug users' physiological and mental health. Previous research has suggested that physical activity levels change when drug users enter prison. METHODS: Twenty-five class A drug users who were new to prison answered physical activity and drug use cross-sectional questionnaires, took a submaximal fitness test and wore a pedometer for 1 week. RESULTS: Participants' mean aerobic capacity was estimated as 49 mls O2/kg/min (±12 SD). Their mean self-reported walking distance outside of prison was 4.67 miles on an average day (±4.14 SD). Pedometer data suggest they walked a mean of 1.8 miles/day in prison. CONCLUSION: Many class A drug users entering prison had high levels of fitness and physical activity before admission, often gained from walking. Walking activity reduced when they entered prison, posing a challenge to maintaining healthy activity levels.

Herbert K, Plugge E, Foster C, Doll H. 2012. Prevalence of risk factors for non-communicable diseases in prison populations worldwide: a systematic review. Lancet, 379 (9830), pp. 1975-1982. | Citations: 44 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The burden of non-communicable diseases (NCDs) is disproportionately carried by low-income and middle-income countries and disadvantaged sectors of society such as prisoners. No systematic analysis has been done to assess the prevalence of poor diet, inadequate physical activity, and overweight and obesity in prisoners. We aim to synthesise current evidence and to highlight areas for action and further research. METHODS: We systematically searched online databases for reports published between 1948 and May, 2011. Studies were screened against eligibility criteria; two authors then independently extracted data with previously agreed proformas. The risk of bias was assessed for each study with a domain-based assessment. Data on body-mass index and physical activity were presented in forest plots; no overall estimates were calculated on account of data heterogeneity. Available data from the population subgroup most similar in terms of age and sex were used to calculate age-adjusted and sex-adjusted prevalence ratios, which estimate the likelihood of insufficient activity and obesity prevalence in prisoners compared with the national population. FINDINGS: 31 eligible studies were reported in 29 publications, including more than 60,000 prisoners in 884 institutions in 15 countries. Male prisoners were less likely to be obese than males in the general population (prevalence ratios ranged from 0·33 to 0·87) in all but one study (1·02, 0·92-1·07), whereas female prisoners were more likely to be obese than non-imprisoned women in the USA (1·18, 1·08-1·30) and Australia (prevalence ratios ranged from 1·15 to 1·20). Australian prisoners were more likely to achieve sufficient activity levels than the general population compared with prisoners in the UK (prevalence ratio 1·19, 95% CI 1·04-1·37, for women in Australia in 2009 vs 0·32, 0·21-0·47, for women in the UK; prevalence ratios ranged from 1·37 to 1·59 for men in Australia vs 0·71, 0·34-0·78, for men in the UK). Female mean energy intake exceeded recommended levels and sodium intake was about two to three times the recommended intake for all prisoners. INTERPRETATION: Contact with the criminal justice system is a public-health opportunity to promote health in this vulnerable population; the costs to the individual and to society of failing to do so are likely to be substantial. Improved monitoring and further research is essential to inform appropriate targeting of public health interventions. FUNDING: Oxford University Department of Public Health, Oxford University Hospitals NHS Trust.

Veiga MI, Ferreira PE, Malmberg M, Jörnhagen L, Björkman A, Nosten F, Gil JP. 2012. pfmdr1 amplification is related to increased Plasmodium falciparum in vitro sensitivity to the bisquinoline piperaquine. Antimicrob Agents Chemother, 56 (7), pp. 3615-3619. | Citations: 15 (Scopus) | Show Abstract | Read more

The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC(50)s) and IC(90)s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC(50) and P = 0.002 for IC(90)) and chloroquine, reaching statistical significance at IC(90)s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.

Boel ME, Rijken MJ, Brabin BJ, Nosten F, McGready R. 2012. The epidemiology of postpartum malaria: a systematic review. Malar J, 11 (1), pp. 114. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

Pregnant women are more susceptible to malaria than their non-pregnant counterparts. Less is known about the risk of malaria in the postpartum period. The epidemiology of postpartum malaria was systematically reviewed. Eleven articles fitted the inclusion criteria. Of the 10 studies that compared malaria data from the postpartum period with pregnancy data, nine studies suggested that the risk for malaria infection decreased after delivery. All three studies that compared postpartum data with non-pregnant non-postpartum women concluded that the risk did not return to pre-pregnancy levels immediately after delivery. The results of this review have to be carefully interpreted, as the majority of studies were not designed to study postpartum malaria, and there was large variability in study designs and reported outcomes. Current evidence suggests an effort should be made to detect and radically cure malaria during pregnancy so that women do not enter the postpartum period with residual parasites.

Horowitz A, Hafalla JCR, King E, Lusingu J, Dekker D, Leach A, Moris P, Cohen J, Vekemans J, Villafana T et al. 2012. Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine. J Immunol, 188 (10), pp. 5054-5062. | Citations: 37 (Web of Science Lite) | Show Abstract | Read more

RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum, is undergoing clinical trials. We report an analysis of cellular immune response to component Ags of RTS,S-hepatitis B surface Ag (HBs) and P. falciparum circumsporozoite (CS) protein-among Tanzanian children in a phase IIb RTS,S/AS01(E) trial. RTS,S/AS01 (E) vaccinees make stronger T cell IFN-γ, CD69, and CD25 responses to HBs peptides than do controls, indicating that RTS,S boosts pre-existing HBs responses. T cell CD69 and CD25 responses to CS and CS-specific secreted IL-2 were augmented by RTS,S vaccination. Importantly, more than 50% of peptide-induced IFN-γ(+) lymphocytes were NK cells, and the magnitude of the NK cell CD69 response to HBs peptides correlated with secreted IL-2 concentration. CD69 and CD25 expression and IL-2 secretion may represent sensitive markers of RTS,S-induced, CS-specific T cells. The potential for T cell-derived IL-2 to augment NK cell activation in RTS,S-vaccinated individuals, and the relevance of this for protection, needs to be explored further.

Mutua G, Sanders E, Mugo P, Anzala O, Haberer JE, Bangsberg D, Barin B, Rooney JF, Mark D, Chetty P et al. 2012. Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PLoS One, 7 (4), pp. e33103. | Citations: 64 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). METHODS/PRINCIPAL FINDINGS: MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. CONCLUSIONS/SIGNIFICANCE: Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT00971230.

Durier N, Nguyen C, White LJ. 2012. Treatment of hepatitis C as prevention: a modeling case study in Vietnam. PLoS One, 7 (4), pp. e34548. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Treatment of hepatitis C (HCV) is very effective, achieving a cure in 50-90% of patients. Besides its own good for individuals, this most likely translates in reduced transmission, but this phenomenon has yet to be fully explored. METHODS AND FINDINGS: In this mathematical modeling study done in the context of Vietnam, we estimated the public health benefit that HCV therapy for injecting drug users (IDUs) may achieve. Treatment coverage of 25, 50 and 75% of chronically HCV-infected IDUs (4 years into infection) is predicted to reduce the chronic HCV viremia prevalence respectively by 21, 37 and 50%, 11 years after full scale up to the intended coverage. At a constant 50% coverage level, earlier treatment, 3, 2, and 1 year into infection is predicted to reduce the chronic HCV viremia prevalence by 46, 60 and 85%. In these later 3 scenarios, for every 100 treatment courses provided, a total of respectively 50, 61 and 94 new infections could be averted. These benefits were projected in the context of current low coverage of methadone maintenance therapy and needles/syringes exchange programs, and these services expansion showed complementary preventive benefits to HCV therapy. The program treatment commitment associated with the various scenarios is deemed reasonable. Our model projections are robust under adjustment for uncertainty in the model parameter values. CONCLUSIONS: In this case study in Vietnam, we project that treatment of HCV for injecting drug users will have a preventative herd effect in addition to curing patients in need for therapy, achieving a substantial reduction in HCV transmission and prevalence.

Winterberg M, Rajendran E, Baumeister S, Bietz S, Kirk K, Lingelbach K. 2012. Chemical activation of a high-affinity glutamate transporter in human erythrocytes and its implications for malaria-parasite-induced glutamate uptake. Blood, 119 (15), pp. 3604-3612. | Citations: 10 (Scopus) | Show Abstract | Read more

Human erythrocytes have a low basal permeability to L-glutamate and are not known to have a functional glutamate transporter. Here, treatment of human erythrocytes with arsenite was shown to induce the uptake of L-glutamate and D-aspartate, but not that of D-glutamate or L-alanine. The majority of the arsenite-induced L-glutamate influx was via a high-affinity, Na(+)-dependent system showing characteristics of members of the "excitatory amino acid transporter" (EAAT) family. Western blots and immunofluorescence assays revealed the presence of a member of this family, EAAT3, on the erythrocyte membrane. Erythrocytes infected with the malaria parasite Plasmodium falciparum take up glutamate from the extracellular environment. Although the majority of uptake is via a low-affinity Na(+)-independent pathway there is, in addition, a high-affinity uptake component, raising the possibility that the parasite activates the host cell glutamate transporter.

Warimwe GM, Fegan G, Musyoki JN, Newton CRJC, Opiyo M, Githinji G, Andisi C, Menza F, Kitsao B, Marsh K, Bull PC. 2012. Prognostic indicators of life-threatening malaria are associated with distinct parasite variant antigen profiles. Sci Transl Med, 4 (129), pp. 129ra45. | Citations: 43 (Scopus) | Show Abstract | Read more

PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called "group A" in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the var genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A-like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population.

van Noort SP, Águas R, Ballesteros S, Gomes MGM. 2012. The role of weather on the relation between influenza and influenza-like illness. J Theor Biol, 298 pp. 131-137. | Citations: 35 (Scopus) | Show Abstract | Read more

Influenza epidemics, enabled by viral antigenic drift, occur invariably each winter in temperate climates. However, attempts to correlate the magnitude of virus change and epidemic size have been unsatisfactory. The incidence of influenza is not typically measured directly, but rather derived from the incidence of influenza-like illness (ILI), a clinical syndrome. Weather factors have been shown to influence the manifestation of influenza-like symptoms. We fitted an influenza transmission model to time series of influenza-like illness as monitored from 2003 to 2010 by two independent symptomatic surveillance systems (Influenzanet and EISN) in three European countries. By assuming that seasonality only acts upon the manifestation of symptoms, the model shows a significant correlation between the absolute humidity and temperature at the time of infection, and the proportion of influenza infections fulfilling the clinical ILI case definition, the so-called ILI factor. When a weather-dependent ILI factor is included in the model, the epidemic size of influenza-like illness becomes dependent not only on the susceptibility of the population at the beginning of the epidemic season but also on the weather conditions during which the epidemic unfolds. The combination reduces season-to-season variation in epidemic size and, interestingly, leads to a non-monotonic trend whereby the largest ILI epidemic occurs for moderate initial susceptibility.

Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, ler Moo C, Al-Saai S, Dondorp AM, Lwin KM et al. 2012. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet, 379 (9830), pp. 1960-1966. | Citations: 473 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border. METHODS: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. FINDINGS: 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. INTERPRETATION: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years. FUNDING: The Wellcome Trust and National Institutes of Health.

Tho DQ, Török ME, Yen NTB, Bang ND, Lan NTN, Kiet VS, van Vinh Chau N, Dung NH, Day J, Farrar J et al. 2012. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother, 56 (6), pp. 3074-3079. | Citations: 20 (Web of Science Lite) | Show Abstract | Read more

HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.

Akbar NA, Allende I, Balmaseda A, Coelho ICB, da Cunha RV, Datta B, Devi SS, Farrar J, Gaczkowski R, Guzman MG et al. 2012. Regarding "Dengue--how best to classify it". Clin Infect Dis, 54 (12), pp. 1820-1821. | Citations: 8 (Scopus) | Read more

Turner GDH, Bunthi C, Wonodi CB, Morpeth SC, Molyneux CS, Zaki SR, Levine OS, Murdoch DR, Scott JAG. 2012. The role of postmortem studies in pneumonia etiology research. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S165-S171. | Citations: 14 (Scopus) | Show Abstract | Read more

The diagnosis of etiology in severe pneumonia remains a challenging area. Postmortem lung tissue potentially increases the sensitivity of investigations for identification of causative pathogens in fatal cases of pneumonia and can confirm antemortem microbiological diagnoses. Tissue sampling allows assessment of histological patterns of disease and ancillary immunohistochemical or molecular diagnostic techniques. It may also enhance the recognition of noninfectious conditions that clinically simulate acute pneumonia. Biobanking of lung tissue or postmortem culture isolates offers opportunities for new pathogen discovery and research into host-pathogen interactions. The Pneumonia Etiology Research for Child Health study proposes a percutaneous needle biopsy approach to obtain postmortem samples, rather than a full open autopsy. This has the advantage of greater acceptability to relatives, but risks greater sampling error. Both approaches may be susceptible to microbiological contamination or pathogen degradation. However, previous autopsy studies have confirmed the value of histological examination in revealing unsuspected pathogens and influencing clinical guidelines for the diagnosis and treatment of future pneumonia cases.

Conlan JV, Khamlome B, Vongxay K, Elliot A, Pallant L, Sripa B, Blacksell SD, Fenwick S, Thompson RCA. 2012. Soil-transmitted helminthiasis in Laos: a community-wide cross-sectional study of humans and dogs in a mass drug administration environment. Am J Trop Med Hyg, 86 (4), pp. 624-634. | Citations: 48 (Scopus) | Show Abstract | Read more

We conducted a community cross-sectional survey of soil-transmitted helminthiasis in humans and dogs in four provinces in northern Laos. We collected and tested human and dog fecal samples and analyzed results against sociodemographic data. The prevalence of Ascaris lumbricoides, Trichuris trichiura, hookworm, and Strongyloides stercoralis was 26.1% (95% confidence interval [CI] = 23.7-28.4%), 41.5% (95% CI = 38.8-44.1%), 46.3% (95% CI = 43.3-49.0%), and 8.9% (95% CI = 7.4-10.4%), respectively. We observed strong heterogeneity for helminthiasis by ethnicity, province, and wealth status, which coincided with a risk profile demonstrating that Mon-Khmer persons and the poorest households are highly vulnerable. Necator americanus was the dominant hookworm species infecting humans and Ancylostoma ceylanicum was the only Ancylostoma species detected. Hookworm prevalence in village dogs was 94%, and the dominant species was A. ceylanicum. Necator americanus was also detected in dogs. It appears that dogs have a role in human hookworm transmission and warrant further investigation.

Cooper BS, Kypraios T, Batra R, Wyncoll D, Tosas O, Edgeworth JD. 2012. Quantifying type-specific reproduction numbers for nosocomial pathogens: evidence for heightened transmission of an Asian sequence type 239 MRSA clone. PLoS Comput Biol, 8 (4), pp. e1002454. | Citations: 18 (Scopus) | Show Abstract | Read more

An important determinant of a pathogen's success is the rate at which it is transmitted from infected to susceptible hosts. Although there are anecdotal reports that methicillin-resistant Staphylococcus aureus (MRSA) clones vary in their transmissibility in hospital settings, attempts to quantify such variation are lacking for common subtypes, as are methods for addressing this question using routinely-collected MRSA screening data in endemic settings. Here we present a method to quantify the time-varying transmissibility of different subtypes of common bacterial nosocomial pathogens using routine surveillance data. The method adapts approaches for estimating reproduction numbers based on the probabilistic reconstruction of epidemic trees, but uses relative hazards rather than serial intervals to assign probabilities to different sources for observed transmission events. The method is applied to data collected as part of a retrospective observational study of a concurrent MRSA outbreak in the United Kingdom with dominant endemic MRSA clones (ST22 and ST36) and an Asian ST239 MRSA strain (ST239-TW) in two linked adult intensive care units, and compared with an approach based on a fully parametric transmission model. The results provide support for the hypothesis that the clones responded differently to an infection control measure based on the use of topical antiseptics, which was more effective at reducing transmission of endemic clones. They also suggest that in one of the two ICUs patients colonized or infected with the ST239-TW MRSA clone had consistently higher risks of transmitting MRSA to patients free of MRSA. These findings represent some of the first quantitative evidence of enhanced transmissibility of a pandemic MRSA lineage, and highlight the potential value of tailoring hospital infection control measures to specific pathogen subtypes.

Warrell DA. 2012. Mechanisms of Envenoming: An Overview of their Relevance in Treating Patients CLINICAL TOXICOLOGY, 50 (4), pp. 279-280.

Holloway C, Ntusi N, Suttie J, Mahmod M, Clutton G, Hancock G, Wainwright E, Angus B, Asaad M, Beak P et al. 2012. Comprehensive Cardiac Magnetic Resonance Reveals HIV is Associated with High Burden of Myocardial Disease HIV MEDICINE, 13 pp. 3-3.

Dünser MW, Festic E, Dondorp A, Kissoon N, Ganbat T, Kwizera A, Haniffa R, Baker T, Schultz MJ, Global Intensive Care Working Group of European Society of Intensive Care Medicine. 2012. Recommendations for sepsis management in resource-limited settings. Intensive Care Med, 38 (4), pp. 557-574. | Citations: 63 (Web of Science Lite) | Show Abstract | Read more

PURPOSE: To provide clinicians practicing in resource-limited settings with a framework to improve the diagnosis and treatment of pediatric and adult patients with sepsis. METHODS: The medical literature on sepsis management was reviewed. Specific attention was paid to identify clinical evidence on sepsis management from resource-limited settings. RESULTS: Recommendations are grouped into acute and post-acute interventions. Acute interventions include liberal fluid resuscitation to achieve adequate tissue perfusion, normal heart rate and arterial blood pressure, use of epinephrine or dopamine for inadequate tissue perfusion despite fluid resuscitation, frequent measurement of arterial blood pressure in hemodynamically unstable patients, administration of hydrocortisone or prednisolone to patients requiring catecholamines, oxygen administration to achieve an oxygen saturation >90%, semi-recumbent and/or lateral position, non-invasive ventilation for increased work of breathing or hypoxemia despite oxygen therapy, timely administration of adequate antimicrobials, thorough clinical investigation for infectious source identification, fluid/tissue sampling and microbiological work-up, removal, drainage or debridement of the infectious source. Post-acute interventions include regular re-assessment of antimicrobial therapy, administration of antimicrobials for an adequate but not prolonged duration, avoidance of hypoglycemia, pharmacological or mechanical deep vein thrombosis prophylaxis, resumption of oral food intake after resuscitation and regaining of consciousness, careful use of opioids and sedatives, early mobilization, and active weaning of invasive support. Specific considerations for malaria, puerperal sepsis and HIV/AIDS patients with sepsis are included. CONCLUSION: Only scarce evidence exists for the management of pediatric and adult sepsis in resource-limited settings. The presented recommendations may help to improve sepsis management in middle- and low-income countries.

Khan MI, Ochiai RL, Soofi SB, Von-Seidlein L, Khan MJ, Sahito SM, Habib MA, Puri MK, Park JK, You YA et al. 2012. Risk factors associated with typhoid fever in children aged 2-16 years in Karachi, Pakistan. Epidemiol Infect, 140 (4), pp. 665-672. | Citations: 8 (Scopus) | Show Abstract | Read more

We analysed the data from the control group in a typhoid vaccine trial in Karachi to assess the differences in individual-, household- and cluster-level characteristics for developing typhoid fever. The annual incidence of typhoid in children aged 2-16 years in the control arm of the vaccine trial was 151/100 000 population. After adjustment, the risk of typhoid was lower with increasing age [risk ratio (RR) 0·89, 95% confidence interval (CI) 0·83-0·95], was higher with an increase in population density (RR 1·13, 95% CI 1·05-1·21) and was lower in the households using a safe drinking-water source (RR 0·63, 95% CI 0·41-0·99). Typhoid fever affects younger children living in areas of high population density and lack of access to safe water in Pakistan. A combination of environmental and biological interventions is required to prevent the continued epidemiological and economic impact of typhoid fever in high-risk areas of Pakistan.

Tan CYQ, Gonfrier G, Ninove L, Zandotti C, Dubot-Pérès A, de Lamballerie X, Charrel RN. 2012. Screening and detection of human enterovirus 71 infection by a real-time RT-PCR assay in Marseille, France, 2009-2011. Clin Microbiol Infect, 18 (4), pp. E77-E80. | Citations: 5 (Scopus) | Show Abstract | Read more

Enterovirus-positive samples diagnosed in Marseille (January 2009 to September 2011) were screened for EV71 by real-time RT-PCR. EV71 was detected in three children below the age of 2 years with no history of overseas travel; two of these cases were associated with severe clinical presentation. Viruses demonstrated genetic similarity to other European genogroup C2 strains. Strain MRS/09/3663 complete sequencing revealed 97.6% identity across the entire genome with a 2008 Singapore isolate, without signs of possible recombination events. To our knowledge, this is the first detection of EV71 infection in Marseille, France, that confirms the current circulation of EV71 in France.

Hamers RL, Schuurman R, Sigaloff KCE, Wallis CL, Kityo C, Siwale M, Mandaliya K, Ive P, Botes ME, Wellington M et al. 2012. Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study. Lancet Infect Dis, 12 (4), pp. 307-317. | Citations: 77 (Scopus) | Show Abstract | Read more

BACKGROUND: The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. METHODS: HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. FINDINGS: Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44-3·14; p<0·0001) and acquired drug-resistance (2·30, 1·55-3·40; p<0·0001) was increased in participants with pretreatment drug resistance to at least one prescribed drug, but not in those with pretreatment drug resistance and fully active ART. CD4 count increased less in participants with pretreatment drug resistance than in those without (35 cells per μL difference after 12 months; 95% CI 13-58; p=0·002). INTERPRETATION: At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. FUNDING: The Netherlands Ministry of Foreign Affairs.

Clutterbuck EA, Lazarus R, Yu L-M, Bowman J, Bateman EAL, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. 2012. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J Infect Dis, 205 (9), pp. 1408-1416. | Citations: 125 (Scopus) | Show Abstract | Read more

BACKGROUND: A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults. METHODS: We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved. RESULTS: A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans. CONCLUSIONS: This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP. Clinical Trials Registration. ISRCTN: 78768849.

Ch'ng J-H, Renia L, Nosten F, Tan KSW. 2012. Can we teach an old drug new tricks? Trends Parasitol, 28 (6), pp. 220-224. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions.

Schlackow I, Stoesser N, Walker AS, Crook DW, Peto TEA, Wyllie DH, Infections in Oxfordshire Research Database Team. 2012. Increasing incidence of Escherichia coli bacteraemia is driven by an increase in antibiotic-resistant isolates: electronic database study in Oxfordshire 1999-2011. J Antimicrob Chemother, 67 (6), pp. 1514-1524. | Citations: 16 (Scopus) | Show Abstract | Read more

OBJECTIVES: To investigate trends in Escherichia coli resistance, bacteraemia rates and post-bacteraemia outcomes over time. METHODS: Trends in E. coli bacteraemia incidence were monitored from January 1999 to June 2011 using an infection surveillance database including microbiological, clinical risk factor, infection severity and outcome data in Oxfordshire, UK, with imported temperature/rainfall data. RESULTS: A total of 2240 E. coli (from 2080 patients) were studied, of which 1728 (77%) were susceptible to co-amoxiclav, cefotaxime, ciprofloxacin and gentamicin. E. coli bacteraemia incidence increased from 3.4/10,000 bedstays in 1999 to 5.7/10,000 bedstays in 2011. The increase was fastest around 2006, and was essentially confined to organisms resistant to ciprofloxacin, co-amoxiclav, cefotaxime and/or aminoglycosides. Resistant E. coli isolation rates increased similarly in those with and without recent hospital contact. The sharp increase also occurred in urinary isolates, with similar timing. In addition to these long-term trends, increases in ambient temperature, but not rainfall, were associated with increased E. coli bacteraemia rates. It is unclear whether resistant E. coli bacteraemia rates are currently still increasing [incidence rate ratio = 1.07 per annum (95% CI = 0.99-1.16), P = 0.07], whereas current susceptible E. coli bacteraemia rates are not changing significantly [incidence rate ratio = 1.01 (95% CI = 0.99-1.02)]. However, neither mortality nor biomarkers associated with mortality (blood creatinine, urea/albumin concentrations, neutrophil counts) changed during the study. CONCLUSIONS: E. coli bacteraemia rates have risen due to rising rates of resistant organisms; little change occurred in susceptible E. coli. Although the severity of resistant infections, and their outcome, appear similar to susceptible E. coli in the setting studied, the increasing burden of highly resistant organisms is alarming and merits on-going surveillance.

Blacksell SD, Jarman RG, Gibbons RV, Tanganuchitcharnchai A, Mammen MP, Nisalak A, Kalayanarooj S, Bailey MS, Premaratna R, de Silva HJ et al. 2012. Comparison of seven commercial antigen and antibody enzyme-linked immunosorbent assays for detection of acute dengue infection. Clin Vaccine Immunol, 19 (5), pp. 804-810. | Citations: 64 (Scopus) | Show Abstract | Read more

Seven commercial assays were evaluated to determine their suitability for the diagnosis of acute dengue infection: (i) the Panbio dengue virus Pan-E NS1 early enzyme-linked immunosorbent assay (ELISA), second generation (Alere, Australia); (ii) the Panbio dengue virus IgM capture ELISA (Alere, Australia); (iii) the Panbio dengue virus IgG capture ELISA (Alere, Australia); (iv) the Standard Diagnostics dengue virus NS1 antigen ELISA (Standard Diagnostics, South Korea); (v) the Standard Diagnostics dengue virus IgM ELISA (Standard Diagnostics, South Korea); (vi) the Standard Diagnostics dengue virus IgG ELISA (Standard Diagnostics, South Korea); and (vii) the Platelia NS1 antigen ELISA (Bio-Rad, France). Samples from 239 Thai patients confirmed to be dengue virus positive and 98 Sri Lankan patients negative for dengue virus infection were tested. The sensitivities and specificities of the NS1 antigen ELISAs ranged from 45 to 57% and 93 to 100% and those of the IgM antibody ELISAs ranged from 85 to 89% and 88 to 100%, respectively. Combining the NS1 antigen and IgM antibody results from the Standard Diagnostics ELISAs gave the best compromise between sensitivity and specificity (87 and 96%, respectively), as well as providing the best sensitivity for patients presenting at different times after fever onset. The Panbio IgG capture ELISA correctly classified 67% of secondary dengue infection cases. This study provides strong evidence of the value of combining dengue virus antigen- and antibody-based test results in the ELISA format for the diagnosis of acute dengue infection.

Chairat K, Tarning J, White NJ, Lindegardh N. 2012. Pharmacokinetic Properties of Anti-Influenza Neuraminidase Inhibitors. J Clin Pharmacol, 53 (2), pp. 119-139. | Citations: 21 (Scopus) | Show Abstract | Read more

Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t(&frac12;β)) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t(&frac12;β) of approximately 3.0 hours). Peramivir is slowly eliminated (t(&frac12;β) of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation.

Thao VP, Le T, Török EM, Yen NTB, Chau TTH, Jurriaans S, van Doorn HR, de Jong MD, Farrar JJ, Dunstan SJ. 2012. HIV-1 drug resistance in antiretroviral-naive individuals with HIV-1-associated tuberculous meningitis initiating antiretroviral therapy in Vietnam. Antivir Ther, 17 (5), pp. 905-913. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Access to antiretroviral therapy (ART) for HIV-infected individuals in Vietnam is rapidly expanding, but there are limited data on HIV drug resistance (HIVDR) to guide ART strategies. METHODS: We retrospectively conducted HIVDR testing in 220 ART-naive individuals recruited to a randomized controlled trial of immediate versus deferred ART in individuals with HIV-associated tuberculous meningitis in Ho Chi Minh City (HCMC) from 2005-2008. HIVDR mutations were identified by population sequencing of the HIV pol gene and were defined based on 2009 WHO surveillance drug resistance mutations (SDRMs). RESULTS: We successfully sequenced 219/220 plasma samples of subjects prior to ART; 218 were subtype CRF01_AE and 1 was subtype B. SDRMs were identified in 14/219 (6.4%) subjects; 8/14 were resistant to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; T69D, L74V, V75M, M184V/I and K219R), 5/14 to non-nucleoside reverse transcriptase inhibitors (NNRTIs; K103N, V106M, Y181C, Y188C and G190A), 1/14 to both NRTIs and NNRTIs (D67N and Y181C) and none to protease inhibitors. After 6 months of ART, eight subjects developed protocol-defined virological failure. HIVDR mutations were identified in 5/8 subjects. All five had mutations with high-level resistance to NNRTIs and three had mutations with high-level resistance to NRTIs. Due to a high early mortality rate (58%), the effect of pre-existing HIVDR mutations on treatment outcome could not be accurately assessed. CONCLUSIONS: The prevalence of WHO SDRMs in ART-naive individuals with HIV-associated tuberculous meningitis in HCMC from 2005-2008 is 6.4%. The SDRMs identified conferred resistance to NRTIs and/or NNRTIs, reflecting the standard first-line ART regimens in Vietnam.

Pratt B, Zion D, Lwin KM, Cheah PY, Nosten F, Loff B. 2012. Closing the translation gap for justice requirements in international research. J Med Ethics, 38 (9), pp. 552-558. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

Bioethicists have long debated the content of sponsors and researchers' obligations of justice in international clinical research. However, there has been little empirical investigation as to whether and how obligations of responsiveness, ancillary care, post-trial benefits and research capacity strengthening are upheld in low- and middle-income country settings. In this paper, the authors argue that research ethics guidelines need to be more informed by international research practice. Practical guidance on how to fulfil these obligations is needed if research groups and other actors are to successfully translate them into practice because doing so is often a complicated, context-specific process. Case study research methods offer one avenue for collecting data to develop this guidance. The authors describe how such methods have been used in relation to the Shoklo Malaria Research Unit's vivax malaria treatment (VHX) trial (NCT01074905). Relying on the VHX trial example, the paper shows how information can be gathered from not only international clinical researchers but also trial participants, community advisory board members and research funder representatives in order to: (1) measure evidence of responsiveness, provision of ancillary care, access to post-trial benefits and research capacity strengthening in international clinical research; and (2) identify the contextual factors and roles and responsibilities that were instrumental in the fulfilment of these ethical obligations. Such empirical work is necessary to inform the articulation of obligations of justice in international research and to develop guidance on how to fulfil them in order to facilitate better adherence to guidelines' requirements.

Baird JK. 2012. Elimination therapy for the endemic malarias. Curr Infect Dis Rep, 14 (3), pp. 227-237. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

Most malaria diagnosed outside endemic zones occurs in patients experiencing the consequences of what was likely a single infectious bite by an anopheline mosquito. A single species of parasite is nearly always involved and expert opinion on malaria chemotherapy uniformly prescribes species- and stage-specific treatments. However the vast majority of people experiencing malaria, those resident in endemic zones, do so repeatedly and very often with the involvement of two or more species and stages of parasite. Silent forms of these infections-asymptomatic and beyond the reach of diagnostics-may accumulate to form substantial and unchallenged reservoirs of infection. In such settings treating only the species and stage of malaria revealed by diagnosis and not others may not be sensible or appropriate. Developing therapeutic strategies that address all species and stages independently of diagnostic evidence may substantially improve the effectiveness of the control and elimination of endemic malaria.

Bakker OJ, van Santvoort HC, van Brunschot S, Geskus RB, Besselink MG, Bollen TL, van Eijck CH, Fockens P, Hazebroek EJ, Nijmeijer RM et al. 2012. Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis: a randomized trial. JAMA, 307 (10), pp. 1053-1061. | Citations: 245 (Scopus) | Show Abstract | Read more

CONTEXT: Most patients with infected necrotizing pancreatitis require necrosectomy. Surgical necrosectomy induces a proinflammatory response and is associated with a high complication rate. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, may reduce the proinflammatory response and reduce complications. OBJECTIVE: To compare the proinflammatory response and clinical outcome of endoscopic transgastric and surgical necrosectomy. DESIGN, SETTING, AND PATIENTS: Randomized controlled assessor-blinded clinical trial in 3 academic hospitals and 1 regional teaching hospital in The Netherlands between August 20, 2008, and March 3, 2010. Patients had signs of infected necrotizing pancreatitis and an indication for intervention. INTERVENTIONS: Random allocation to endoscopic transgastric or surgical necrosectomy. Endoscopic necrosectomy consisted of transgastric puncture, balloon dilatation, retroperitoneal drainage, and necrosectomy. Surgical necrosectomy consisted of video-assisted retroperitoneal debridement or, if not feasible, laparotomy. MAIN OUTCOME MEASURES: The primary end point was the postprocedural proinflammatory response as measured by serum interleukin 6 (IL-6) levels. Secondary clinical end points included a predefined composite end point of major complications (new-onset multiple organ failure, intra-abdominal bleeding, enterocutaneous fistula, or pancreatic fistula) or death. RESULTS: We randomized 22 patients, 2 of whom did not undergo necrosectomy following percutaneous catheter drainage and could not be analyzed for the primary end point. Endoscopic transgastric necrosectomy reduced the postprocedural IL-6 levels compared with surgical necrosectomy (P = .004). The composite clinical end point occurred less often after endoscopic necrosectomy (20% vs 80%; risk difference [RD], 0.60; 95% CI, 0.16-0.80; P = .03). Endoscopic necrosectomy did not cause new-onset multiple organ failure (0% vs 50%, RD, 0.50; 95% CI, 0.12-0.76; P = .03) and reduced the number of pancreatic fistulas (10% vs 70%; RD, 0.60; 95% CI, 0.17-0.81; P = .02). CONCLUSION: In patients with infected necrotizing pancreatitis, endoscopic necrosectomy reduced the proinflammatory response as well as the composite clinical end point compared with surgical necrosectomy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN07091918.

Horby P, Mai LQ, Fox A, Thai PQ, Thi Thu Yen N, Thanh LT, Le Khanh Hang N, Duong TN, Thoang DD, Farrar J et al. 2012. The epidemiology of interpandemic and pandemic influenza in Vietnam, 2007-2010: the Ha Nam household cohort study I. Am J Epidemiol, 175 (10), pp. 1062-1074. | Citations: 46 (Web of Science Lite) | Show Abstract | Read more

Prospective community-based studies have provided fundamental insights into the epidemiology of influenza in temperate regions, but few comparable studies have been undertaken in the tropics. The authors conducted prospective influenza surveillance and intermittent seroprevalence surveys in a household-based cohort in Vietnam between December 2007 and April 2010, resulting in 1,793 person-seasons of influenza surveillance. Age- and sex-standardized estimates of the risk of acquiring any influenza infection per season in persons 5 years of age or older were 21.1% (95% confidence interval: 17.4, 24.7) in season 1, 26.4% (95% confidence interval: 22.6, 30.2) in season 2, and 17.0% (95% confidence interval: 13.6, 20.4) in season 3. Some individuals experienced multiple episodes of infection with different influenza types/subtypes in the same season (n = 27) or reinfection with the same subtype in different seasons (n = 22). The highest risk of influenza infection was in persons 5-9 years old, in whom the risk of influenza infection per season was 41.8%. Although the highest infection risk was in school-aged children, there were important heterogeneities in the age of infection by subtype and season. These heterogeneities could influence the impact of school closure and childhood vaccination on influenza transmission in tropical areas, such as Vietnam.

von Seidlein L, Olaosebikan R, Hendriksen ICE, Lee SJ, Adedoyin OT, Agbenyega T, Nguah SB, Bojang K, Deen JL, Evans J et al. 2012. Predicting the clinical outcome of severe falciparum malaria in african children: findings from a large randomized trial. Clin Infect Dis, 54 (8), pp. 1080-1090. | Citations: 60 (Scopus) | Show Abstract | Read more

BACKGROUND: Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. METHODS: African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model. RESULTS: Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models. CONCLUSIONS: Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.

Nkhoma SC, Nair S, Cheeseman IH, Rohr-Allegrini C, Singlam S, Nosten F, Anderson TJC. 2012. Close kinship within multiple-genotype malaria parasite infections. Proc Biol Sci, 279 (1738), pp. 2589-2598. | Citations: 37 (Web of Science Lite) | Show Abstract | Read more

Malaria infections containing multiple parasite genotypes are ubiquitous in nature, and play a central role in models of recombination, intra-host dynamics, virulence, sex ratio, immunity and drug resistance evolution in Plasmodium. While these multiple infections (MIs) are often assumed to result from superinfection (bites from multiple infected mosquitoes), we know remarkably little about their composition or generation. We isolated 336 parasite clones from eight patients from Malawi (high transmission) and six from Thailand (low transmission) by dilution cloning. These were genotyped using 384 single-nucleotide polymorphisms, revealing 22 independent haplotypes in Malawi (2-6 per MI) and 15 in Thailand (2-5 per MI). Surprisingly, all six patients from Thailand and six of eight from Malawi contained related haplotypes, and haplotypes were more similar within- than between-infections. These results argue against a simple superinfection model. Instead, the observed kinship patterns may be explained by inoculation of multiple related haploid sporozoites from single mosquito bites, by immune suppression of parasite subpopulations within infections, and serial transmission of related parasites between people. That relatedness is maintained in endemic areas in the face of repeated bites from infected mosquitoes has profound implications for understanding malaria transmission, immunity and intra-host dynamics of co-infecting parasite genotypes.

Mayxay M, Khanthavong M, Chanthongthip O, Imwong M, Lee SJ, Stepniewska K, Soonthornsata B, Pongvongsa T, Phompida S, Hongvanthong B et al. 2012. No evidence for spread of Plasmodium falciparum artemisinin resistance to Savannakhet Province, Southern Laos. Am J Trop Med Hyg, 86 (3), pp. 403-408. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

We conducted an open-label, randomized clinical trial to assess parasite clearance times (PCT) and the efficacy of 4 mg/kg (group 1, n = 22) and 2 mg/kg (group 2, n = 22) of oral artesunate for three days followed by artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria at Xepon Interdistrict Hospital, Savannakhet Province in southern Laos. Slides were read in duplicate. The overall mean (95% confidence interval; range) PCT in hours was 23.2 (21.2-25.3; 12-46) and 22.4 (20.3-24.5; 12-46) for the first and second microscopists, respectively (P = 0.57). Ten (23%) patients remained parasitemic on day 1 after treatment (4 [18%] in group 1 and 6 [27%] in group 2; P = 0.47). No patient had patent asexual parasitemia on the second and third days of treatment. The 42-day polymerase chain reaction-corrected cure rates were 100% in both treatment groups. Serious adverse events did not develop during or after treatment in any patients. In conclusion, no evidence of P. falciparum in vivo resistance to artesunate was found in southern Laos.

Desakorn V, Wuthiekanun V, Thanachartwet V, Sahassananda D, Chierakul W, Apiwattanaporn A, Day NP, Limmathurotsakul D, Peacock SJ. 2012. Accuracy of a commercial IgM ELISA for the diagnosis of human leptospirosis in Thailand. Am J Trop Med Hyg, 86 (3), pp. 524-527. | Citations: 23 (Scopus) | Show Abstract | Read more

The Leptospira immunoglobulin M enzyme-linked immunosorbent assay (IgM ELISA) has been recommended for the rapid diagnosis of leptospirosis in endemic areas. We conducted a retrospective case-control study of 218 patients (109 leptospirosis cases confirmed by Leptospira culture and/or microscopic agglutination test and 109 control patients with acute febrile illness) to evaluate the diagnostic accuracy of a commercial IgM ELISA (Panbio) in northeast Thailand. Paired serum samples taken on admission and at least 10 days after the onset of symptoms were tested. Using the cutoff value recommended by the manufacturer (11 Panbio units), sensitivity and specificity of IgM ELISA on paired sera were 90.8% and 55.1%. A receiver operating characteristic curve was used to determine the optimal cutoff value. This was 20 Panbio units, which gave a sensitivity and specificity of 76.1% and 82.6%, respectively, on paired sera. We conclude that using either cutoff value, the accuracy of IgM ELISA is limited in our setting.

Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. 2012. Into the eye of the cytokine storm. Microbiol Mol Biol Rev, 76 (1), pp. 16-32. | Citations: 235 (Scopus) | Show Abstract | Read more

The cytokine storm has captured the attention of the public and the scientific community alike, and while the general notion of an excessive or uncontrolled release of proinflammatory cytokines is well known, the concept of a cytokine storm and the biological consequences of cytokine overproduction are not clearly defined. Cytokine storms are associated with a wide variety of infectious and noninfectious diseases. The term was popularized largely in the context of avian H5N1 influenza virus infection, bringing the term into popular media. In this review, we focus on the cytokine storm in the context of virus infection, and we highlight how high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. We also address evidence for and against the role of the cytokine storm in the pathology of clinical and infectious disease and discuss why it has been so difficult to use knowledge of the cytokine storm and immunomodulatory therapies to improve the clinical outcomes for patients with severe acute infections.

Shrestha P, Basnyat B, Küpper T, van der Giet S. 2012. Cerebral venous sinus thrombosis at high altitude. High Alt Med Biol, 13 (1), pp. 60-62. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Cerebral venous sinus thrombosis (CVST) is a rare but potentially life-threatening medical condition. We describe a case of a 47-year-old woman who presented with headache, speech defects, and visual disturbances, and was later diagnosed with cerebral venous sinus thrombosis. The article describes a possible risk of such thrombotic events with exposure to high altitude environment in patients with coagulation defects such as Factor V Leiden mutation. Besides, such neurological conditions can occur independent of altitude illness and need to be recognized as their management differs.

Ferguson ME, Hearne SJ, Close TJ, Wanamaker S, Moskal WA, Town CD, de Young J, Marri PR, Rabbi IY, de Villiers EP. 2012. Identification, validation and high-throughput genotyping of transcribed gene SNPs in cassava. Theor Appl Genet, 124 (4), pp. 685-695. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

The availability of genomic resources can facilitate progress in plant breeding through the application of advanced molecular technologies for crop improvement. This is particularly important in the case of less researched crops such as cassava, a staple and food security crop for more than 800 million people. Here, expressed sequence tags (ESTs) were generated from five drought stressed and well-watered cassava varieties. Two cDNA libraries were developed: one from root tissue (CASR), the other from leaf, stem and stem meristem tissue (CASL). Sequencing generated 706 contigs and 3,430 singletons. These sequences were combined with those from two other EST sequencing initiatives and filtered based on the sequence quality. Quality sequences were aligned using CAP3 and embedded in a Windows browser called HarvEST:Cassava which is made available. HarvEST:Cassava consists of a Unigene set of 22,903 quality sequences. A total of 2,954 putative SNPs were identified. Of these 1,536 SNPs from 1,170 contigs and 53 cassava genotypes were selected for SNP validation using Illumina's GoldenGate assay. As a result 1,190 SNPs were validated technically and biologically. The location of validated SNPs on scaffolds of the cassava genome sequence (v.4.1) is provided. A diversity assessment of 53 cassava varieties reveals some sub-structure based on the geographical origin, greater diversity in the Americas as opposed to Africa, and similar levels of diversity in West Africa and southern, eastern and central Africa. The resources presented allow for improved genetic dissection of economically important traits and the application of modern genomics-based approaches to cassava breeding and conservation.

Kroon MW, Joore ICKW, Wind BS, Leloup MAC, Wolkerstorfer A, Luiten RM, Bos JD, Geskus RB, van der Veen JPW. 2012. Low yield of routine screening for thyroid dysfunction in asymptomatic patients with vitiligo. Br J Dermatol, 166 (3), pp. 532-538. | Citations: 12 (Scopus) | Show Abstract | Read more

BACKGROUND: Nonsegmental vitiligo is considered to be an autoimmune disease and is known to be associated with other autoimmune diseases, particularly affecting the thyroid. Screening patients with nonsegmental vitiligo for thyroid function and for the presence of thyroid autoantibodies has been recommended. OBJECTIVE: To investigate the prevalence of thyroid dysfunction and thyroid peroxidase-specific (TPO) antibodies in a large cohort of patients with nonsegmental vitiligo in order to help decide whether routine screening is justified. METHODS: A total of 434 adults with nonsegmental vitiligo who were referred to our institute were enrolled. Thyroid function and anti-TPO antibody titres were assessed in those patients who had no history of thyroid disease or recent thyroid screening. RESULTS: Forty-three patients had already been diagnosed with thyroid dysfunction, and in 27 patients the general practitioner had performed a thyroid function test with negative results <3months previously. In these patients, thyroid function assessment was not repeated. The remaining 364 patients were screened for thyroid dysfunction. Overt hypothyroidism was newly diagnosed in three (0·8%) patients; subclinical disease was found in 10 (2·7%) patients and increased levels of TPO antibodies, without thyroid disease, were found in 49 (13·5%) patients. An elevated risk for thyroid disease was found among older women and in women with a positive family history of thyroid disease. CONCLUSION: The overall prevalence of thyroid dysfunction in adult patients with nonsegmental vitiligo was higher than reported in the general population. However, the number of newly diagnosed cases with overt and subclinical thyroid dysfunction in our population was low. Most patients had already been diagnosed by their general practitioner and had symptoms indicative for thyroid disease. Thyroid disease was found predominantly among older women and in subjects with a positive family history of thyroid disease. Thyroid screening including anti-TPO antibodies is advisable in these high-risk subpopulations.

Matser A, Urbanus A, Geskus R, Kretzschmar M, Xiridou M, Buster M, Coutinho R, Prins M. 2012. The effect of hepatitis C treatment and human immunodeficiency virus (HIV) co-infection on the disease burden of hepatitis C among injecting drug users in Amsterdam. Addiction, 107 (3), pp. 614-623. | Citations: 18 (Scopus) | Show Abstract | Read more

AIMS: The hepatitis C virus (HCV) disease burden among injecting drug users (IDUs) is determined by HCV incidence, the long latency period of HCV, competing mortality causes, presence of co-infection and HCV treatment uptake. We examined the effect of these factors and estimated the HCV disease burden in Amsterdam. DESIGN: A Markov model was developed, incorporating HCV and human immunodeficiency virus (HIV), and parameterized with data from the Amsterdam Cohort Studies, surveillance studies and literature. SETTING: IDU population of Amsterdam. MEASUREMENTS: HCV infection simulated from its acute phase to HCV-related liver disease (i.e. decompensated cirrhosis and hepatocellular carcinoma). FINDINGS: The HCV prevalence among IDUs in Amsterdam increased to approximately 80% in the 1980s. From 2011 to 2025, the HCV-related disease prevalence will accordingly rise by 36%, from 57 cases (95% range 33-94) to 78 (95% range 43-138), respectively. In total, 945 (95% range 617-1309) individuals will develop HCV-related liver disease. This burden would have been 33% higher in the absence of HIV, resulting in 1219 cases (95% range 796-1663). In Amsterdam, 25% of HIV-negative IDUs receive successful HCV treatment, reducing the cumulative disease burden by 14% to 810 (95% range 520-1120). Further reduction of 36% can be achieved by improving treatment, resulting in 603 cases (95% range 384-851). CONCLUSIONS: The hepatitis C virus burden among injecting drug users in Amsterdam has been reduced by a high competing mortality rate, particularly caused by HIV infection, and to a smaller extent by hepatitis C virus treatment. Improved hepatitis C virus treatment is expected to contribute to reduce the future hepatitis C virus disease burden.

Koirala KD, Thanh DP, Thapa SD, Arjyal A, Karkey A, Dongol S, Shrestha UM, Farrar JJ, Basnyat B, Baker S. 2012. Highly resistant Salmonella enterica serovar Typhi with a novel gyrA mutation raises questions about the long-term efficacy of older fluoroquinolones for treating typhoid fever. Antimicrob Agents Chemother, 56 (5), pp. 2761-2762. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

As a consequence of multidrug resistance, clinicians are highly dependent on fluoroquinolones for treating the serious systemic infection typhoid fever. While reduced susceptibility to fluoroquinolones, which lessens clinical efficacy, is becoming ubiquitous, comprehensive resistance is exceptional. Here we report ofloxacin treatment failure in typhoidal patient infected with a novel, highly fluoroquinolone-resistant isolate of Salmonella enterica serovar Typhi. The isolation of this organism has serious implications for the long-term efficacy of ciprofloxacin and ofloxacin for typhoid treatment.

Mwangome MK, Fegan G, Mbunya R, Prentice AM, Berkley JA. 2012. Reliability and accuracy of anthropometry performed by community health workers among infants under 6 months in rural Kenya. Trop Med Int Health, 17 (5), pp. 622-629. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To assess the inter-observer variability and accuracy of Mid Upper Arm Circumference (MUAC) and weight-for-length Z score (WFLz) among infants aged <6 months performed by community health workers (CHWs) in Kilifi District, Kenya. METHODS: A cross-sectional repeatability study estimated inter-observer variation and accuracy of measurements initially undertaken by an expert anthropometrist, nurses and public health technicians. Then, after training, 18 CHWs (three at each of six sites) repeatedly measured MUAC, weight and length of infants aged <6 months. Intra-class correlations (ICCs) and the Pitman's statistic were calculated. RESULTS: Among CHWs, ICCs pooled across the six sites (924 infants) were 0.96 (95% CI 0.95-0.96) for MUAC and 0.71 (95% CI 0.68-0.74) for WFLz. MUAC measures by CHWs differed little from their trainers: the mean difference in MUAC was 0.65 mm (95% CI 0.023-1.07), with no significant difference in variance (P = 0.075). CONCLUSION: Mid Upper Arm Circumference is more reliably measured by CHWs than WFLz among infants aged <6 months. Further work is needed to define cut-off values based on MUAC's ability to predict mortality among younger infants.

van Doorn HR, Kinh NV, Tuan HM, Tuan TA, Minh NNQ, Bryant JE, Hang VTT, Uyen LTT, Thinh LQ, Anh TTN et al. 2012. Clinical validation of a point-of-care multiplexed in vitro immunoassay using monoclonal antibodies (the MSD influenza test) in four hospitals in Vietnam. J Clin Microbiol, 50 (5), pp. 1621-1625. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

Point-of-care (POC) diagnostic tests for influenza can considerably shorten the time to clinical decision making. An investigational POC test based on a multiplexed immunoassay was developed by Meso Scale Diagnostics, LLC (MSD), with the objective to make a more sensitive rapid test that can also subtype influenza A viruses (1977 H1, H3, and H5). Between February and November 2010, we conducted a prospective multicenter study at four hospitals in Vietnam and compared the performance of this test to that of the WHO/CDC real-time reverse transcriptase PCR (RT-PCR) on nasal and throat swab specimens from patients presenting with influenza-like illness. Five hundred sixty-three adults and children with a median age of 25 months were enrolled. Sensitivity and specificity of the test with combined results from nasal and throat swab samples were 74.0% (131/177) and 99.7% (351/352), respectively, compared to RT-PCR. The POC test was as sensitive for influenza virus B as for influenza virus A (74.4% [64/86] versus 73.6% [67/91]). The positivity rate was associated with lower cycle threshold values (a marker for higher viral loads), sample type (73.6% for nasal swab versus 52.4% for throat swab), and younger age. A total of 210 (18.7%) out of 1,126 MSD tests failed, and for 34 (6%) of patients, both test samples failed (these were excluded from the performance analysis). Subtyping could be assessed only for influenza virus A/H3N2, as 1977 H1N1 was not circulating at the time and no H5N1-infected patients were enrolled, and was successful only in 9/54 patients infected with H3 influenza virus who had a positive POC test result for influenza virus A. This novel POC test provided highly sensitive detection of influenza viruses A and B compared to the reported sensitivities of other rapid tests. However, 18.7% of tests failed for technical reasons and subtyping for H3 was poor. Drawbacks to the technology include the requirement for a dedicated reader instrument and the need for continual updating of subtyping antibodies within the test array.

Heuker J, Sonder GJB, Stolte I, Geskus R, van den Hoek A. 2012. High HIV incidence among MSM prescribed postexposure prophylaxis, 2000-2009: indications for ongoing sexual risk behaviour. AIDS, 26 (4), pp. 505-512. | Citations: 25 (Scopus) | Show Abstract | Read more

OBJECTIVE: To determine (trends in) HIV incidence among MSM\ who have recently had postexposure prophylaxis (PEP) prescribed in Amsterdam, compared with MSM participating in the Amsterdam Cohort Studies (ACS). DESIGN AND METHODS: We used data from MSM who were prescribed PEP in Amsterdam between 2000 and 2009, who were HIV-negative at the time of PEP prescription and had follow-up HIV testing 3 and/or 6 months after PEP prescription (n = 395). For comparison, cohort data from MSM participating in the ACS in the same period were used (n = 782). Poisson log-linear regression analyses were performed to model trends in HIV incidence and identify differences in HIV incidence between both cohorts at different time points. RESULTS: Between 2000 and 2009, among MSM who were prescribed PEP, an overall HIV incidence of 6.4 [95% confidence interval (CI) 3.4-11.2] per 100 person-years was found, compared with an HIV incidence of 1.6 (95% CI 1.3-2.1) per 100 person-years among MSM participating in the ACS (P < 0.01). In both cohorts, an increasing trend in HIV incidence over time was observed [incidence rate ratio (IRR(per calendar year)) 1.3 (95% CI 0.9-1.7) and 1.1 (95% CI 1.0-1.2) among MSM prescribed PEP and MSM of the ACS, respectively]. The difference in HIV incidence between both cohorts was most evident in more recent years [IRR(PEP versus ACS in 2009) 4.8 (95% CI 2.0-11.5)]. CONCLUSION: Particularly in more recent years, MSM recently prescribed PEP had a higher HIV incidence compared with MSM participating in the ACS, indicating ongoing sexual risk behaviour.

Heijman T, Geskus RB, Davidovich U, Coutinho RA, Prins M, Stolte IG. 2012. Less decrease in risk behaviour from pre-HIV to post-HIV seroconversion among MSM in the combination antiretroviral therapy era compared with the pre-combination antiretroviral therapy era. AIDS, 26 (4), pp. 489-495. | Citations: 28 (Scopus) | Show Abstract | Read more

OBJECTIVE: To gain insight in the ongoing HIV transmission, we compared sexual risk behaviour pre-HIV and post-HIV seroconversion in 206 MSM participating in the Amsterdam Cohort Studies (1984-2008) before and after the introduction of combination antiretroviral therapy (cART). DESIGN AND METHODS: MSM completed behavioural questionnaires and were tested for HIV antibodies every 6 months. Trends in anal intercourse and number of sex partners from 4 years before HIV seroconversion until 4 years after diagnosis were analysed with latent class random effects logistic regression models. RESULTS: The risk of having unprotected anal intercourse (UAI) 1 year after HIV diagnosis decreased significantly when compared with 1 year before diagnosis in both the pre-cART era [difference, 30%; 95% confidence interval (CI), 22-36%] and cART era (difference, 19%; 95% CI, 9-30%). In contrast to a continuing decrease of UAI in the pre-cART era, the probability of UAI in the cART era increased again to preseroconversion levels (61%; 95% CI, 48-74%)) 4 years after diagnosis. CONCLUSION: This study provides evidence that recently seroconverted MSM reduce their sexual risk behaviour following HIV diagnosis both in the pre-cART as well as the cART period. However, in the cART period this reduction in sexual risk behaviour is less and returns to pre-cART levels within 4 years. These findings not only confirm the need for early HIV testing but also make it clear that much more effort should go into identifying, counselling, and possibly treating recently seroconverted MSM who have been found to be one of the most important drivers of HIV transmission among MSM.

Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. 2012. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol, 8 (2), pp. 108-117. | Show Abstract | Read more

Severe organophosphate compound (OPC) poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine the best therapy. A study was therefore undertaken to determine the optimal dosing regimen for atropine in the treatment of OPC poisoning. An open-label randomized clinical trial was conducted in Chittagong Medical College Hospital, Chittagong, Bangladesh, on 156 hospitalized individuals with OPC poisoning from June to September 2006. The aim was to compare the efficacy and safety of conventional bolus doses with individualized incremental doses of atropine for atropinization followed by continuous atropine infusion for management of OPC poisoning. Inclusion criteria were patients with a clear history of OPC poisoning with clear clinical signs of toxicity, i.e. features of cholinergic crisis. The patients were observed for at least 96 h. Immediate outcome and complications were recorded. Out of 156 patients, 81 patients received conventional bolus dose atropine (group A) and 75 patients received rapidly incremental doses of atropine followed by infusion (group B). The mortality in group 'A' was 22.5% (18/80) and in group 'B' 8% (6/75) (p < 0.05). The mean duration of atropinization in group 'A' was 151.74 min compared to 23.90 min for group 'B' (p < 0.001). More patients in group A experienced atropine toxicity than in group 'B' (28.4% versus 12.0%, p < 0.05); intermediate syndrome was more common in group 'A' than in group 'B' (13.6% versus 4%, p < 0.05), and respiratory support was required more often for patients in group 'A' than in group 'B' (24.7% versus 8%, p < 0.05). Rapid incremental dose atropinization followed by atropine infusion reduces mortality and morbidity from OPC poisoning and shortens the length of hospital stay and recovery. Incremental atropine and infusion should become the treatment of choice for OPC poisoning. Given the paucity of existing evidence, further clinical studies should be performed to determine the optimal dosing regimen of atropine that most rapidly and safely achieves atropinization in these patients.

Thriemer K, Ley B, Ame S, von Seidlein L, Pak GD, Chang NY, Hashim R, Schmied WH, Busch CJ-L, Nixon S et al. 2012. The burden of invasive bacterial infections in Pemba, Zanzibar. PLoS One, 7 (2), pp. e30350. | Citations: 27 (Scopus) | Show Abstract | Read more

BACKGROUND: We conducted a surveillance study to determine the leading causes of bloodstream infection in febrile patients seeking treatment at three district hospitals in Pemba Island, Zanzibar, Tanzania, an area with low malaria transmission. METHODS: All patients above two months of age presenting to hospital with fever were screened, and blood was collected for microbiologic culture and malaria testing. Bacterial sepsis and malaria crude incidence rates were calculated for a one-year period and were adjusted for study participation and diagnostic sensitivity of blood culture. RESULTS: Blood culture was performed on 2,209 patients. Among them, 166 (8%) samples yielded bacterial growth; 87 (4%) were considered as likely contaminants; and 79 (4%) as pathogenic bacteria. The most frequent pathogenic bacteria isolated were Salmonella Typhi (n = 46; 58%), followed by Streptococcus pneumoniae (n = 12; 15%). The crude bacteremia rate was 6/100,000 but when adjusted for potentially missed cases the rate may be as high as 163/100,000. Crude and adjusted rates for S. Typhi infections and malaria were 4 and 110/100,000 and 4 and 47/100,000, respectively. Twenty three (51%), 22 (49%) and 22 (49%) of the S. Typhi isolates were found to be resistant toward ampicillin, chloramphenicol and cotrimoxazole, respectively. Multidrug resistance (MDR) against the three antimicrobials was detected in 42% of the isolates. CONCLUSIONS: In the presence of very low malaria incidence we found high rates of S. Typhi and S. pneumoniae infections on Pemba Island, Zanzibar. Preventive measures such as vaccination could reduce the febrile disease burden.

Sudoi RK, Githinji S, Nyandigisi A, Muturi A, Snow RW, Zurovac D. 2012. The magnitude and trend of artemether-lumefantrine stock-outs at public health facilities in Kenya. Malar J, 11 (1), pp. 37. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Health facility stock-outs of artemether-lumefantrine (AL), the common first-line therapy for uncomplicated malaria across Africa, adversely affect effective malaria case-management. They have been previously reported on various scales in time and space, however the magnitude of the problem and trends over time are less clear. Here, 2010-2011 data are reported from public facilities in Kenya where alarming stock-outs were revealed in 2008. METHODS: Data were collected between January 2010 and June 2011 as part of 18 monthly cross-sectional surveys undertaken at nationally representative samples of public health facilities. The primary monitoring indicator was total stock-out of all four weight-specific AL packs. The secondary indicators were stock-outs of at least one AL pack and individual stock-outs for each AL pack. Monthly proportions and summary means of the proportions over the monitoring period were measured for each indicator. Stock-out trends were assessed using linear regression. RESULTS: The number of surveyed facilities across 18 time points ranged between 162 and 176 facilities. The stock-out means of the proportion of health facilities were 11.6% for total AL stock-out, 40.6% for stock-out of at least one AL pack, and between 20.5% and 27.4% for stock-outs of individual AL packs. Monthly decrease of the total AL stock-out was 0.005% (95% CI: -0.5 to +0.5; p = 0.983). Monthly decrease in the stock-out of at least one AL pack was 0.7% (95% CI: -1.5 to +0.3; p = 0.058) while stock-outs of individual AL packs decreased monthly between 0.2% for AL 24-pack and 0.7% for AL six-pack without statistical significance for any of the weight-specific packs. CONCLUSIONS: Despite lower levels of AL stock-outs compared to the reports in 2008, the stock-outs at Kenyan facilities during 2010-2011 are still substantial and of particular worry for the most detrimental:- simultaneous absence of any AL pack. Only minor decrease was observed in the stock-outs of individual AL packs. Recently launched interventions to eliminate AL stock-outs in Kenya are fully justified.

Turner C, Turner P, Po L, Maner N, De Zoysa A, Afshar B, Efstratiou A, Heath PT, Nosten F. 2012. Group B streptococcal carriage, serotype distribution and antibiotic susceptibilities in pregnant women at the time of delivery in a refugee population on the Thai-Myanmar border. BMC Infect Dis, 12 (1), pp. 34. | Citations: 19 (Scopus) | Show Abstract | Read more

BACKGROUND: Group B Streptococcus (GBS) is the leading cause of neonatal sepsis in the developed world. Little is known about its epidemiology in the developing world, where the majority of deaths from neonatal infections occur. Maternal carriage of GBS is a prerequisite for the development of early onset GBS neonatal sepsis but there is a paucity of carriage data published from the developing world, in particular South East Asia. METHODS: We undertook a cross sectional study over a 13 month period in a remote South East Asian setting on the Thai-Myanmar border. During labour, 549 mothers had a combined vaginal rectal swab taken for GBS culture. All swabs underwent both conventional culture as well as PCR for GBS detection. Cultured GBS isolates were serotyped by latex agglutination, those that were negative or had a weak positive reaction and those that were PCR positive but culture negative were additionally tested using multiplex PCR based on the detection of GBS capsular polysaccharide genes. RESULTS: The GBS carriage rate was 12.0% (95% CI: 9.4-15.0), with 8.6% positive by both culture and PCR and an additional 3.5% positive by PCR alone. Serotypes, Ia, Ib, II, III, IV, V, VI and VII were identified, with II the predominant serotype. All GBS isolates were susceptible to penicillin, ceftriaxone and vancomycin and 43/47 (91.5%) were susceptible to erythromycin and clindamycin. CONCLUSIONS: GBS carriage is not uncommon in pregnant women living on the Thai-Myanmar border with a large range of serotypes represented.

Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, Mayanja-Kizza H, Katabira E, Hanpithakpong W, Pakker N, Dorlo TPC, Tarning J, Lindegardh N et al. 2012. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother, 67 (5), pp. 1217-1223. | Citations: 22 (Scopus) | Show Abstract | Read more

BACKGROUND: Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. METHODS: A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured. RESULTS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01]. CONCLUSIONS: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.

Price MA, Rida W, Mwangome M, Mutua G, Middelkoop K, Roux S, Okuku HS, Bekker L-G, Anzala O, Ngugi E et al. 2012. Identifying at-risk populations in Kenya and South Africa: HIV incidence in cohorts of men who report sex with men, sex workers, and youth. J Acquir Immune Defic Syndr, 59 (2), pp. 185-193. | Citations: 61 (Scopus) | Show Abstract | Read more

OBJECTIVE: To identify and describe populations at risk for HIV in 3 clinical research centers in Kenya and South Africa. DESIGN: Prospective cohort study. METHODS: Volunteers reporting recent sexual activity, multiple partners, transactional sex, sex with an HIV-positive partner, or, if male, sex with men (MSM; in Kenya only) were enrolled. Sexually active minors were enrolled in South Africa only. Risk behavior, HIV testing, and clinical data were obtained at follow-up visits. RESULTS: From 2005 to 2008, 3023 volunteers were screened, 2113 enrolled, and 1834 contributed data on HIV incidence. MSM had the highest HIV incidence rate of 6.8 cases per 100 person-years [95% confidence interval (CI): 4.9 to 9.2] followed by women in Kilifi and Cape Town (2.7 cases per 100 person-years, 95% CI: 1.7 to 4.2). No seroconversions were observed in Nairobi women or men in Nairobi or Cape Town who were not MSM. In 327 MSM, predictors of HIV acquisition included report of genital ulcer (Hazard Ratio: 4.5, 95% CI: 1.7 to 11.6), not completing secondary school education (HR: 3.4, 95% CI: 1.6 to 7.2) and reporting receptive anal intercourse (HR: 8.2, 95% CI: 2.7 to 25.0). Paying for sex was inversely associated with HIV infection (HR: 0.2, 95% CI: 0.04 to 0.8). 279 (13.0%) volunteers did not return after the first visit; subsequent attrition rates ranged from 10.4 to 21.8 volunteers per 100 person-years across clinical research centers. CONCLUSIONS: Finding, enrolling, and retaining risk populations for HIV prevention trials is challenging in Africa. African MSM are not frequently engaged for research, have high HIV incidence, need urgent risk reduction counseling, and may represent a suitable population for future HIV prevention trials.

Limmathurotsakul D, Thammasart S, Warrasuth N, Thapanagulsak P, Jatapai A, Pengreungrojanachai V, Anun S, Joraka W, Thongkamkoon P, Saiyen P et al. 2012. Melioidosis in animals, Thailand, 2006-2010. Emerg Infect Dis, 18 (2), pp. 325-327. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

We retrospectively estimated the incidence of culture-proven melioidosis in animals in Thailand during 2006-2010. The highest incidence was in goats (1.63/100,000/year), followed by incidence in pigs and cattle. The estimated incidence of melioidosis in humans in a given region paralleled that of melioidosis in goats.

Zurovac D, Talisuna AO, Snow RW. 2012. Mobile phone text messaging: tool for malaria control in Africa. PLoS Med, 9 (2), pp. e1001176. | Citations: 51 (Scopus) | Read more

Hué S, Hassan AS, Nabwera H, Sanders EJ, Pillay D, Berkley JA, Cane PA. 2012. HIV type 1 in a rural coastal town in Kenya shows multiple introductions with many subtypes and much recombination. AIDS Res Hum Retroviruses, 28 (2), pp. 220-224. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

The extent of HIV-1 diversity was examined among patients attending a rural district hospital in a coastal area of Kenya. The pol gene was sequenced in samples from 153 patients. Subtypes were designated using the REGA, SCUEAL, and jpHMM programs. The most common subtype was A1, followed by C and D; A2 and G were also detected. However, a large proportion of the samples was found to be recombinants, which clustered within the pure subtype branches. Phylogeographic analysis of Kilifi sequences compared with those from other regions of Africa showed that while many sequences were closely related to sequences from Kenya, others were most closely related to known sequences from other parts of Africa, including West Africa. Overall, these data indicate that there have been multiple introductions of HIV-1 into this small rural town and surroundings with ongoing diversity being generated by recombination.

Eskes SA, Endert E, Fliers E, Geskus RB, Dullaart RPF, Links TP, Wiersinga WM. 2012. Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial. J Clin Endocrinol Metab, 97 (2), pp. 499-506. | Citations: 21 (Scopus) | Show Abstract | Read more

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) type 2 is self-limiting in nature, but most physicians are reluctant to continue amiodarone. When prednisone fails to restore euthyroidism, possibly due to mixed cases of AIT type 1 and 2, perchlorate (ClO(4)) might be useful because ClO(4) reduces the cytotoxic effect of amiodarone on thyrocytes. OBJECTIVES: Our objectives were to demonstrate the feasibility of continuation of amiodarone in AIT type 2 and to evaluate the usefulness of ClO(4) (given alone or in combination with prednisone) in AIT type 2. DESIGN AND SETTING: A randomized multicenter study was conducted in 10 Dutch hospitals. METHODS: Patients with AIT type 2 were randomized to receive prednisone 30 mg/d (group A, n = 12), sodium perchlorate 500 mg twice daily (group B, n = 14), or prednisone plus perchlorate (group C, n = 10); all patients continued amiodarone and were also treated with methimazole 30 mg/d. Follow-up was 2 yr. MAIN OUTCOME MEASURES: Treatment efficacy (defined as TSH values ≥ 0.4 mU/liter under continuation of amiodarone) and recurrent thyrotoxicosis were evaluated. RESULTS: Initial therapy was efficacious in 100, 71, and 100% of groups A, B, and C, respectively (P = 0.03). The 29% failures in group B became euthyroid after addition of prednisone. Neither the time to reach TSH of 0.4 mU/liter or higher [8 wk (4-20), 14 wk (4-32), and 12 wk (4-28) in groups A, B, and C respectively] nor the time to reach free T(4) of 25 pmol/liter or below [4 wk (4-20), 12 wk (4-20), and 8 wk (4-20) in groups A, B, and C) were significantly different between groups (values as median with range). Recurrent thyrotoxicosis occurred in 8.3%. CONCLUSION: Euthyroidism was reached despite continuation of amiodarone in all patients. Prednisone remains the preferred treatment modality of AIT type 2, because perchlorate given alone or in combination with prednisone had no better outcomes.

Hamers RL, Oyomopito R, Kityo C, Phanuphak P, Siwale M, Sungkanuparph S, Conradie F, Kumarasamy N, Botes ME, Sirisanthana T et al. 2012. Cohort profile: The PharmAccess African (PASER-M) and the TREAT Asia (TASER-M) monitoring studies to evaluate resistance--HIV drug resistance in sub-Saharan Africa and the Asia-Pacific. Int J Epidemiol, 41 (1), pp. 43-54. | Citations: 37 (Scopus) | Read more

Molyneux S, Atela M, Angwenyi V, Goodman C. 2012. Community accountability at peripheral health facilities: a review of the empirical literature and development of a conceptual framework. Health Policy Plan, 27 (7), pp. 541-554. | Citations: 52 (Web of Science Lite) | Show Abstract | Read more

Public accountability has re-emerged as a top priority for health systems all over the world, and particularly in developing countries where governments have often failed to provide adequate public sector services for their citizens. One approach to strengthening public accountability is through direct involvement of clients, users or the general public in health delivery, here termed 'community accountability'. The potential benefits of community accountability, both as an end in itself and as a means of improving health services, have led to significant resources being invested by governments and non-governmental organizations. Data are now needed on the implementation and impact of these initiatives on the ground. A search of PubMed using a systematic approach, supplemented by a hand search of key websites, identified 21 papers from low- or middle-income countries describing at least one measure to enhance community accountability that was linked with peripheral facilities. Mechanisms covered included committees and groups (n = 19), public report cards (n = 1) and patients' rights charters (n = 1). In this paper we summarize the data presented in these papers, including impact, and factors influencing impact, and conclude by commenting on the methods used, and the issues they raise. We highlight that the international interest in community accountability mechanisms linked to peripheral facilities has not been matched by empirical data, and present a conceptual framework and a set of ideas that might contribute to future studies.

Rijken MJ, Mulder EJH, Papageorghiou AT, Thiptharakun S, Wah N, Paw TK, Dwell SLM, Visser GHA, Nosten FH, McGready R. 2012. Quality of ultrasound biometry obtained by local health workers in a refugee camp on the Thai-Burmese border. Ultrasound Obstet Gynecol, 40 (2), pp. 151-157. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: In a refugee camp on the Thai-Burmese border, accurate dating of pregnancy relies on ultrasound measurements obtained by locally trained health workers. The aim of this study was to substantiate the accuracy of fetal biometry measurements performed by locally trained health workers by comparing derived reference equations with those published for Asian and European hospitals. METHODS: This prospective observational study included 1090 women who had a dating crown-rump length (CRL) scan and one study-appointed ultrasound biometry scan between 16 and 40 weeks of gestation. The average of two measurements of each of biparietal diameter, head circumference, abdominal circumference and femur length was used in a polynomial regression model for the mean and SD against gestational age (GA). The biometry equations obtained were compared with published equations of professional sonographers from Asian and European hospitals by evaluation of the SD and Z-scores of differences between models. RESULTS: Reference equations of biometric parameters were found to fit cubic polynomial models. The observed SD values, for any given GA, of fetal biometric measurements obtained by locally trained health workers were lower than those previously reported by centers with professional sonographers. For nearly the entire GA range considered, the mean values of the Asian and European equations for all four biometric measurements were within the 90% expected range (mean ± 1.645 SD) of our equations. CONCLUSION: Locally trained health workers in a refugee camp on the Thai-Burmese border can obtain measurements that are associated with low SD values and within the normal limits of published Asian and European equations. The fact that the SD values were lower than in other studies may be explained by the use of the average of two measurements, CRL dating or motivation of the locally trained sonographers.

Tarning J, Zongo I, Somé FA, Rouamba N, Parikh S, Rosenthal PJ, Hanpithakpong W, Jongrak N, Day NPJ, White NJ et al. 2012. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clin Pharmacol Ther, 91 (3), pp. 497-505. | Citations: 51 (Web of Science Lite) | Show Abstract | Read more

Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated.

Brooker SJ, Pullan RL, Gitonga CW, Ashton RA, Kolaczinski JH, Kabatereine NB, Snow RW. 2012. Plasmodium-helminth coinfection and its sources of heterogeneity across East Africa. J Infect Dis, 205 (5), pp. 841-852. | Citations: 33 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium-helminth coinfection can have a number of consequences for infected hosts, yet our knowledge of the epidemiology of coinfection across multiple settings is limited. This study investigates the distribution and heterogeneity of coinfection with Plasmodium falciparum and 3 major helminth species across East Africa. METHODS: Cross-sectional parasite surveys were conducted among 28 050 children in 299 schools across a range of environmental settings in Kenya, Uganda, and Ethiopia. Data on individual, household, and environmental risk factors were collected and a spatially explicit Bayesian modeling framework was used to investigate heterogeneities of species infection and coinfection and their risk factors as well as school- and individual-level associations between species. RESULTS: Broad-scale geographical patterns of Plasmodium-helminth coinfection are strongly influenced by the least common infection and by species-specific environmental factors. At the individual level, there is an enduring positive association between P. falciparum and hookworm but no association between P. falciparum and Schistosoma species. However, the relative importance of such within-individual associations is less than the role of spatial factors in influencing coinfection risks. CONCLUSIONS: Patterns of coinfection seem to be influenced more by the distribution of the least common species and its environmental risk factors, rather than any enduring within-individual associations.

Tarning J, Rijken MJ, McGready R, Phyo AP, Hanpithakpong W, Day NPJ, White NJ, Nosten F, Lindegardh N. 2012. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria. Antimicrob Agents Chemother, 56 (4), pp. 1997-2007. | Citations: 51 (Web of Science Lite) | Show Abstract | Read more

Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.

Gillrie MR, Lee K, Gowda DC, Davis SP, Monestier M, Cui L, Hien TT, Day NPJ, Ho M. 2012. Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction. Am J Pathol, 180 (3), pp. 1028-1039. | Citations: 43 (Web of Science Lite) | Show Abstract | Read more

Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria.

Wall K, Karita E, Nizam A, Bekan B, Sardar G, Casanova D, Joseph Davey D, De Clercq F, Kestelyn E, Bayingana R et al. 2012. Influence network effectiveness in promoting couples' HIV voluntary counseling and testing in Kigali, Rwanda. AIDS, 26 (2), pp. 217-227. | Citations: 21 (Scopus) | Show Abstract | Read more

OBJECTIVE: To identify predictors of promotion of couples' HIV voluntary counseling and testing (CVCT) in Kigali, Rwanda. DESIGN: Analysis of CVCT promotional agent [influential network leaders (INLs), influential network agents (INAs)], and couple/invitation-level predictors of CVCT uptake. METHODS: Number of invitations and couples tested were evaluated by INL, INA, and couple/contextual factors. Multivariable logistic regression accounting for two-level clustering analyzed factors predictive of couples' testing. RESULTS: Twenty-six INLs recruited and mentored 118 INAs who delivered 24 991 invitations. 4513 couples sought CVCT services after invitation. INAs distributed an average of 212 invitations resulting in an average of 38 couples tested/agent. Characteristics predictive of CVCT in multivariate analyses included the invitee and INA being socially acquainted [adjusted odds ratio (aOR) = 1.4; 95% confidence interval (CI) 1.2-1.6]; invitations delivered after public endorsement (aOR = 1.3; 95% CI 1.1-1.5); and presence of a mobile testing unit (aOR = 1.4; 95% CI 1.0-2.0). In stratified analyses, predictors significant among cohabiting couples included invitation delivery to the couple (aOR = 1.2; 95% CI 1.0-1.4) and in the home (aOR = 1.3; 95% CI 1.1-1.4), whereas among noncohabiting couples, predictors included invitations given by unemployed INAs (aOR = 1.7; 95% CI 1.1-2.7). Cohabiting couples with older men were more likely to test, whereas younger age was associated with testing among men in noncohabiting unions. CONCLUSIONS: Invitations distributed by influential people were successful in prompting couples to seek joint HIV testing, particularly if the invitation was given in the home to someone known to the INA and accompanied by a public endorsement of CVCT. Mobile units also increased the number of couples tested. Country-specific strategies to promote CVCT programs are needed to reduce HIV transmission among those at highest risk for HIV in sub-Saharan Africa.

Yalcindag E, Elguero E, Arnathau C, Durand P, Akiana J, Anderson TJ, Aubouy A, Balloux F, Besnard P, Bogreau H et al. 2012. Multiple independent introductions of Plasmodium falciparum in South America. Proc Natl Acad Sci U S A, 109 (2), pp. 511-516. | Citations: 42 (Scopus) | Show Abstract | Read more

The origin of Plasmodium falciparum in South America is controversial. Some studies suggest a recent introduction during the European colonizations and the transatlantic slave trade. Other evidence--archeological and genetic--suggests a much older origin. We collected and analyzed P. falciparum isolates from different regions of the world, encompassing the distribution range of the parasite, including populations from sub-Saharan Africa, the Middle East, Southeast Asia, and South America. Analyses of microsatellite and SNP polymorphisms show that the populations of P. falciparum in South America are subdivided in two main genetic clusters (northern and southern). Phylogenetic analyses, as well as Approximate Bayesian Computation methods suggest independent introductions of the two clusters from African sources. Our estimates of divergence time between the South American populations and their likely sources favor a likely introduction from Africa during the transatlantic slave trade.

Abdelgader TM, Ibrahim AM, Elmardi KA, Githinji S, Zurovac D, Snow RW, Noor AM. 2012. Progress towards implementation of ACT malaria case-management in public health facilities in the Republic of Sudan: a cluster-sample survey. BMC Public Health, 12 (1), pp. 11. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Effective malaria case-management based on artemisinin-based combination therapy (ACT) and parasitological diagnosis is a major pillar within the 2007-2012 National Malaria Strategic Plan in the Sudan. Three years after the launch of the strategy a health facility survey was undertaken to evaluate case-management practices and readiness of the health facilities and health workers to implement a new malaria case-management strategy. METHODS: A cross-sectional, cluster sample survey was undertaken at public health facilities in 15 states of Sudan. Data were collected using quality-of-care assessment methods. The main outcomes were the proportions of facilities with ACTs and malaria diagnostics; proportions of health workers exposed to malaria related health systems support activities; and composite and individual indicators of case-management practices for febrile outpatients stratified by age, availability of ACTs and diagnostics, use of malaria diagnostics, and test result. RESULTS: We evaluated 244 facilities, 294 health workers and 1,643 consultations for febrile outpatients (425 < 5 years and 1,218 ≥ 5 years). Health facility and health worker readiness was variable: chloroquine was available at only 5% of facilities, 73% stocked recommended artesunate and sulfadoxine/pyrimethamine (AS+SP), 51% had the capacity to perform parasitological diagnosis, 53% of health workers had received in-service training on ACTs, 24% were trained in the use of malaria Rapid Diagnostic Tests, and 19% had received a supervisory visit including malaria case-management. At all health facilities 46% of febrile patients were parasitologically tested and 35% of patients were both, tested and treated according to test result. At facilities where AS+SP and malaria diagnostics were available 66% of febrile patients were tested and 51% were both, tested and treated according to test result. Among test positive patients 64% were treated with AS+SP but 24% were treated with artemether monotherapy. Among test negative patients only 17% of patients were treated for malaria. The majority of ACT dispensing and counseling practices were suboptimal. CONCLUSIONS: Five years following change of the policy from chloroquine to ACTs and 3 years before the end of the new malaria strategic plan chloroquine was successfully phased out from public facilities in Sudan, however, an important gap remained in the availability of ACTs, diagnostic capacities and coverage with malaria case-management activities. The national scale-up of diagnostics, using the findings of this survey as well as future qualitative research, should present an opportunity not only to expand existing testing capacities but also to implement effective support interventions to bridge the health systems gaps and support corrective case-management measures, including the discontinuation of artemether monotherapy treatment.

Rijken MJ, Moroski WE, Kiricharoen S, Karunkonkowit N, Stevenson G, Ohuma EO, Noble JA, Kennedy SH, McGready R, Papageorghiou AT, Nosten FH. 2012. Effect of malaria on placental volume measured using three-dimensional ultrasound: a pilot study. Malar J, 11 (1), pp. 5. | Citations: 11 (Scopus) | Show Abstract | Read more

BACKGROUND: The presence of malaria parasites and histopathological changes in the placenta are associated with a reduction in birth weight, principally due to intrauterine growth restriction. The aim of this study was to examine the feasibility of studying early pregnancy placental volumes using three-dimensional (3D) ultrasound in a malaria endemic area, as a small volume in the second trimester may be an indicator of intra-uterine growth restriction and placental insufficiency. METHODS: Placenta volumes were acquired using a portable ultrasound machine and a 3D ultrasound transducer and estimated using the Virtual Organ Computer-aided AnaLysis (VOCAL) image analysis software package. Intra-observer reliability and limits of agreement of the placenta volume measurements were calculated. Polynomial regression models for the mean and standard deviation as a function of gestational age for the placental volumes of uninfected women were created and tested. Based on these equations each measurement was converted into a z -score. The z-scores of the placental volumes of malaria infected and uninfected women were then compared. RESULTS: Eighty-four women (uninfected = 65; infected = 19) with a posterior placenta delivered congenitally normal, live born, single babies. The mean placental volumes in the uninfected women were modeled to fit 5th, 10th, 50th, 90th and 95th centiles for 14-24 weeks' gestation. Most placenta volumes in the infected women were below the 50th centile for gestational age; most of those with Plasmodium falciparum were below the 10th centile. The 95% intra-observer limits of agreement for first and second measurements were ± 37.0 mL and ± 25.4 mL at 30 degrees and 15 degrees rotation respectively. CONCLUSION: The new technique of 3D ultrasound volumetry of the placenta may be useful to improve our understanding of the pathophysiological constraints on foetal growth caused by malaria infection in early pregnancy.

Blacksell SD, Paris DH, Chierakul W, Wuthiekanun V, Teeratakul A, Kantipong P, Day NPJ. 2012. Prospective evaluation of commercial antibody-based rapid tests in combination with a loop-mediated isothermal amplification PCR assay for detection of Orientia tsutsugamushi during the acute phase of scrub typhus infection. Clin Vaccine Immunol, 19 (3), pp. 391-395. | Citations: 16 (Scopus) | Show Abstract | Read more

Samples from 160 prospectively recruited febrile patients with typhus-like illness in an area of Thailand (Chiang Rai, northern Thailand) where scrub typhus is endemic were used to evaluate the diagnostic capabilities of four rapid immunochromatographic tests (ICTs) for the detection of Orientia tsutsugamushi IgM and total antibodies during acute scrub typhus infection. Of the 160 cases, 54 (34%) had been confirmed to have scrub typhus using the reference scrub typhus infection criteria (STIC), i.e., positive cell culture isolation, an admission IgM antibody titer of ≥1:12,800, a 4-fold rising IgM antibody titer, and/or positivity for ≥2 out of 3 PCR gene targets). The ICTs gave the following sensitivities and specificities: the Panbio IgM ICT, 46% (95% confidence interval [CI], 33 to 60) and 95% (95% CI, 89 to 98), respectively; the Standard Diagnostics IgM ICT, 68% (95% CI, 60 to 75) and 73% (95% CI, 68 to 78), respectively; the AccessBio IgM ICT, 56% (95% CI, 48 to 63) and 90% (95% CI, 87 to 94), respectively; and the AccessBio total antibody ABt ICT, 61% (95% CI, 53 to 68) and 68% (95% CI, 63 to 73), respectively. An isothermal loop amplification (LAMP) PCR assay for scrub typhus demonstrated a sensitivity of 52% (95% CI, 38 to 66) and a specificity of 94% (95% CI, 88 to 98). This study has revealed the diagnostic limitations of antibody-based assays in an acute care setting. However, the combination of ICTs with LAMP usually increased sensitivity with a minimal reduction in specificity. The best combination, the Panbio IgM ICT and LAMP, resulted in a sensitivity of 67% (95% CI, 53 to 79) and a specificity of 91% (95% CI, 83 to 95). The combination of antibody-based assays with DNA- or antigen-based tests shows promise for improved diagnostic sensitivity.

Nga TVT, Parry CM, Le T, Lan NPH, Diep TS, Campbell JI, Hoang NVM, Dung LT, Wain J, Dolecek C et al. 2012. The decline of typhoid and the rise of non-typhoid salmonellae and fungal infections in a changing HIV landscape: bloodstream infection trends over 15 years in southern Vietnam. Trans R Soc Trop Med Hyg, 106 (1), pp. 26-34. | Citations: 37 (Scopus) | Show Abstract | Read more

The etiological spectrum of bloodstream infections is variable between industrialized and developing countries and even within a defined location over time. We investigated trends in bloodstream infections at an infectious disease hospital in Ho Chi Minh City, Vietnam, from 1994-2008. Amongst 66,111 blood cultures performed, a clinically relevant pathogen was isolated in 7645 episodes (positivity rate; 116/1000 cultures). Salmonella Typhi was the predominant pathogen until 2002; however, a considerable annual decline in the proportion of S. Typhi was observed (OR 0.6993, 95% CI [0.6885, 0.7103], p<0.0001). Conversely, there was a significant increase in the proportions of non-typhoidal Salmonella (NTS), Cryptococcus neoformans and Penicillium marneffei, concurrent with increasing HIV prevalence. These data document a substantial longitudinal shift in bloodstream infection etiology in southern Vietnam. We propose such changes are related to increasing economic prosperity and HIV prevalence, and this pattern marks a substantial change in the epidemiology of invasive salmonellosis in Southeast Asia.

Rijken MJ, McGready R, Boel ME, Poespoprodjo R, Singh N, Syafruddin D, Rogerson S, Nosten F. 2012. Malaria in pregnancy in the Asia-Pacific region. Lancet Infect Dis, 12 (1), pp. 75-88. | Citations: 78 (Scopus) | Show Abstract | Read more

Most pregnant women at risk of for infection with Plasmodium vivax live in the Asia-Pacific region. However, malaria in pregnancy is not recognised as a priority by many governments, policy makers, and donors in this region. Robust data for the true burden of malaria throughout pregnancy are scarce. Nevertheless, when women have little immunity, each infection is potentially fatal to the mother, fetus, or both. WHO recommendations for the control of malaria in pregnancy are largely based on the situation in Africa, but strategies in the Asia-Pacific region are complicated by heterogeneous transmission settings, coexistence of multidrug-resistant Plasmodium falciparum and Plasmodium vivax parasites, and different vectors. Most knowledge of the epidemiology, effect, treatment, and prevention of malaria in pregnancy in the Asia-Pacific region comes from India, Papua New Guinea, and Thailand. Improved estimates of the morbidity and mortality of malaria in pregnancy are urgently needed. When malaria in pregnancy cannot be prevented, accurate diagnosis and prompt treatment are needed to avert dangerous symptomatic disease and to reduce effects on fetuses.

Miller CE, Batra R, Cooper BS, Patel AK, Klein J, Otter JA, Kypraios T, French GL, Tosas O, Edgeworth JD. 2012. An association between bacterial genotype combined with a high-vancomycin minimum inhibitory concentration and risk of endocarditis in methicillin-resistant Staphylococcus aureus bloodstream infection. Clin Infect Dis, 54 (5), pp. 591-600. | Citations: 27 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Antimicrobial resistance and bacterial virulence factors may increase the risk of hematogenous complications during methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI). This study reports on the impact of increasing vancomycin minimum inhibitory concentrations (V-MICs) and MRSA clone type on risk of hematogenous complications from MRSA BSI during implementation of an effective MRSA control program. METHODS: In sum, spa typing, staphylococcal cassette chromosome mec allotyping, and vancomycin and teicoplanin MICs were performed on 821 consecutive MRSA bloodstream isolates from 1999 to 2009. Prospectively collected data, including focus of infection, were available for 695 clinically significant cases. Logistic and multinomial logistic regression was used to determine the association between clone type, vancomycin MIC (V-MIC), and focus of infection. RESULTS: MRSA BSIs decreased by ∼90% during the 11 years. Typing placed isolates into 3 clonal complex (CC) groups that had different population median V-MICs (CC30, 0.5 μg/mL [n = 349]; CC22, 0.75 μg/mL [n = 272]; non-CC22/30, 1.5 μg/mL [n = 199]). There was a progressive increase in the proportion of isolates with a V-MIC above baseline median in each clonal group and a disproportionate fall in the clone group with lowest median V-MIC (CC30). In contrast, there were no increases in teicoplanin MICs. High V-MIC CC22 isolates (1.5-2 μg/mL) were strongly associated with endocarditis (odds ratio, 12; 95% confidence interval, 3.72-38.9) and with a septic metastasis after catheter-related BSI (odds ratio, 106; 95% confidence interval, 12.6-883) compared with other clone type/V-MIC combinations. CONCLUSIONS: An interaction between clone type and V-MIC can influence the risk of endocarditis associated with MRSA BSI, implying involvement of both therapeutic and host-pathogen factors.

Paris DH, Phetsouvanh R, Tanganuchitcharnchai A, Jones M, Jenjaroen K, Vongsouvath M, Ferguson DPJ, Blacksell SD, Newton PN, Day NPJ, Turner GDH. 2012. Orientia tsutsugamushi in human scrub typhus eschars shows tropism for dendritic cells and monocytes rather than endothelium. PLoS Negl Trop Dis, 6 (1), pp. e1466. | Citations: 43 (Scopus) | Show Abstract | Read more

Scrub typhus is a common and underdiagnosed cause of febrile illness in Southeast Asia, caused by infection with Orientia tsutsugamushi. Inoculation of the organism at a cutaneous mite bite site commonly results in formation of a localized pathological skin reaction termed an eschar. The site of development of the obligate intracellular bacteria within the eschar and the mechanisms of dissemination to cause systemic infection are unclear. Previous postmortem and in vitro reports demonstrated infection of endothelial cells, but recent pathophysiological investigations of typhus patients using surrogate markers of endothelial cell and leucocyte activation indicated a more prevalent host leucocyte than endothelial cell response in vivo. We therefore examined eschar skin biopsies from patients with scrub typhus to determine and characterize the phenotypes of host cells in vivo with intracellular infection by O. tsutsugamushi, using histology, immunohistochemistry, double immunofluorescence confocal laser scanning microscopy and electron microscopy. Immunophenotyping of host leucocytes infected with O. tsutsugamushi showed a tropism for host monocytes and dendritic cells, which were spatially related to different histological zones of the eschar. Infected leucocyte subsets were characterized by expression of HLADR+, with an "inflammatory" monocyte phenotype of CD14/LSP-1/CD68 positive or dendritic cell phenotype of CD1a/DCSIGN/S100/FXIIIa and CD163 positive staining, or occasional CD3 positive T-cells. Endothelial cell infection was rare, and histology did not indicate a widespread inflammatory vasculitis as the cause of the eschar. Infection of dendritic cells and activated inflammatory monocytes offers a potential route for dissemination of O. tsutsugamushi from the initial eschar site. This newly described cellular tropism for O. tsutsugamushi may influence its interaction with local host immune responses.

Dhorda M, Piola P, Nyehangane D, Tumwebaze B, Nalusaji A, Nabasumba C, Turyakira E, McGready R, Ashley E, Guerin PJ, Snounou G. 2012. Performance of a histidine-rich protein 2 rapid diagnostic test, Paracheck Pf®, for detection of malaria infections in Ugandan pregnant women. Am J Trop Med Hyg, 86 (1), pp. 93-95. | Citations: 18 (Scopus) | Show Abstract | Read more

Improved laboratory diagnosis is critical to reduce the burden of malaria in pregnancy. Peripheral blood smears appear less sensitive than Plasmodium falciparum histidine-rich protein 2-based rapid diagnostic tests (RDTs) for placental malaria infections in studies conducted at delivery. In this study, 81 women in Uganda in the second or third trimester of pregnancy were followed-up until delivery. At each visit, peripheral blood was tested by blood smear, RDT, and nested species-specific polymerase chain reaction (PCR). Sensitivity and specificity of the tests was calculated with PCR, which detected 22 infections of P. falciparum, as the gold standard. The sensitivity and specificity of blood smears were 36.4% (95% confidence interval [CI] = 18.0-59.2%) and 99.6% (95% CI = 97.7-100%), respectively. The corresponding values for RDT were 31.8% (95% CI = 14.7-54.9%) and 100% (95% CI = 98.3-100%). The RDTs could replace blood smears for diagnosis of malaria in pregnancy by virtue of their relative ease of use. Field-based sensitive tests for malaria in pregnancy are urgently needed.

Hassan AS, Fielding KL, Thuo NM, Nabwera HM, Sanders EJ, Berkley JA. 2012. Early loss to follow-up of recently diagnosed HIV-infected adults from routine pre-ART care in a rural district hospital in Kenya: a cohort study TROPICAL MEDICINE & INTERNATIONAL HEALTH, 17 (1), pp. 82-93. | Citations: 29 (Scopus) | Show Abstract | Read more

Objective To determine the rate and predictors of early loss to follow-up (LTFU) for recently diagnosed HIV-infected, antiretroviral therapy (ART)-ineligible adults in rural Kenya. Methods Prospective cohort study. Clients registering for HIV care between July 2008 and August 2009 were followed up for 6months. Baseline data were used to assess predictors of pre-ART LTFU (not returning for care within 2months of a scheduled appointment), LTFU before the second visit and LTFU after the second visit. Logistic regression was used to determine factors associated with LTFU before the second visit, while Cox regression was used to assess predictors of time to LTFU and LTFU after the second visit. Results Of 530 eligible clients, 178 (33.6%) were LTFU from pre-ART care (11.1/100 person-months). Of these, 96 (53.9%) were LTFU before the second visit. Distance ( > 5km vs. < 1km: adjusted hazard ratio 2.6 [1.9-3.7], P < 0.01) and marital status (married vs. single: 0.5 [0.3-0.6], P < 0.01) independently predicted pre-ART LTFU. Distance and marital status were independently associated with LTFU before the second visit, while distance, education status and seasonality showed weak evidence of predicting LTFU after the second visit. HIV disease severity did not predict pre-ART LTFU. Conclusions A third of recently diagnosed HIV-infected, ART-ineligible clients were LTFU within 6months of registration. Predictors of LTFU among ART-ineligible clients are different from those among clients on ART. These findings warrant consideration of an enhanced pre-ART care package aimed at improving retention and timely ART initiation. © 2011 Blackwell Publishing Ltd.

Gitau EN, Tuju J, Stevenson L, Kimani E, Karanja H, Marsh K, Bull PC, Urban BC. 2012. T-cell responses to the DBLα-tag, a short semi-conserved region of the Plasmodium falciparum membrane erythrocyte protein 1. PLoS One, 7 (1), pp. e30095. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant surface antigen expressed on mature forms of infected erythrocytes. It is considered an important target of naturally acquired immunity. Despite its extreme sequence heterogeneity, variants of PfEMP1 can be stratified into distinct groups. Group A PfEMP1 have been independently associated with low host immunity and severe disease in several studies and are now of potential interest as vaccine candidates. Although antigen-specific antibodies are considered the main effector mechanism in immunity to malaria, the induction of efficient and long-lasting antibody responses requires CD4+ T-cell help. To date, very little is known about CD4+ T-cell responses to PfEMP1 expressed on clinical isolates. The DBLα-tag is a small region from the DBLα-domain of PfEMP1 that can be amplified with universal primers and is accessible in clinical parasite isolates. We identified the dominant expressed PfEMP1 in 41 individual clinical parasite isolates and expressed the corresponding DBLα-tag as recombinant antigen. Individual DBLα-tags were then used to activate CD4+ T-cells from acute and convalescent blood samples in children who were infected with the respective clinical parasite isolate. Here we show that CD4+ T-cell responses to the homologous DBLα-tag were induced in almost all children during acute malaria and maintained in some for 4 months. Children infected with parasites that dominantly expressed group A-like PfEMP1 were more likely to maintain antigen-specific IFNγ-producing CD4+ T-cells than children infected with parasites dominantly expressing other PfEMP1. These results suggest that group A-like PfEMP1 may induce long-lasting effector memory T-cells that might be able to provide rapid help to variant-specific B cells. Furthermore, a number of children induced CD4+ T-cell responses to heterologous DBLα-tags, suggesting that CD4+ T-cells may recognise shared epitopes between several DBLα-tags.

Do LAH, van Doorn HR, Bryant JE, Nghiem MN, Nguyen Van VC, Vo CK, Nguyen MD, Tran TH, Farrar J, De Jong MD. 2012. A sensitive real-time PCR for detection and subgrouping of human respiratory syncytial virus Journal of Virological Methods, 179 (1), pp. 250-255. | Citations: 13 (Scopus) | Show Abstract | Read more

Improved diagnostic tools for rapid detection, quantitation, and subgrouping of human respiratory syncytial virus (RSV) are needed to aid the development and evaluation of novel intervention strategies. A quantitative real-time RT-PCR using specific locked nucleic acid (LNA) probes was developed to identify RSV and to distinguish RSV subgroups A and B (RSV LNA assay). RSV subgroup diversity and the relationship between viral load and disease severity in confirmed RSV infections were also explored. 264 archived respiratory specimens from pediatric patients were tested in parallel using the commercial multiplex Seeplex™ RV detection kit (Seegene) and the novel RSV LNA assay. The LNA assay demonstrated a significantly higher sensitivity than Seeplex, improving overall detection rates from 24% (64/264) to 32% (84/264). Detection limits of 9.0×10 1 and 6.0×10 2 copies/mL were observed for RSV A and B, respectively. RSV A was detected in 53/84 (63%) cases, and 31/84 (37%) were positive for RSV B. This novel method offers a rapid, quantitative, highly specific and sensitive approach to laboratory diagnosis of RSV. © 2011 Elsevier B.V.

Weiss GE, Ndungu FM, McKittrick N, Li S, Kimani D, Crompton PD, Marsh K, Pierce SK. 2012. High efficiency human memory B cell assay and its application to studying Plasmodium falciparum-specific memory B cells in natural infections Journal of Immunological Methods, 375 (1-2), pp. 68-74. | Citations: 16 (Scopus) | Show Abstract | Read more

Memory B cells (MBCs) are a key component of long term humoral immunity to many human infectious diseases. Despite their importance, we know little about the generation or maintenance of antigen-(Ag)-specific MBCs in humans in response to infection. A frequently employed method for quantifying Ag-specific MBCs in human peripheral blood (Crotty et al., 2004) relies on the ability of MBCs but not naïve B cells to differentiate into antibody secreting cells (ASCs) in response to polyclonal activators and Toll-like receptor agonists in vitro and the measurement of Ag-specific ASCs by ELISPOT assays. Here we report on studies to optimize the efficiency of this ELISPOT-based assay and to apply this assay to the detection of Plasmodium falciparum (Pf)-specific MBCs in adults living in a malaria endemic area where immunity to Pf is acquired through natural infection. We show that the addition of IL-10 to in vitro cultures of human peripheral blood mononuclear cells increased the efficiency of the assay from 10% to over 90% without increasing the ASC burst size and without any substantial increase in background from naïve B cells or plasma cells (PCs). Using this assay we were able to quantify the frequency of Pf-specific MBCs in peripheral blood of adults living in a malaria endemic area. Thus, this highly efficient assay appears to be well suited to field studies of the generation and maintenance of MBCs where the volumes of blood obtainable are often limiting. © 2011 Elsevier B.V.

Kernif T, Socolovschi C, Wells K, Lakim MB, Inthalad S, Slesak G, Boudebouch N, Beaucournu J-C, Newton PN, Raoult D, Parola P. 2012. Bartonella and Rickettsia in arthropods from the Lao PDR and from Borneo, Malaysia. Comp Immunol Microbiol Infect Dis, 35 (1), pp. 51-57. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

Rickettsioses and bartonelloses are arthropod-borne diseases of mammals with widespread geographical distributions. Yet their occurrence in specific regions, their association with different vectors and hosts and the infection rate of arthropod-vectors with these agents remain poorly studied in South-east Asia. We conducted entomological field surveys in the Lao PDR (Laos) and Borneo, Malaysia by surveying fleas, ticks, and lice from domestic dogs and collected additional samples from domestic cows and pigs in Laos. Rickettsia felis was detected by real-time PCR with similar overall flea infection rate in Laos (76.6%, 69/90) and Borneo (74.4%, 268/360). Both of the encountered flea vectors Ctenocephalides orientis and Ctenocephalides felis felis were infected with R. felis. The degrees of similarity of partial gltA and ompA genes with recognized species indicate the rickettsia detected in two Boophilus spp. ticks collected from a cow in Laos may be a new species. Isolation and further characterization will be necessary to specify it as a new species. Bartonella clarridgeiae was detected in 3/90 (3.3%) and 2/360 (0.6%) of examined fleas from Laos and Borneo, respectively. Two fleas collected in Laos and one flea collected in Borneo were co-infected with both R. felis and B. clarridgeiae. Further investigations are needed in order to isolate these agents and to determine their epidemiology and aetiological role in unknown fever in patients from these areas.

Peacock SJ, Limmathurotsakul D, Lubell Y, Koh GCKW, White LJ, Day NPJ, Titball RW. 2012. Melioidosis vaccines: a systematic review and appraisal of the potential to exploit biodefense vaccines for public health purposes. PLoS Negl Trop Dis, 6 (1), pp. e1488. | Citations: 51 (Scopus) | Show Abstract | Read more

BACKGROUND: Burkholderia pseudomallei is a Category B select agent and the cause of melioidosis. Research funding for vaccine development has largely considered protection within the biothreat context, but the resulting vaccines could be applicable to populations who are at risk of naturally acquired melioidosis. Here, we discuss target populations for vaccination, consider the cost-benefit of different vaccination strategies and review potential vaccine candidates. METHODS AND FINDINGS: Melioidosis is highly endemic in Thailand and northern Australia, where a biodefense vaccine might be adopted for public health purposes. A cost-effectiveness analysis model was developed, which showed that a vaccine could be a cost-effective intervention in Thailand, particularly if used in high-risk populations such as diabetics. Cost-effectiveness was observed in a model in which only partial immunity was assumed. The review systematically summarized all melioidosis vaccine candidates and studies in animal models that had evaluated their protectiveness. Possible candidates included live attenuated, whole cell killed, sub-unit, plasmid DNA and dendritic cell vaccines. Live attenuated vaccines were not considered favorably because of possible reversion to virulence and hypothetical risk of latent infection, while the other candidates need further development and evaluation. Melioidosis is acquired by skin inoculation, inhalation and ingestion, but routes of animal inoculation in most published studies to date do not reflect all of this. We found a lack of studies using diabetic models, which will be central to any evaluation of a melioidosis vaccine for natural infection since diabetes is the most important risk factor. CONCLUSION: Vaccines could represent one strand of a public health initiative to reduce the global incidence of melioidosis.

Midega JT, Smith DL, Olotu A, Mwangangi JM, Nzovu JG, Wambua J, Nyangweso G, Mbogo CM, Christophides GK, Marsh K, Bejon P. 2012. Wind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya. Nat Commun, 3 (1), pp. 674. | Citations: 35 (Web of Science Lite) | Show Abstract | Read more

Studies of the fine-scale spatial epidemiology of malaria consistently identify malaria hotspots, comprising clusters of homesteads at high transmission intensity. These hotspots sustain transmission, and may be targeted by malaria-control programmes. Here we describe the spatial relationship between the location of Anopheles larval sites and human malaria infection in a cohort study of 642 children, aged 1-10-years-old. Our data suggest that proximity to larval sites predict human malaria infection, when homesteads are upwind of larval sites, but not when homesteads are downwind of larval sites. We conclude that following oviposition, female Anophelines fly upwind in search for human hosts and, thus, malaria transmission may be disrupted by targeting vector larval sites in close proximity, and downwind to malaria hotspots.

Loan HT, Parry J, Nga NTN, Yen LM, Binh NT, Thuy TTD, Duong NM, Campbell JI, Thwaites L, Farrar JJ, Parry CM. 2012. Semi-recumbent body position fails to prevent healthcare-associated pneumonia in Vietnamese patients with severe tetanus Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (2), pp. 90-97. | Citations: 6 (Scopus) | Show Abstract | Read more

Healthcare-associated pneumonia (HCAP) is a common complication in patients with severe tetanus. Nursing tetanus patients in a semi-recumbent body position could reduce the incidence of HCAP. In a randomised controlled trial we compared the occurrence of HCAP in patients with severe tetanus nursed in a semi-recumbent (30°) or supine position. A total of 229 adults and children (aged ≥1 year) with severe tetanus admitted to hospital in Vietnam, were randomly assigned to a supine (n = 112) or semi-recumbent (n = 117) position. For patients maintaining their assigned positions and in hospital for > 48. h there was no significant difference between the two groups in the frequency of clinically suspected pneumonia [22/106 (20.8%) vs 26/104 (25.0%); p = 0.464], pneumonia rate/1000 intensive care unit days (13.9 vs 14.6; p = 0.48) and pneumonia rate/1000 ventilated days (39.2 vs 38.1; p = 0.72). Mortality in the supine patients was 11/112 (9.8%) compared with 17/117 (14.5%) in the semi-recumbent patients (p = 0.277). The overall complication rate [57/112 (50.9%) vs 76/117 (65.0%); p = 0.03] and need for tracheostomy [51/112 (45.5%) vs 69/117 (58.9%); p = 0.04) was greater in semi-recumbent patients. Semi-recumbent body positioning did not prevent the occurrence of HCAP in severe tetanus patients. [Clinical Trials.gov Identifier: NCT01331252]. © 2011 Royal Society of Tropical Medicine and Hygiene.

Fox A, Le NMH, Horby P, van Doorn HR, Nguyen VT, Nguyen HH, Nguyen TC, Vu DP, Nguyen MH, Diep NTN et al. 2012. Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses. PLoS One, 7 (2), pp. e31535. | Citations: 27 (Scopus) | Show Abstract | Read more

BACKGROUND: It is unclear why the severity of influenza varies in healthy adults or why the burden of severe influenza shifts to young adults when pandemic strains emerge. One possibility is that cross-protective T cell responses wane in this age group in the absence of recent infection. We therefore compared the acute cellular immune response in previously healthy adults with severe versus mild pandemic H1N1 infection. METHODS AND PRINCIPAL FINDINGS: 49 previously healthy adults admitted to the National Hospital of Tropical Diseases, Viet Nam with RT-PCR-confirmed 2009 H1N1 infection were prospectively enrolled. 39 recovered quickly whereas 10 developed severe symptoms requiring supplemental oxygen and prolonged hospitalization. Peripheral blood lymphocyte subset counts and activation (HLADR, CD38) and differentiation (CD27, CD28) marker expression were determined on days 0, 2, 5, 10, 14 and 28 by flow cytometry. NK, CD4 and CD8 lymphopenia developed in 100%, 90% and 60% of severe cases versus 13% (p<0.001), 28%, (p = 0.001) and 18% (p = 0.014) of mild cases. CD4 and NK counts normalized following recovery. B cell counts were not significantly associated with severity. CD8 activation peaked 6-8 days after mild influenza onset, when 13% (6-22%) were HLADR+CD38+, and was accompanied by a significant loss of resting/CD27+CD28+ cells without accumulation of CD27+CD28- or CD27-CD28- cells. In severe influenza CD8 activation peaked more than 9 days post-onset, and/or was excessive (30-90% HLADR+CD38+) in association with accumulation of CD27+CD28- cells and maintenance of CD8 counts. CONCLUSION: Severe influenza is associated with transient T and NK cell deficiency. CD8 phenotype changes during mild influenza are consistent with a rapidly resolving memory response whereas in severe influenza activation is either delayed or excessive, and partially differentiated cells accumulate within blood indicating that recruitment of effector cells to the lung could be impaired.

Linard C, Gilbert M, Snow RW, Noor AM, Tatem AJ. 2012. Population distribution, settlement patterns and accessibility across Africa in 2010. PLoS One, 7 (2), pp. e31743. | Citations: 183 (Scopus) | Show Abstract | Read more

The spatial distribution of populations and settlements across a country and their interconnectivity and accessibility from urban areas are important for delivering healthcare, distributing resources and economic development. However, existing spatially explicit population data across Africa are generally based on outdated, low resolution input demographic data, and provide insufficient detail to quantify rural settlement patterns and, thus, accurately measure population concentration and accessibility. Here we outline approaches to developing a new high resolution population distribution dataset for Africa and analyse rural accessibility to population centers. Contemporary population count data were combined with detailed satellite-derived settlement extents to map population distributions across Africa at a finer spatial resolution than ever before. Substantial heterogeneity in settlement patterns, population concentration and spatial accessibility to major population centres is exhibited across the continent. In Africa, 90% of the population is concentrated in less than 21% of the land surface and the average per-person travel time to settlements of more than 50,000 inhabitants is around 3.5 hours, with Central and East Africa displaying the longest average travel times. The analyses highlight large inequities in access, the isolation of many rural populations and the challenges that exist between countries and regions in providing access to services. The datasets presented are freely available as part of the AfriPop project, providing an evidence base for guiding strategic decisions.

Mwai L, Diriye A, Masseno V, Muriithi S, Feltwell T, Musyoki J, Lemieux J, Feller A, Mair GR, Marsh K et al. 2012. Genome wide adaptations of Plasmodium falciparum in response to lumefantrine selective drug pressure. PLoS One, 7 (2), pp. e31623. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

The combination therapy of the Artemisinin-derivative Artemether (ART) with Lumefantrine (LM) (Coartem®) is an important malaria treatment regimen in many endemic countries. Resistance to Artemisinin has already been reported, and it is feared that LM resistance (LMR) could also evolve quickly. Therefore molecular markers which can be used to track Coartem® efficacy are urgently needed. Often, stable resistance arises from initial, unstable phenotypes that can be identified in vitro. Here we have used the Plasmodium falciparum multidrug resistant reference strain V1S to induce LMR in vitro by culturing the parasite under continuous drug pressure for 16 months. The initial IC(50) (inhibitory concentration that kills 50% of the parasite population) was 24 nM. The resulting resistant strain V1S(LM), obtained after culture for an estimated 166 cycles under LM pressure, grew steadily in 378 nM of LM, corresponding to 15 times the IC(50) of the parental strain. However, after two weeks of culturing V1S(LM) in drug-free medium, the IC(50) returned to that of the initial, parental strain V1S. This transient drug tolerance was associated with major changes in gene expression profiles: using the PFSANGER Affymetrix custom array, we identified 184 differentially expressed genes in V1S(LM). Among those are 18 known and putative transporters including the multidrug resistance gene 1 (pfmdr1), the multidrug resistance associated protein and the V-type H+ pumping pyrophosphatase 2 (pfvp2) as well as genes associated with fatty acid metabolism. In addition we detected a clear selective advantage provided by two genomic loci in parasites grown under LM drug pressure, suggesting that all, or some of those genes contribute to development of LM tolerance--they may prove useful as molecular markers to monitor P. falciparum LM susceptibility.

Rijken MJ, Papageorghiou AT, Thiptharakun S, Kiricharoen S, Dwell SLM, Wiladphaingern J, Pimanpanarak M, Kennedy SH, Nosten F, McGready R. 2012. Ultrasound evidence of early fetal growth restriction after maternal malaria infection. PLoS One, 7 (2), pp. e31411. | Citations: 39 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Intermittent preventive treatment (IPT), the main strategy to prevent malaria and reduce anaemia and low birthweight, focuses on the second half of pregnancy. However, intrauterine growth restriction may occur earlier in pregnancy. The aim of this study was to measure the effects of malaria in the first half of pregnancy by comparing the fetal biparietal diameter (BPD) of infected and uninfected women whose pregnancies had been accurately dated by crown rump length (CRL) before 14 weeks of gestation. METHODOLOGY/PRINCIPAL FINDINGS: In 3,779 women living on the Thai-Myanmar border who delivered a normal singleton live born baby between 2001-10 and who had gestational age estimated by CRL measurement <14 weeks, the observed and expected BPD z-scores (<24 weeks) in pregnancies that were (n = 336) and were not (n = 3,443) complicated by malaria between the two scans were compared. The mean (standard deviation) fetal BPD z-scores in women with Plasmodium (P) falciparum and/or P.vivax malaria infections were significantly lower than in non-infected pregnancies; -0.57 (1.13) versus -0.10 (1.17), p<0.001. Even a single or an asymptomatic malaria episode resulted in a significantly lower z-score. Fetal female sex (p<0.001) and low body mass index (p = 0.01) were also independently associated with a smaller BPD in multivariate analysis. CONCLUSIONS/SIGNIFICANCE: Despite early treatment in all positive women, one or more (a)symptomatic P.falciparum or P.vivax malaria infections in the first half of pregnancy result in a smaller than expected mid-trimester fetal head diameter. Strategies to prevent malaria in pregnancy should include early pregnancy.

Mahavanakul W, Nickerson EK, Srisomang P, Teparrukkul P, Lorvinitnun P, Wongyingsinn M, Chierakul W, Hongsuwan M, West TE, Day NP et al. 2012. Feasibility of modified surviving sepsis campaign guidelines in a resource-restricted setting based on a cohort study of severe S. aureus sepsis [corrected]. PLoS One, 7 (2), pp. e29858. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The Surviving Sepsis Campaign (SSC) guidelines describe best practice for the management of severe sepsis and septic shock in developed countries, but most deaths from sepsis occur where healthcare is not sufficiently resourced to implement them. Our objective was to define the feasibility and basis for modified guidelines in a resource-restricted setting. METHODS AND FINDINGS: We undertook a detailed assessment of sepsis management in a prospective cohort of patients with severe sepsis caused by a single pathogen in a 1,100-bed hospital in lower-middle income Thailand. We compared their management with the SSC guidelines to identify care bundles based on existing capabilities or additional activities that could be undertaken at zero or low cost. We identified 72 patients with severe sepsis or septic shock associated with S. aureus bacteraemia, 38 (53%) of who died within 28 days. One third of patients were treated in intensive care units (ICUs). Numerous interventions described by the SSC guidelines fell within existing capabilities, but their implementation was highly variable. Care available to patients on general wards covered the fundamental principles of sepsis management, including non-invasive patient monitoring, antimicrobial administration and intravenous fluid resuscitation. We described two additive care bundles, one for general wards and the second for ICUs, that if consistently performed would be predicted to improve outcome from severe sepsis. CONCLUSION: It is feasible to implement modified sepsis guidelines that are scaled to resource availability, and that could save lives prior to the publication of international guidelines for developing countries.

Lairumbi GM, Parker M, Fitzpatrick R, English MC. 2012. Forms of benefit sharing in global health research undertaken in resource poor settings: a qualitative study of stakeholders' views in Kenya. Philos Ethics Humanit Med, 7 (1), pp. 7. | Citations: 25 (Scopus) | Show Abstract | Read more

BACKGROUND: Increase in global health research undertaken in resource poor settings in the last decade though a positive development has raised ethical concerns relating to potential for exploitation. Some of the suggested strategies to address these concerns include calls for providing universal standards of care, reasonable availability of proven interventions and more recently, promoting the overall social value of research especially in clinical research. Promoting the social value of research has been closely associated with providing fair benefits to various stakeholders involved in research. The debate over what constitutes fair benefits; whether those that addresses micro level issues of justice or those focusing on the key determinants of health at the macro level has continued. This debate has however not benefited from empirical work on what stakeholders consider fair benefits. This study explores practical experiences of stakeholders involved in global health research in Kenya, over what benefits are fair within a developing world context. METHODS AND RESULTS: We conducted in-depth interviews with key informants drawn from within the broader health research system in Kenya including researchers from the mainstream health research institutions, networks and universities, teaching hospitals, policy makers, institutional review boards, civil society organisations and community representative groups.The range of benefits articulated by stakeholders addresses both micro and macro level concerns for justice by for instance, seeking to engage with interests of those facilitating research, and the broader systemic issues that make resource poor settings vulnerable to exploitation. We interpret these views to suggest a need for global health research to engage with current crises that face people in these settings as well as the broader systemic issues that produce them. CONCLUSION: Global health research should provide benefits that address both the micro and macro level issues of justice in order to forestall exploitation. Embracing the two is however challenging in terms of how the various competing interests/needs should be balanced ethically, especially in the absence of structures to guide the process. This challenge should point to the need for greater dialogue to facilitate value clarification among stakeholders.

Agweyu A, Opiyo N, English M. 2012. Experience developing national evidence-based clinical guidelines for childhood pneumonia in a low-income setting--making the GRADE? BMC Pediatr, 12 (1), pp. 1. | Citations: 24 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The development of evidence-based clinical practice guidelines has gained wide acceptance in high-income countries and reputable international organizations. Whereas this approach may be a desirable standard, challenges remain in low-income settings with limited capacity and resources for evidence synthesis and guideline development. We present our experience using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for the recent revision of the Kenyan pediatric clinical guidelines focusing on antibiotic treatment of pneumonia. METHODS: A team of health professionals, many with minimal prior experience conducting systematic reviews, carried out evidence synthesis for structured clinical questions. Summaries were compiled and distributed to a panel of clinicians, academicians and policy-makers to generate recommendations based on best available research evidence and locally-relevant contextual factors. RESULTS: We reviewed six eligible articles on non-severe and 13 on severe/very severe pneumonia. Moderate quality evidence suggesting similar clinical outcomes comparing amoxicillin and cotrimoxazole for non-severe pneumonia received a strong recommendation against adopting amoxicillin. The panel voted strongly against amoxicillin for severe pneumonia over benzyl penicillin despite moderate quality evidence suggesting clinical equivalence between the two and additional factors favoring amoxicillin. Very low quality evidence suggesting ceftriaxone was as effective as the standard benzyl penicillin plus gentamicin for very severe pneumonia received a strong recommendation supporting the standard treatment. CONCLUSIONS: Although this exercise may have fallen short of the rigorous requirements recommended by the developers of GRADE, it was arguably an improvement on previous attempts at guideline development in low-income countries and offers valuable lessons for future similar exercises where resources and locally-generated evidence are scarce.

Yacoub S, Griffiths A, Hong Chau TT, Simmons CP, Wills B, Hien TT, Henein M, Farrar J. 2012. Cardiac function in Vietnamese patients with different dengue severity grades Critical Care Medicine, 40 (2), pp. 477-483. | Citations: 23 (Scopus) | Show Abstract | Read more

Objective: Dengue continues to cause significant global morbidity and mortality. Severe disease is characterized by cardiovascular compromise from capillary leakage. Cardiac involvement in dengue has also been reported but has not been adequately studied. Setting: H ospital for Tropical Diseases, Ho Chi Minh City, Vietnam. Subjects and Design: Seventy-nine patients aged 8-6 yrs with different dengue severity grades were studied using echocardiography including tissue Doppler imaging. The patients were split into severity grades: dengue, dengue with warning signs, and severe dengue. Changes in cardiac functional parameters and hemodynamic indices were monitored over the hospital stay. Intervention: None. Measurements and Main Results; Patients with severe dengue had worse cardiac function compared with dengue in the form of left ventricular systolic dysfunction with increased left myocardial performance index (0.58 [0.26-0.80] vs. 0.38 [0.22-0.70] , p = .006). Septal myocardial systolic velocities were reduced (6.4 [4.8-10] vs. 8.1 [6-13] cm/s, p = .01) as well as right ventricular systolic (11.4 [7.5-17] vs. 13.5 [10-17] cm/s, p = .016) and diastolic velocities (13 [8-23] vs. 17 [12-25] cm/s, p = .0026). In the severe group, these parameters improved from hospital admission to discharge; septal myocardial systolic velocities to 8.8 (7-11) cm/s (p = .002), right ventricular myocardial systolic velocities to 15.0 (11.8-23) cm/s, (p = .003), and diastolic velocity to 21 (11-25) cm/s (p = .002). Patients with cardiac impairment were more likely to have significant pleural effusions. Conclusions: Patients with severe dengue have evidence of systolic and diastolic cardiac impairment with septal and right ventricular wall being predominantly affected. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Wongtanachai J, Silamut K, Day NPJ, Dondorp A, Chaisri U. 2012. Effects of antimalarial drugs on movement of Plasmodium falciparum. Southeast Asian J Trop Med Public Health, 43 (1), pp. 1-9. | Citations: 2 (Web of Science Lite) | Show Abstract

In vitro antimalarial drug susceptibility is conventionally assessed by the concentration dependent growth inhibition of Plasmodium in an in vitro culture system. Inhibition of the kinetic properties of the parasites could provide an alternative method to assess in vitro antimalarial drugs sensitivity. In this study we used a novel real time microscopic technique, which does not require fixation and staining of the parasite, to study the effects of antimalarial drugs on the intracellular movement of Plasmodium (P.) falciparum trophozoites. Using real time microscopy movement of P. falciparum pigment within erythrocytes was investigated before and after antimalarial drugs exposure (artesunate, quinine, and piperaquine). For artesunate, the 50% inhibition concentration (IC50) at which movement in half of the trophozoites was abolished was estimated by sigmoid curve fitting. Intra- and inter-observer agreements were also assessed. Healthy unexposed P. falciparum trophozoites in culture showed very active movement of malaria pigment. Quinine and piperaquine had no effect but artesunate did reduce pigment movement which started after 2.5 hours exposure to the drug. The mean (SD) IC50 for artesunate regarding abolishment of pigment movement was 54 (14) ng/ml. Assessments of intra- and inter-rater agreement showed good reproducibility of the technique (Kappa value 0.82 to 0.91). Abolishment of active movement of malaria pigment is an alternative approach to assess drug sensitivity for artesunate. Malaria pigment movement is abolished by artesunate early after exposure, but at concentrations higher than those inhibiting growth.

Pitman RJ, White LJ, Sculpher M. 2012. Estimating the clinical impact of introducing paediatric influenza vaccination in England and Wales Vaccine, 30 (6), pp. 1208-1224. | Citations: 23 (Scopus) | Show Abstract | Read more

Influenza causes a significant burden of disease each year in England and Wales, with the young and the elderly suffering the greatest burden. Children are recognised as playing an important role in the dissemination of the influenza virus. This study examines the population impact of implementing a programme of paediatric vaccination. A dynamic transmission model was used to simulate the impact of vaccination programmes with varying levels of coverage across pre-school and school age children. These analyses suggest that vaccinating as few as 50% of 2-18 year olds could result in a substantial reduction in the annual incidence of influenza related morbidity and mortality across the population. Herd immunity may extend this protection to the young and the elderly. It is assumed that such programmes would be implemented in concert with the current strategy of vaccinating the elderly and younger at risk groups with an inactivated vaccine. In England and Wales, paediatric vaccination of two to eighteen year olds reduced the estimated number of general practice consultations, hospitalisations and deaths arising from influenza A and B infections by up to 95%. This translates into an annual average reduction of approximately 52,000, 1500 and 1200 events, respectively. A policy of paediatric vaccination could significantly reduce the clinical burden of influenza in England and Wales, in all age groups, with the added value of herd immunity helping to protect the young and the elderly who are at highest risk of complications. © 2011 Elsevier Ltd.

Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TTH et al. 2012. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell, 148 (3), pp. 434-446. | Citations: 246 (Scopus) | Show Abstract | Read more

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Auburn S, Campino S, Miotto O, Djimde AA, Zongo I, Manske M, Maslen G, Mangano V, Alcock D, MacInnis B et al. 2012. Characterization of within-host Plasmodium falciparum diversity using next-generation sequence data. PLoS One, 7 (2), pp. e32891. | Citations: 32 (Scopus) | Show Abstract | Read more

Our understanding of the composition of multi-clonal malarial infections and the epidemiological factors which shape their diversity remain poorly understood. Traditionally within-host diversity has been defined in terms of the multiplicity of infection (MOI) derived by PCR-based genotyping. Massively parallel, single molecule sequencing technologies now enable individual read counts to be derived on genome-wide datasets facilitating the development of new statistical approaches to describe within-host diversity. In this class of measures the F(WS) metric characterizes within-host diversity and its relationship to population level diversity. Utilizing P. falciparum field isolates from patients in West Africa we here explore the relationship between the traditional MOI and F(WS) approaches. F(WS) statistics were derived from read count data at 86,158 SNPs in 64 samples sequenced on the Illumina GA platform. MOI estimates were derived by PCR at the msp-1 and -2 loci. Significant correlations were observed between the two measures, particularly with the msp-1 locus (P = 5.92×10(-5)). The F(WS) metric should be more robust than the PCR-based approach owing to reduced sensitivity to potential locus-specific artifacts. Furthermore the F(WS) metric captures information on a range of parameters which influence out-crossing risk including the number of clones (MOI), their relative proportions and genetic divergence. This approach should provide novel insights into the factors which correlate with, and shape within-host diversity.

Alegana VA, Wright JA, Pentrina U, Noor AM, Snow RW, Atkinson PM. 2012. Spatial modelling of healthcare utilisation for treatment of fever in Namibia. Int J Health Geogr, 11 (1), pp. 6. | Citations: 45 (Scopus) | Show Abstract | Read more

BACKGROUND: Health care utilization is affected by several factors including geographic accessibility. Empirical data on utilization of health facilities is important to understanding geographic accessibility and defining health facility catchments at a national level. Accurately defining catchment population improves the analysis of gaps in access, commodity needs and interpretation of disease incidence. Here, empirical household survey data on treatment seeking for fever were used to model the utilisation of public health facilities and define their catchment areas and populations in northern Namibia. METHOD: This study uses data from the Malaria Indicator Survey (MIS) of 2009 on treatment seeking for fever among children under the age of five years to characterize facility utilisation. Probability of attendance of public health facilities for fever treatment was modelled against a theoretical surface of travel times using a three parameter logistic model. The fitted model was then applied to a population surface to predict the number of children likely to use a public health facility during an episode of fever in northern Namibia. RESULTS: Overall, from the MIS survey, the prevalence of fever among children was 17.6% CI [16.0-19.1] (401 of 2,283 children) while public health facility attendance for fever was 51.1%, [95%CI: 46.2-56.0]. The coefficients of the logistic model of travel time against fever treatment at public health facilities were all significant (p < 0.001). From this model, probability of facility attendance remained relatively high up to 180 minutes (3 hours) and thereafter decreased steadily. Total public health facility catchment population of children under the age five was estimated to be 162,286 in northern Namibia with an estimated fever burden of 24,830 children. Of the estimated fevers, 8,021 (32.3%) were within 30 minutes of travel time to the nearest health facility while 14,902 (60.0%) were within 1 hour. CONCLUSION: This study demonstrates the potential of routine household surveys to empirically model health care utilisation for the treatment of childhood fever and define catchment populations enhancing the possibilities of accurate commodity needs assessment and calculation of disease incidence. These methods could be extended to other African countries where detailed mapping of health facilities exists.

Kosaisavee V, Lek-Uthai U, Suwanarusk R, Grüner AC, Russell B, Nosten F, Rénia L, Snounou G. 2012. Genetic diversity in new members of the reticulocyte binding protein family in Thai Plasmodium vivax isolates. PLoS One, 7 (3), pp. e32105. | Citations: 10 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax merozoites specifically invade reticulocytes. Until recently, two reticulocyte-binding proteins (Pvrbp1 and Pvrbp2) expressed at the apical pole of the P. vivax merozoite were considered to be involved in reticulocyte recognition. The genome sequence recently obtained for the Salvador I (Sal-I) strain of P. vivax revealed additional genes in this family, and in particular Pvrbp2a, Pvrbp2b (Pvrbp2 has been renamed as Pvrbp2c) and two pseudogenes Pvrbp2d and Pvrbp3. It had been previously found that Pvrbp2c is substantially more polymorphic than Pvrbp1. The primary goal of this study was to ascertain the level of polymorphism of these new genes. METHODOLOGY/PRINCIPAL FINDINGS: The sequence of the Pvrbp2a, Pvrbp2b, Pvrbp2d and Pvrbp3 genes were obtained by amplification/cloning using DNA purified from four isolates collected from patients that acquired the infection in the four cardinal regions of Thailand (west, north, south and east). An additional seven isolates from western Thailand were analyzed for gene copy number variation. There were significant polymorphisms exhibited by these genes (compared to the reference Sal-I strain) with the ratio of mutations leading to a non-synonymous or synonymous amino acid change close to 3∶1 for Pvrbp2a and Pvrbp2b. Although the degree of polymorphism exhibited by these two genes was higher than that of Pvrbp1, it did not reach the exceptional diversity noted for Pvrbp2c. It was interesting to note that variations in the copy number of Pvrbp2a and Pvrbp2b occurred in some isolates. CONCLUSIONS/SIGNIFICANCE: The evolution of different members of the Pvrbp2 family and their relatively high degree of polymorphism suggests that the proteins encoded by these genes are important for parasite survival and are under immune selection. Our data also shows that there are highly conserved regions in rbp2a and rbp2b, which might provide suitable targets for future vaccine development against the blood stage of P. vivax.

Tran HD, Alam M, vu Trung N, van Kinh N, Nguyen HH, Pham VC, Ansaruzzaman M, Rashed SM, Bhuiyan NA, Dao TT et al. 2012. Multi-drug resistant vibrio cholerae O1 variant El Tor isolated in northern Vietnam between 2007 and 2010 Journal of Medical Microbiology, 61 (3), pp. 431-437. | Citations: 24 (Scopus) | Show Abstract | Read more

Since 2007, there has been a re-emergence of cholera outbreaks in northern Vietnam. To understand the molecular epidemiological relatedness and determine the antibiotic susceptibility profiles of responsible V. cholerae O1 outbreak strains, a representative collection of 100 V. cholerae O1 strains was characterized. V. cholerae O1 strains isolated from diarrhoeal patients in northern Vietnam between 2007 and 2010 were investigated for antibiotic susceptibility and characterized by using phenotypic and genotypic tests, including PFGE analysis. Ten clinical V. cholerae O1 isolates from Bangladesh and Zimbabwe were included for comparison. The results revealed that all isolates were resistant to co-trimoxazole and nalidixic acid, 29% were resistant to tetracycline and 1% were resistant to azithromycin. All strains were susceptible to ampicillin-sulbactam, doxycycline, chloramphenicol and ciprofloxacin and 95% were susceptible to azithromycin. MIC values did show reduced susceptibility to fluoroquinolones and 63% of the strains were intermediately resistant to tetracycline. The isolates expressed phenotypic traits of both serogroup O1 Ogawa and El Tor and harboured an rstR El Tor and ctxB classical biotype. Among the outbreak isolates, only a single PFGE pattern was observed throughout the study period. This study shows that multi-drug resistant V. cholerae altered El Tor producing classical CT strains are now predominant in northern Vietnam. © 2012 SGM.

Tarning J, Zongo I, Somé FA, Rouamba N, Parikh S, Rosenthal PJ, Hanpithakpong W, Jongrak N, Day NPJ, White NJ et al. 2012. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria Clinical Pharmacology and Therapeutics, 91 (3), pp. 497-505. | Citations: 54 (Scopus) | Show Abstract | Read more

Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin- piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated. © 2012 american Society for clinical Pharmacology and Therapeutics.

Warrell DA. 2012. Venomous animals Medicine, 40 (3), pp. 159-163. | Citations: 6 (Scopus) | Show Abstract | Read more

Bites by venomous snakes cause more than 100,000 deaths and many permanent sequelae each year, while scorpion stings kill thousands of children. Hypersensitization to bee, wasp and ant venoms is a common cause of anaphylaxis but mass attacks by African killer bees can kill by direct envenoming. Aquatic venomous animals include sea snakes, stinging fish, jellyfish, corals, cone shells, blue-ringed octopuses and sea urchins. Treatment of severe envenoming by all these groups of animals requires specific antivenom, supportive treatment for cardiorespiratory and renal failure, and surgical management of wounds. Animal bites and stings can be prevented by learning about local venomous fauna, wearing protective clothing, using a light after dark, and sleeping off the ground or under a bed net. © 2011 Published by Elsevier Ltd.

Abdullahi O, Karani A, Tigoi CC, Mugo D, Kungu S, Wanjiru E, Jomo J, Musyimi R, Lipsitch M, Scott JAG. 2012. The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya. PLoS One, 7 (2), pp. e30787. | Citations: 42 (Scopus) | Show Abstract | Read more

BACKGROUND: Pneumococcal conjugate vaccines (PCV) reduce nasopharyngeal carriage of vaccine-serotype pneumococci but increase in the carriage of non-vaccine serotypes. We studied the epidemiology of carriage among children 3-59 months old before vaccine introduction in Kilifi, Kenya. METHODS: In a rolling cross-sectional study from October 2006 to December 2008 we approached 3570 healthy children selected at random from the population register of the Kilifi Health and Demographic Surveillance System and 134 HIV-infected children registered at a specialist clinic. A single nasopharyngeal swab was transported in STGG and cultured on gentamicin blood agar. A single colony of pneumococcus was serotyped by Quellung reaction. RESULTS: Families of 2840 children in the population-based sample and 99 in the HIV-infected sample consented to participate; carriage prevalence was 65.8% (95% CI, 64.0-67.5%) and 76% (95% CI, 66-84%) in the two samples, respectively. Carriage prevalence declined progressively with age from 79% at 6-11 months to 51% at 54-59 months (p<0.0005). Carriage was positively associated with coryza (Odds ratio 2.63, 95%CI 2.12-3.25) and cough (1.55, 95%CI 1.26-1.91) and negatively associated with recent antibiotic use (0.53 95%CI 0.34-0.81). 53 different serotypes were identified and 42% of isolates were of serotypes contained in the 10-valent PCV. Common serotypes declined in prevalence with age while less common serotypes did not. CONCLUSION: Carriage prevalence in children was high, serotypes were diverse, and the majority of strains were of serotypes not represented in the 10-valent PCV. Vaccine introduction in Kenya will provide a natural test of virulence for the many circulating non-vaccine serotypes.

Horby P, Nguyen NY, Dunstan SJ, Baillie JK. 2012. The role of host genetics in susceptibility to influenza: a systematic review. PLoS One, 7 (3), pp. e33180. | Citations: 53 (Scopus) | Show Abstract | Read more

BACKGROUND: The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380). METHODS AND FINDINGS: PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven. CONCLUSION: The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.

Lang TA, Gould J, von Seidlein L, Lusingu JP, Mshamu S, Ismael S, Liheluka E, Kamuya D, Mwachiro D, Olotu A et al. 2012. Approaching the community about screening children for a multicentre malaria vaccine trial International Health, 4 (1), pp. 47-54. | Citations: 10 (Scopus) | Show Abstract | Read more

Community sensitisation, as a component of community engagement, plays an important role in strengthening the ethics of community-based trials in developing countries and is fundamental to trial success. However, few researchers have shared their community sensitisation strategies and experiences. We report on our perspective as researchers on the sensitisation activities undertaken for a phase II malaria vaccine trial in Kilifi District (Kenya) and Korogwe District (Tanzania), with the aim of informing and guiding the operational planning of future trials. We report wide variability in recruitment rates within both sites; a variability that occurred against a backdrop of similarity in overall approaches to sensitisation across the two sites but significant differences in community exposure to biomedical research. We present a range of potential factors contributing to these differences in recruitment rates, which we believe are worth considering in future community sensitisation plans. We conclude by arguing for carefully designed social science research around the implementation and impact of community sensitisation activities. © 2011 Royal Society of Tropical Medicine and Hygiene.

Seth-Smith HMB, Fookes MC, Okoro CK, Baker S, Harris SR, Scott P, Pickard D, Quail MA, Churcher C, Sanders M et al. 2012. Structure, diversity, and mobility of the Salmonella pathogenicity island 7 family of integrative and conjugative elements within Enterobacteriaceae. J Bacteriol, 194 (6), pp. 1494-1504. | Citations: 25 (Scopus) | Show Abstract | Read more

Integrative and conjugative elements (ICEs) are self-mobile genetic elements found in the genomes of some bacteria. These elements may confer a fitness advantage upon their host bacteria through the cargo genes that they carry. Salmonella pathogenicity island 7 (SPI-7), found within some pathogenic strains of Salmonella enterica, possesses features indicative of an ICE and carries genes implicated in virulence. We aimed to identify and fully analyze ICEs related to SPI-7 within the genus Salmonella and other Enterobacteriaceae. We report the sequence of two novel SPI-7-like elements, found within strains of Salmonella bongori, which share 97% nucleotide identity over conserved regions with SPI-7 and with each other. Although SPI-7 within Salmonella enterica serovar Typhi appears to be fixed within the chromosome, we present evidence that these novel elements are capable of excision and self-mobility. Phylogenetic analyses show that these Salmonella mobile elements share an ancestor which existed approximately 3.6 to 15.8 million years ago. Additionally, we identified more distantly related ICEs, with distinct cargo regions, within other strains of Salmonella as well as within Citrobacter, Erwinia, Escherichia, Photorhabdus, and Yersinia species. In total, we report on a collection of 17 SPI-7 related ICEs within enterobacterial species, of which six are novel. Using comparative and mutational studies, we have defined a core of 27 genes essential for conjugation. We present a growing family of SPI-7-related ICEs whose mobility, abundance, and cargo variability indicate that these elements may have had a large impact on the evolution of the Enterobacteriaceae.

Wonodi CB, Deloria-Knoll M, Feikin DR, DeLuca AN, Driscoll AJ, Moïsi JC, Johnson HL, Murdoch DR, O'Brien KL, Levine OS et al. 2012. Evaluation of risk factors for severe pneumonia in children: the Pneumonia Etiology Research for Child Health study. Clin Infect Dis, 54 Suppl 2 (suppl 2), pp. S124-S131. | Citations: 21 (Scopus) | Show Abstract | Read more

As a case-control study of etiology, the Pneumonia Etiology Research for Child Health (PERCH) project also provides an opportunity to assess the risk factors for severe pneumonia in hospitalized children at 7 sites. We identified relevant risk factors by literature review and iterative expert consultation. Decisions for inclusion in PERCH were based on comparability to published data, analytic plans, data collection costs and logistic feasibility, including interviewer time and subject fatigue. We aimed to standardize questions at all sites, but significant variation in the economic, cultural, and geographic characteristics of sites made it difficult to obtain this objective. Despite these challenges, the depth of the evaluation of multiple risk factors across the breadth of the PERCH sites should furnish new and valuable information about the major risk factors for childhood severe and very severe pneumonia, including risk factors for pneumonia caused by specific etiologies, in developing countries.

Hammitt LL, Murdoch DR, Scott JAG, Driscoll A, Karron RA, Levine OS, O'Brien KL, Pneumonia Methods Working Group. 2012. Specimen collection for the diagnosis of pediatric pneumonia. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S132-S139. | Citations: 36 (Web of Science Lite) | Show Abstract | Read more

Diagnosing the etiologic agent of pneumonia has an essential role in ensuring the most appropriate and effective therapy for individual patients and is critical to guiding the development of treatment and prevention strategies. However, establishing the etiology of pneumonia remains challenging because of the relative inaccessibility of the infected tissue and the difficulty in obtaining samples without contamination by upper respiratory tract secretions. Here, we review the published and unpublished literature on various specimens available for the diagnosis of pediatric pneumonia. We discuss the advantages and limitations of each specimen, and discuss the rationale for the specimens to be collected for the Pneumonia Etiology Research for Child Health study.

Grant LR, Hammitt LL, Murdoch DR, O'Brien KL, Scott JA. 2012. Procedures for collection of induced sputum specimens from children. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S140-S145. | Citations: 33 (Web of Science Lite) | Show Abstract | Read more

In most settings, sputum is not routinely collected for microbiological diagnosis from children with lower respiratory disease. To evaluate whether it is feasible and diagnostically useful to collect sputum in the Pneumonia Etiology Research for Child Health (PERCH) study, we reviewed the literature on induced sputum procedures. Protocols for induced sputum in children were collated from published reports and experts on respiratory disease and reviewed by an external advisory group for recommendation in the PERCH study. The advisory group compared 6 protocols: 4 followed a nebulization technique using hypertonic saline, and 2 followed a chest or abdomen massage technique. Grading systems for specimen quality were evaluated. Collecting sputum from children with lower respiratory tract illness is feasible and is performed around the world. An external advisory group recommended that sputum be collected from children hospitalized with severe and very severe pneumonia who participate in the PERCH study provided no contraindications exist. PERCH selected the nebulization technique using hypertonic saline.

Deloria-Knoll M, Feikin DR, Scott JAG, O'Brien KL, DeLuca AN, Driscoll AJ, Levine OS, Pneumonia Methods Working Group. 2012. Identification and selection of cases and controls in the Pneumonia Etiology Research for Child Health project. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S117-S123. | Citations: 30 (Web of Science Lite) | Show Abstract | Read more

Methods for the identification and selection of patients (cases) with severe or very severe pneumonia and controls for the Pneumonia Etiology Research for Child Health (PERCH) project were needed. Issues considered include eligibility criteria and sampling strategies, whether to enroll hospital or community controls, whether to exclude controls with upper respiratory tract infection (URTI) or nonsevere pneumonia, and matching criteria, among others. PERCH ultimately decided to enroll community controls and an additional human immunodeficiency virus (HIV)-infected control group at high HIV-prevalence sites matched on age and enrollment date of cases; controls with symptoms of URTI or nonsevere pneumonia will not be excluded. Systematic sampling of cases (when necessary) and random sampling of controls will be implemented. For each issue, we present the options that were considered, the advantages and disadvantages of each, the rationale for the methods selected for PERCH, and remaining implications and limitations.

Gilani Z, Kwong YD, Levine OS, Deloria-Knoll M, Scott JAG, O'Brien KL, Feikin DR. 2012. A literature review and survey of childhood pneumonia etiology studies: 2000-2010. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S102-S108. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

The Pneumonia Etiology Research for Child Health (PERCH) project is the largest multicountry etiology study of childhood pneumonia since the Board on Science and Technology in International Development studies of the 1980s. However, it is not the only recent or ongoing pneumonia etiology study, and even with seven sites, it cannot capture all epidemiologic settings in the developing world. Funding providers, researchers and policymakers rely on the best available evidence to strategically plan programs, new research directions and interventions. We aimed to describe the current landscape of recent pneumonia etiology studies in children under 5 years of age in the developed and developing world, as ascertained by a literature review of relevant studies with data since the year 2000 and a survey of researchers in the field of childhood pneumonia. We collected information on the study population, study design, case definitions, laboratory samples and methods and identified pathogens. A literature review identified 88 studies with child pneumonia etiology results. As of June 2010, our survey of researchers identified an additional 65 ongoing and recently completed child pneumonia etiology studies. This demonstrates the broad existing context into which the PERCH study must be placed. However, the landscape analysis also reveals a multiplicity of case definitions, levels of clinician involvement, facility types, specimen collection, and laboratory techniques. It reinforces the need for the standardization of methods and analyses for present and future pneumonia etiology studies in order to optimize their cumulative potential to accurately describe the microbial causes of childhood pneumonia.

Hammitt LL, Kazungu S, Morpeth SC, Gibson DG, Mvera B, Brent AJ, Mwarumba S, Onyango CO, Bett A, Akech DO et al. 2012. A preliminary study of pneumonia etiology among hospitalized children in Kenya. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S190-S199. | Citations: 69 (Scopus) | Show Abstract | Read more

BACKGROUND: Pneumonia is the leading cause of childhood death in the developing world. Higher-quality etiological data are required to reduce this mortality burden. METHODS: We conducted a case-control study of pneumonia etiology among children aged 1-59 months in rural Kenya. Case patients were hospitalized with World Health Organization-defined severe pneumonia (SP) or very severe pneumonia (VSP); controls were outpatient children without pneumonia. We collected blood for culture, induced sputum for culture and multiplex polymerase chain reaction (PCR), and obtained oropharyngeal swab specimens for multiplex PCR from case patients, and serum for serology and nasopharyngeal swab specimens for multiplex PCR from case patients and controls. RESULTS: Of 984 eligible case patients, 810 (84%) were enrolled in the study; 232 (29%) had VSP. Blood cultures were positive in 52 of 749 case patients (7%). A predominant potential pathogen was identified in sputum culture in 70 of 417 case patients (17%). A respiratory virus was detected by PCR from nasopharyngeal swab specimens in 486 of 805 case patients (60%) and 172 of 369 controls (47%). Only respiratory syncytial virus (RSV) showed a statistically significant association between virus detection in the nasopharynx and pneumonia hospitalization (odds ratio, 12.5; 95% confidence interval, 3.1-51.5). Among 257 case patients in whom all specimens (excluding serum specimens) were collected, bacteria were identified in 24 (9%), viruses in 137 (53%), mixed viral and bacterial infection in 39 (15%), and no pathogen in 57 (22%); bacterial causes outnumbered viral causes when the results of the case-control analysis were considered. CONCLUSIONS: A potential etiology was detected in >75% of children admitted with SP or VSP. Except for RSV, the case-control analysis did not detect an association between viral detection in the nasopharynx and hospitalization for pneumonia.

Levine OS, O'Brien KL, Deloria-Knoll M, Murdoch DR, Feikin DR, DeLuca AN, Driscoll AJ, Baggett HC, Brooks WA, Howie SRC et al. 2012. The Pneumonia Etiology Research for Child Health Project: a 21st century childhood pneumonia etiology study. Clin Infect Dis, 54 Suppl 2 (suppl 2), pp. S93-101. | Citations: 91 (Web of Science Lite) | Show Abstract | Read more

The Pneumonia Etiology Research for Child Health (PERCH) project is a 7-country, standardized, comprehensive evaluation of the etiologic agents causing severe pneumonia in children from developing countries. During previous etiology studies, between one-quarter and one-third of patients failed to yield an obvious etiology; PERCH will employ and evaluate previously unavailable innovative, more sensitive diagnostic techniques. Innovative and rigorous epidemiologic and analytic methods will be used to establish the causal association between presence of potential pathogens and pneumonia. By strategic selection of study sites that are broadly representative of regions with the greatest burden of childhood pneumonia, PERCH aims to provide data that reflect the epidemiologic situation in developing countries in 2015, using pneumococcal and Haemophilus influenzae type b vaccines. PERCH will also address differences in host, environmental, and/or geographic factors that might determine pneumonia etiology and, by preserving specimens, will generate a resource for future research and pathogen discovery.

Scott JAG, Wonodi C, Moïsi JC, Deloria-Knoll M, DeLuca AN, Karron RA, Bhat N, Murdoch DR, Crawley J, Levine OS et al. 2012. The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health study. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S109-S116. | Citations: 65 (Scopus) | Show Abstract | Read more

To develop a case definition for the Pneumonia Etiology Research for Child Health (PERCH) project, we sought a widely acceptable classification that was linked to existing pneumonia research and focused on very severe cases. We began with the World Health Organization's classification of severe/very severe pneumonia and refined it through literature reviews and a 2-stage process of expert consultation. PERCH will study hospitalized children, aged 1-59 months, with pneumonia who present with cough or difficulty breathing and have either severe pneumonia (lower chest wall indrawing) or very severe pneumonia (central cyanosis, difficulty breastfeeding/drinking, vomiting everything, convulsions, lethargy, unconsciousness, or head nodding). It will exclude patients with recent hospitalization and children with wheeze whose indrawing resolves after bronchodilator therapy. The PERCH investigators agreed upon standard interpretations of the symptoms and signs. These will be maintained by a clinical standardization monitor who conducts repeated instruction at each site and by recurrent local training and testing.

Hassan AS, Sakwa EM, Nabwera HM, Taegtmeyer MM, Kimutai RM, Sanders EJ, Awuondo KK, Mutinda MN, Molyneux CS, Berkley JA. 2012. Dynamics and constraints of early infant diagnosis of HIV infection in rural Kenya AIDS and Behavior, 16 (1), pp. 5-12. | Citations: 48 (Scopus) | Show Abstract | Read more

A cohort design was used to determine uptake and drop out of 213 HIV-exposed infants eligible for Early Infant Diagnosis (EID) of HIV. To explore service providers and care givers knowledge, attitudes and perceptions of the EID process, observations and in-depth interviews were conducted. 145 (68%) infants enrolled after 2 months of age. 139 (65%) dropped out before follow up to 18 months old. 60 (43%) drop outs occurred within 2 months of enrolment. Maternal factors associated with infant drop out were maternal loss to follow up (48 [68%] vs. 8 [20%] , P\0.001) and younger maternal age (27.2 vs. 30.1 years, P = 0.033). Service providers and caregivers had inadequate training, knowledge and understanding of EID. Poverty and lack of social support were challenges in accessing EID services. EID should be more closely aligned within PMTCT services, integrated with routine mother and child health (MCH) activities and its implementation more closely monitored. © 2011. The Author (s).

Olotu A, Fegan G, Wambua J, Nyangweso G, Ogada E, Drakeley C, Marsh K, Bejon P. 2012. Estimating individual exposure to malaria using local prevalence of malaria infection in the field. PLoS One, 7 (3), pp. e32929. | Citations: 22 (Scopus) | Show Abstract | Read more

BACKGROUND: Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level. METHOD AND FINDINGS: We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1(142) were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1(142) antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66-0.73), 0.71 (95%CI: 0.69-0.73) and 0.82 (95%CI: 0.80-0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1(142) antibody levels provided an AUC of 0.83 (95%CI: 0.79-0.88). CONCLUSION: We have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria.

Schut ES, Brouwer MC, Scarborough M, Mai NTH, Thwaites GE, Farrar JJ, Reitsma JB, van de Beek D. 2012. Validation of a Dutch risk score predicting poor outcome in adults with bacterial meningitis in Vietnam and Malawi. PLoS One, 7 (3), pp. e34311. | Citations: 6 (Scopus) | Show Abstract | Read more

We have previously developed and validated a prognostic model to predict the risk for unfavorable outcome in Dutch adults with bacterial meningitis. The aim of the current study was to validate this model in adults with bacterial meningitis from two developing countries, Vietnam and Malawi. Demographic and clinical characteristics of Vietnamese (n = 426), Malawian patients (n = 465) differed substantially from those of Dutch patients (n = 696). The Dutch model underestimated the risk of poor outcome in both Malawi and Vietnam. The discrimination of the original model (c-statistic [c] 0.84; 95% confidence interval 0.81 to 0.86) fell considerably when re-estimated in the Vietnam cohort (c = 0.70) or in the Malawian cohort (c = 0.68). Our validation study shows that new prognostic models have to be developed for these countries in a sufficiently large series of unselected patients.

Simmons CP, Farrar JJ, Chau NVV, Wills B. 2012. CURRENT CONCEPTS Dengue NEW ENGLAND JOURNAL OF MEDICINE, 366 (15), pp. 1423-1432. | Citations: 663 (Scopus) | Read more

Rijken MJ, Gilder ME, Thwin MM, Ladda Kajeechewa HM, Wiladphaingern J, Lwin KM, Jones C, Nosten F, McGready R. 2012. Refugee and migrant women's views of antenatal ultrasound on the Thai Burmese border: a mixed methods study. PLoS One, 7 (4), pp. e34018. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Antenatal ultrasound suits developing countries by virtue of its versatility, relatively low cost and safety, but little is known about women's or local provider's perspectives of this upcoming technology in such settings. This study was undertaken to better understand how routine obstetric ultrasound is experienced in a displaced Burmese population and identify barriers to its acceptance by local patients and providers. METHODOLOGY/PRINCIPAL FINDINGS: Qualitative (30 observations, 19 interviews, seven focus group discussions) and quantitative methods (questionnaire survey with 644 pregnant women) were used to provide a comprehensive understanding along four major themes: safety, emotions, information and communication, and unintended consequences of antenatal ultrasound in refugee and migrant clinics on the Thai Burmese border. One of the main concerns expressed by women was the danger of childbirth which they mainly attributed to fetal malposition. Both providers and patients recognized ultrasound as a technology improving the safety of pregnancy and delivery. A minority of patients experienced transitory shyness or anxiety before the ultrasound, but reported that these feelings could be ameliorated with improved patient information and staff communication. Unintended consequences of overuse and gender selective abortions in this population were not common. CONCLUSIONS/SIGNIFICANCE: The results of this study are being used to improve local practice and allow development of explanatory materials for this population with low literacy. We strongly encourage facilities introducing new technology in resource poor settings to assess acceptability through similar inquiry.

Snow RW, Amratia P, Kabaria CW, Noor AM, Marsh K. 2012. The changing limits and incidence of malaria in Africa: 1939-2009. Adv Parasitol, 78 pp. 169-262. | Citations: 32 (Web of Science Lite) | Show Abstract | Read more

Understanding the historical, temporal changes of malaria risk following control efforts in Africa provides a unique insight into what has been and might be archived towards a long-term ambition of elimination on the continent. Here, we use archived published and unpublished material combined with biological constraints on transmission accompanied by a narrative on malaria control to document the changing incidence of malaria in Africa since earliest reports pre-second World War. One result is a more informed mapped definition of the changing margins of transmission in 1939, 1959, 1979, 1999 and 2009.

Chotivanich K, Udomsangpetch R, Suwanarusk R, Pukrittayakamee S, Wilairatana P, Beeson JG, Day NPJ, White NJ. 2012. Plasmodium vivax adherence to placental glycosaminoglycans. PLoS One, 7 (4), pp. e34509. | Citations: 46 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax infections seldom kill directly but do cause indirect mortality by reducing birth weight and causing abortion. Cytoadherence and sequestration in the microvasculature are central to the pathogenesis of severe Plasmodium falciparum malaria, but the contribution of cytoadherence to pathology in other human malarias is less clear. METHODOLOGY: The adherence properties of P. vivax infected red blood cells (PvIRBC) were evaluated under static and flow conditions. PRINCIPAL FINDINGS: P. vivax isolates from 33 patients were studied. None adhered to immobilized CD36, ICAM-1, or thrombospondin, putative ligands for P. falciparum vascular cytoadherence, or umbilical vein endothelial cells, but all adhered to immobilized chondroitin sulphate A (CSA) and hyaluronic acid (HA), the receptors for adhesion of P. falciparum in the placenta. PvIRBC also adhered to fresh placental cells (N = 5). Pre-incubation with chondroitinase prevented PvIRBC adherence to CSA, and reduced binding to HA, whereas preincubation with hyaluronidase prevented adherence to HA, but did not reduce binding to CSA significantly. Pre-incubation of PvIRBC with soluble CSA and HA reduced binding to the immobilized receptors and prevented placental binding. PvIRBC adhesion was prevented by pre-incubation with trypsin, inhibited by heparin, and reduced by EGTA. Under laminar flow conditions the mean (SD) shear stress reducing maximum attachment by 50% was 0.06 (0.02) Pa but, having adhered, the PvIRBC could then resist detachment by stresses up to 5 Pa. At 37 °C adherence began approximately 16 hours after red cell invasion with maximal adherence at 30 hours. At 39 °C adherence began earlier and peaked at 24 hours. SIGNIFICANCE: Adherence of P. vivax-infected erythrocytes to glycosaminoglycans may contribute to the pathogenesis of vivax malaria and lead to intrauterine growth retardation.

Cheeseman IH, Miller BA, Nair S, Nkhoma S, Tan A, Tan JC, Al Saai S, Phyo AP, Moo CL, Lwin KM et al. 2012. A major genome region underlying artemisinin resistance in malaria. Science, 336 (6077), pp. 79-82. | Citations: 224 (Scopus) | Show Abstract | Read more

Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10(-6) to 10(-12)) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.

Thuong NTT, Hawn TR, Chau TTH, Bang ND, Yen NTB, Thwaites GE, Teo YY, Seielstad M, Hibberd M, Lan NTN et al. 2012. Epiregulin (EREG) variation is associated with susceptibility to tuberculosis. Genes Immun, 13 (3), pp. 275-281. | Citations: 6 (Scopus) | Show Abstract | Read more

Although host genetics influences susceptibility to Mycobacterium tuberculosis, the human genes regulating pathogenesis remain largely unknown. We used M. tuberculosis-stimulated macrophage gene expression profiling in conjunction with a case-control genetic association study to discover epiregulin (EREG), as a novel candidate tuberculosis (TB) susceptibility gene. Using a genome-wide association study dataset, we found that among the 21 genes with greater than 50-fold induction, EREG had the most polymorphisms associated with TB. We genotyped haplotype-tagging polymorphisms in discovery (N = 337 cases, N = 380 controls) and validation (N = 332 cases) datasets and an EREG polymorphism (rs7675690) was associated with susceptibility to TB (genotypic comparison; corrected P = 0.00007). rs7675690 was also associated more strongly with infections caused by the Beijing lineage of M. tuberculosis when compared with non-Beijing strains (controls vs Beijing, OR 7.81, P = 8.7 × 10(-5); non-Beijing, OR 3.13, P = 0.074). Furthermore, EREG expression was induced in monocytes and peripheral blood mononuclear cells stimulated with M. tuberculosis as well as TLR4 and TLR2/1/6 ligands. In murine macrophages, EREG expression induced by M. tuberculosis was MYD88- and TLR2-dependent. Together, these data provide the first evidence for an important role for EREG as a susceptibility gene for human TB.

Aiken AM, Mturi N, Morpeth SC, Seale AC, G Scott JA. 2012. Authors' reply The Lancet, 379 (9825), pp. 1484-1485.

Mwangome MK, Fegan G, Mbunya R, Prentice AM, Berkley JA. 2012. Reliability and accuracy of anthropometry performed by community health workers among infants under 6months in rural Kenya Tropical Medicine and International Health, 17 (5), pp. 622-629. | Citations: 18 (Scopus) | Show Abstract | Read more

Objective To assess the inter-observer variability and accuracy of Mid Upper Arm Circumference (MUAC) and weight-for-length Z score (WFLz) among infants aged < 6months performed by community health workers (CHWs) in Kilifi District, Kenya. Methods A cross-sectional repeatability study estimated inter-observer variation and accuracy of measurements initially undertaken by an expert anthropometrist, nurses and public health technicians. Then, after training, 18 CHWs (three at each of six sites) repeatedly measured MUAC, weight and length of infants aged < 6months. Intra-class correlations (ICCs) and the Pitman's statistic were calculated. Results Among CHWs, ICCs pooled across the six sites (924 infants) were 0.96 (95% CI 0.95-0.96) for MUAC and 0.71 (95% CI 0.68-0.74) for WFLz. MUAC measures by CHWs differed little from their trainers: the mean difference in MUAC was 0.65mm (95% CI 0.023-1.07), with no significant difference in variance (P=0.075). Conclusion Mid Upper Arm Circumference is more reliably measured by CHWs than WFLz among infants aged < 6months. Further work is needed to define cut-off values based on MUAC's ability to predict mortality among younger infants. © 2012 Blackwell Publishing Ltd.

Price EP, Dale JL, Cook JM, Sarovich DS, Seymour ML, Ginther JL, Kaufman EL, Beckstrom-Sternberg SM, Mayo M, Kaestli M et al. 2012. Development and validation of Burkholderia pseudomallei-specific real-time PCR assays for clinical, environmental or forensic detection applications. PLoS One, 7 (5), pp. e37723. | Citations: 19 (Scopus) | Show Abstract | Read more

The bacterium Burkholderia pseudomallei causes melioidosis, a rare but serious illness that can be fatal if untreated or misdiagnosed. Species-specific PCR assays provide a technically simple method for differentiating B. pseudomallei from near-neighbor species. However, substantial genetic diversity and high levels of recombination within this species reduce the likelihood that molecular signatures will differentiate all B. pseudomallei from other Burkholderiaceae. Currently available molecular assays for B. pseudomallei detection lack rigorous validation across large in silico datasets and isolate collections to test for specificity, and none have been subjected to stringent quality control criteria (accuracy, precision, selectivity, limit of quantitation (LoQ), limit of detection (LoD), linearity, ruggedness and robustness) to determine their suitability for environmental, clinical or forensic investigations. In this study, we developed two novel B. pseudomallei specific assays, 122018 and 266152, using a dual-probe approach to differentiate B. pseudomallei from B. thailandensis, B. oklahomensis and B. thailandensis-like species; other species failed to amplify. Species specificity was validated across a large DNA panel (>2,300 samples) comprising Burkholderia spp. and non-Burkholderia bacterial and fungal species of clinical and environmental relevance. Comparison of assay specificity to two previously published B. pseudomallei-specific assays, BurkDiff and TTS1, demonstrated comparable performance of all assays, providing between 99.7 and 100% specificity against our isolate panel. Last, we subjected 122018 and 266152 to rigorous quality control analyses, thus providing quantitative limits of assay performance. Using B. pseudomallei as a model, our study provides a framework for comprehensive quantitative validation of molecular assays and provides additional, highly validated B. pseudomallei assays for the scientific research community.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection. Int J Parasitol, 42 (6), pp. 535-548. | Citations: 26 (Web of Science Lite) | Show Abstract | Read more

Malaria is a vector-borne infectious disease caused by infection with eukaryotic pathogens termed Plasmodium. Epidemiological hallmarks of Plasmodium falciparum malaria are continuous re-infections, over which time the human host may experience several clinical malaria episodes, slow acquisition of partial protection against infection, and its partial decay upon migration away from endemic regions. To overcome the exposure-dependence of naturally acquired immunity and rapidly elicit robust long-term protection are ultimate goals of malaria vaccine development. However, cellular and molecular correlates of naturally acquired immunity against either parasite infection or malarial disease remain elusive. Sero-epidemiological studies consistently suggest that acquired immunity is primarily directed against the asexual blood stages. Here, we review available data on the relationship between immune responses against the Anopheles mosquito-transmitted sporozoite and exo-erythrocytic liver stages and the incidence of malaria. We discuss current limitations and research opportunities, including the identification of additional sporozoite antigens and the use of systematic immune profiling and functional studies in longitudinal cohorts to look for pre-erythrocytic signatures of naturally acquired immunity.

Boyer C, Gaudin K, Kauss T, Gaubert A, Boudis A, Verschelden J, Franc M, Roussille J, Boucher J, Olliaro P et al. 2012. Development of NIRS method for quality control of drug combination artesunate-azithromycin for the treatment of severe malaria. J Pharm Biomed Anal, 67-68 pp. 10-15. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

Near infrared spectroscopy (NIRS) methods were developed for the determination of analytical content of an antimalarial-antibiotic (artesunate and azithromycin) co-formulation in hard gelatin capsule (HGC). The NIRS consists of pre-processing treatment of spectra (raw spectra and first-derivation of two spectral zones), a unique principal component analysis model to ensure the specificity and then two partial least-squares regression models for the determination content of each active pharmaceutical ingredient. The NIRS methods were developed and validated with no reference method, since the manufacturing process of HGC is basically mixed excipients with active pharmaceutical ingredients. The accuracy profiles showed β-expectation tolerance limits within the acceptance limits (±5%). The analytical control approach performed by reversed phase (HPLC) required two different methods involving two different preparation and chromatographic methods. NIRS offers advantages in terms of lower costs of equipment and procedures, time saving, environmentally friendly.

Maude RJ, Socheat D, Nguon C, Saroth P, Dara P, Li G, Song J, Yeung S, Dondorp AM, Day NP et al. 2012. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance. PLoS One, 7 (5), pp. e37166. | Citations: 45 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA) and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria. METHOD AND FINDINGS: A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity. CONCLUSIONS: The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for elimination programmes than numbers of symptomatic cases; combinations of interventions are most effective and sustained efforts are crucial for successful elimination.

Ho Dang Trung N, Le Thi Phuong T, Wolbers M, Nguyen Van Minh H, Nguyen Thanh V, Van MP, Thieu NTV, Van TL, Song DT, Thi PL et al. 2012. Aetiologies of central nervous system infection in Viet Nam: a prospective provincial hospital-based descriptive surveillance study. PLoS One, 7 (5), pp. e37825. | Citations: 29 (Scopus) | Show Abstract | Read more

BACKGROUND: Infectious diseases of the central nervous system (CNS) remain common and life-threatening, especially in developing countries. Knowledge of the aetiological agents responsible for these infections is essential to guide empiric therapy and develop a rational public health policy. To date most data has come from patients admitted to tertiary referral hospitals in Asia and there is limited aetiological data at the provincial hospital level where most patients are seen. METHODS: We conducted a prospective Provincial Hospital-based descriptive surveillance study in adults and children at thirteen hospitals in central and southern Viet Nam between August 2007-April 2010. The pathogens of CNS infection were confirmed in CSF and blood samples by using classical microbiology, molecular diagnostics and serology. RESULTS: We recruited 1241 patients with clinically suspected infection of the CNS. An aetiological agent was identified in 640/1241 (52%) of the patients. The most common pathogens were Streptococcus suis serotype 2 in patients older than 14 years of age (147/617, 24%) and Japanese encephalitis virus in patients less than 14 years old (142/624, 23%). Mycobacterium tuberculosis was confirmed in 34/617 (6%) adult patients and 11/624 (2%) paediatric patients. The acute case fatality rate (CFR) during hospital admission was 73/617 (12%) in adults and to 42/624 (7%) in children. CONCLUSIONS: Zoonotic bacterial and viral pathogens are the most common causes of CNS infection in adults and children in Viet Nam.

Page A-L, Alberti KP, Mondonge V, Rauzier J, Quilici M-L, Guerin PJ. 2012. Evaluation of a rapid test for the diagnosis of cholera in the absence of a gold standard. PLoS One, 7 (5), pp. e37360. | Citations: 21 (Scopus) | Show Abstract | Read more

BACKGROUND: Early detection and confirmation of cholera outbreaks are crucial for rapid implementation of control measures. Because cholera frequently affects regions with limited laboratory resources, rapid diagnostic tests (RDT) designed for field conditions are important to enhance rapid response. Stool culture remains the "gold standard" for cholera diagnosis; however, its lack of sensitivity may lead to underestimation of test specificity. We evaluated the Crystal VC® immunochromatographic test (Span Diagnostics, India) for cholera diagnosis using a modified reference standard that combines culture-dependent and independent assays, or a Bayesian latent class model (LCM) analysis. METHODOLOGY/PRINCIPAL FINDINGS: The study was conducted during a cholera epidemic in 2008, in Lubumbashi, Democratic Republic of Congo. Stools collected from 296 patients were used to perform the RDT on site and sent to Institut Pasteur, Paris, for bacterial culture. In comparison with culture as the gold standard, the RDT showed good sensitivity (92.2%; 95% CI: 86.8%-95.9%) but poor specificity when used by a trained laboratory technician (70.6%; 95% CI: 60.7%-79.2%) or by clinicians with no specific test training (60.4%, 95% CI: 50.2%-70.0%). The specificity of the test performed by the laboratory technician increased to 88.6% (95% CI: 78.7-94.9) when PCR was combined with culture results as the reference standard, and to 85.0% (95% CI: 70.4-99.2), when the Bayesian LCM analysis was used for performance evaluation. In both cases, the sensitivity remained high. CONCLUSION: Using an improved reference standard or appropriate statistical methods for diagnostic test evaluations in the absence of a gold standard, we report better performance of the Crystal VC® RDT than previously published. Our results confirm that this test can be used for early outbreak detection or epidemiological surveillance, key components of efficient global cholera control. Our analysis also highlights the importance of improving evaluations of RDT when no reliable gold standard is available.

Talbert A, Thuo N, Karisa J, Chesaro C, Ohuma E, Ignas J, Berkley JA, Toromo C, Atkinson S, Maitland K. 2012. Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome. PLoS One, 7 (6), pp. e38321. | Citations: 45 (Scopus) | Show Abstract | Read more

BACKGROUND: Severe acute malnutrition (SAM) accounts for two million deaths worldwide annually. In those hospitalised with SAM, concomitant infections and diarrhoea are frequent complications resulting in adverse outcome. We examined the clinical and laboratory features on admission and outcome of children with SAM and diarrhoea at a Kenyan district hospital. METHODS: A 4-year prospective descriptive study involving 1,206 children aged 6 months to 12 years, hospitalized with SAM and managed in accordance with WHO guidelines. Data on clinical features, haematological, biochemical and microbiological findings for children with diarrhoea (≥ 3 watery stools/day) were systematically collected and analyzed to identify risk factors associated with poor outcome. RESULTS: At admission 592 children (49%) had diarrhoea of which 122 (21%) died compared to 72/614 (12%) deaths in those without diarrhoea at admission (Χ(2) = 17.6 p<0.001). A further 187 (16%) children developed diarrhoea after 48 hours of admission and 33 died (18%). Any diarrhoea during admission resulted in a significantly higher mortality 161/852 (19%) than those uncomplicated by diarrhoea 33/351 (9%) (Χ(2) = 16.6 p<0.001). Features associated with a fatal outcome in children presenting with diarrhoea included bacteraemia, hyponatraemia, low mid-upper arm circumference <10 cm, hypoxia, hypokalaemia and oedema. Bacteraemia had the highest risk of death (adjusted OR 6.1; 95% C.I 2.3, 16.3 p<0.001); and complicated 24 (20%) of fatalities. Positive HIV antibody status was more frequent in cases with diarrhoea at admission (23%) than those without (15%, Χ(2) = 12.0 p = 0.001) but did not increase the risk of death in diarrhoea cases. CONCLUSION: Children with SAM complicated by diarrhoea had a higher risk of death than those who did not have diarrhoea during their hospital stay. Further operational and clinical research is needed to reduce mortality in children with SAM in the given setting.

Hall RA, Blitvich BJ, Johansen CA, Blacksell SD. 2012. Advances in arbovirus surveillance, detection and diagnosis. J Biomed Biotechnol, 2012 pp. 512969. | Citations: 6 (Web of Science Lite) | Read more

Blacksell SD. 2012. Commercial dengue rapid diagnostic tests for point-of-care application: recent evaluations and future needs? J Biomed Biotechnol, 2012 pp. 151967. | Citations: 54 (Scopus) | Show Abstract | Read more

Dengue fever, dengue haemorrhagic fever, and dengue shock syndrome (DF/DHF/DSS) are tropical diseases that cause significant humanitarian and economic hardship. It is estimated that more than 2.5 billion people are at risk of infection and more than 100 countries have endemic dengue virus transmission. Laboratory tests are essential to provide an accurate diagnosis of dengue virus infection so that appropriate treatment and patient management may be administered. In many dengue endemic settings, laboratory diagnostic resources are limited and simple rapid diagnostic tests (RDTs) provide opportunities for point-of-care diagnosis. This paper addresses current issues relating to the application of commercial dengue RDTs for the diagnosis of acute dengue virus infection, recent diagnostic evaluations, and identifies future needs.

Turner P, Turner C, Jankhot A, Helen N, Lee SJ, Day NP, White NJ, Nosten F, Goldblatt D. 2012. A longitudinal study of Streptococcus pneumoniae carriage in a cohort of infants and their mothers on the Thailand-Myanmar border. PLoS One, 7 (5), pp. e38271. | Citations: 48 (Scopus) | Show Abstract | Read more

BACKGROUND: Pneumococcal disease is a major cause of childhood death. Almost a third of the world's children live in Southeast Asia, but there are few data from the region on pneumococcal colonization or disease. Our aim was to document the dynamics of pneumococcal carriage in a rural SE Asian birth cohort. METHODS: We studied 234 Karen mother-infant pairs in Northwestern Thailand. Infants were followed from birth and nasopharyngeal swabs were taken from mother and infant at monthly intervals until 24 months old. RESULTS: 8,386 swabs were cultured and 4,396 pneumococci characterized. Infants became colonized early (median 45.5 days; 95% confidence interval [CI] 44.5-46.0) and by 24 months had a median of seven (range 0-15) carriage episodes. Maternal smoking and young children in the house were associated with earlier colonization (hazard ratio [HR] 1.5 (95% CI 1.1-2.1) and 1.4 (95% CI 1.0-1.9)). For the four commonest serotypes and non-typeable pneumococci, previous exposure to homologous or heterologous serotypes resulted in an extended interval to reacquisition of the same serotype. Previous colonization by serotypes 14 and 19F was also associated with reduced carriage duration if subsequently reacquired (HR [first reacquisition] 4.1 (95% CI 1.4-12.6) and 2.6 (1.5-4.7)). Mothers acquired pneumococci less frequently, and carried them for shorter periods, than infants (acquisition rate 0.5 vs. 1.1 /100 person-days, p<0.001; median duration 31.0 vs. 60.5 days, p = 0.001). 55.8% of pneumococci from infants were vaccine serotypes (13-valent pneumococcal conjugate vaccine, PCV13), compared with 27.5% from mothers (p<0.001). Non-typeable pneumococcal carriage was common, being carried at least once by 55.1% of infants and 32.0% of mothers. CONCLUSIONS: Pneumococcal carriage frequency and duration are influenced by previous exposure to both homologous and heterologous serotypes. These data will inform vaccination strategies in this population.

Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, Moo CL, Al-Saai S, Dondorp AM, Lwin KM et al. 2012. Emergence of artemisinin-resistant malaria on the western border of Thailand: A longitudinal study The Lancet, 379 (9830), pp. 1960-1966. | Citations: 494 (Scopus) | Show Abstract | Read more

Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international eff ort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≤4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≤6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identifi ed, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpret ation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years.

Nayyar GML, Breman JG, Newton PN, Herrington J. 2012. Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa. Lancet Infect Dis, 12 (6), pp. 488-496. | Citations: 162 (Scopus) | Show Abstract | Read more

Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin resistance or tolerance in Plasmodium falciparum on the Thailand-Cambodia border makes protection of the effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and 450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is more important than ever.

Sibley CH, Price RN. 2012. Monitoring antimalarial drug resistance: Applying lessons learned from the past in a fast-moving present. Int J Parasitol Drugs Drug Resist, 2 pp. 126-133. | Citations: 13 (Scopus) | Show Abstract | Read more

The need for robust surveillance of antimalarial drugs is more urgent than it has ever been. In the western region of Cambodia, artemisinin resistance has emerged in Plasmodium falciparum and threatens to undermine the efficacy of highly effective artemisinin combination therapies. Although some manfestations of artemisinin tolerance are unique to this class of drug, many of its properties mirror previous experience in understanding and tracking resistance to other antimalarials. In this review we outline the spectrum of approaches that were developed to understand the evolution and spread of antifolate resistance, highlighting the importance of integrating information from different methodologies towards a better understanding of the underlying biologic processes. We consider how to apply our experience in investigating and attempting to contain antifolate resistance to inform our prospective assessment of novel antimalarial resistance patterns and their subsequent spread.

Horby P, Mai LQ, Fox A, Thai PQ, Thi Thu Yen N, Thanh LT, Le Khanh Hang N, Duong TN, Thoang DD, Farrar J et al. 2012. The epidemiology of interpandemic and pandemic influenza in Vietnam, 2007-2010 American Journal of Epidemiology, 175 (10), pp. 1062-1074. | Citations: 46 (Scopus) | Show Abstract | Read more

Prospective community-based studies have provided fundamental insights into the epidemiology of influenza in temperate regions, but few comparable studies have been undertaken in the tropics. The authors conducted prospective influenza surveillance and intermittent seroprevalence surveys in a household-based cohort in Vietnam between December 2007 and April 2010, resulting in 1,793 person-seasons of influenza surveillance. Age-and sex-standardized estimates of the risk of acquiring any influenza infection per season in persons 5 years of age or older were 21.1% (95% confidence interval: 17.4, 24.7) in season 1, 26.4% (95% confidence interval: 22.6, 30.2) in season 2, and 17.0% (95% confidence interval: 13.6, 20.4) in season 3. Some individuals experienced multiple episodes of infection with different influenza types/subtypes in the same season (n = 27) or reinfection with the same subtype in different seasons (n = 22). The highest risk of influenza infection was in persons 5-9 years old, in whom the risk of influenza infection per season was 41.8%. Although the highest infection risk was in school-aged children, there were important heterogeneities in the age of infection by subtype and season. These heterogeneities could influence the impact of school closure and childhood vaccination on influenza transmission in tropical areas, such as Vietnam. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author 2012. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Herbert K, Plugge E, Foster C, Doll H. 2012. Prevalence of risk factors for non-communicable diseases in prison populations worldwide: A systematic review The Lancet, 379 (9830), pp. 1975-1982. | Citations: 51 (Scopus) | Show Abstract | Read more

The burden of non-communicable diseases (NCDs) is disproportionately carried by low-income and middle-income countries and disadvantaged sectors of society such as prisoners. No systematic analysis has been done to assess the prevalence of poor diet, inadequate physical activity, and overweight and obesity in prisoners. We aim to synthesise current evidence and to highlight areas for action and further research. Methods We systematically searched online databases for reports published between 1948 and May, 2011. Studies were screened against eligibility criteria; two authors then independently extracted data with previously agreed proformas. The risk of bias was assessed for each study with a domain-based assessment. Data on body-mass index and physical activity were presented in forest plots; no overall estimates were calculated on account of data heterogeneity. Available data from the population subgroup most similar in terms of age and sex were used to calculate age-adjusted and sex-adjusted prevalence ratios, which estimate the likelihood of insuffi cient activity and obesity prevalence in prisoners compared with the national population. Findings 31 eligible studies were reported in 29 publications, including more than 60 000 prisoners in 884 institutions in 15 countries. Male prisoners were less likely to be obese than males in the general population (prevalence ratios ranged from 0·33 to 0·87) in all but one study (1·02, 0·92-1·07), whereas female prisoners were more likely to be obese than non-imprisoned women in the USA (1·18, 1·08-1·30) and Australia (prevalence ratios ranged from 1·15 to 1·20). Australian prisoners were more likely to achieve suffi cient activity levels than the general population compared with prisoners in the UK (prevalence ratio 1·19, 95% CI 1·04-1·37, for women in Australia in 2009 vs 0·32, 0·21-0·47, for women in the UK; prevalence ratios ranged from 1·37 to 1·59 for men in Australia vs 0·71, 0·34-0·78, for men in the UK). Female mean energy intake exceeded recommended levels and sodium intake was about t wo to three times the recommended intake for all prisoners. Interpretation Contact with the criminal justice system is a public-health opportunity to promote health in this vulnerable population; the costs to the individual and to society of failing to do so are likely to be substantial. Improved monitoring and further research is essential to inform appropriate targeting of public health interventions.

Green LE, Carrique-Mas JJ, Mason SA, Medley GF. 2012. Patterns of delayed detection and persistence of bovine tuberculosis in confirmed and unconfirmed herd breakdowns in cattle and cattle herds in Great Britain. Prev Vet Med, 106 (3-4), pp. 266-274. | Show Abstract | Read more

Approximately 1500/6000 cattle farms that were depopulated during the foot and mouth epidemic in GB in 2001 had been repopulated and subjected to two unrestricted (herd considered free from bovine tuberculosis (bTB)) herd tests. Factors associated with herd breakdown(s) (HBD) and individual cattle reactor status at the second test were investigated. There were 96 HBD in total, with a 3-fold increased risk of HBD in herds that had had a HBD at the first test after restocking. Two mixed effect models were used to investigate factors associated with 324/246,060 reactor cattle at the second bTB test; 228 reactors were at confirmed HBD and 96 at unconfirmed HBD; 253 (79%) reactors at the second test were present and test negative at the first test. In confirmed HBD, the odds of cattle reacting were higher if the restocked farm had a history of bTB before 2001 and if the source and restocked farms were high frequency tested (HFT) farms (routine bTB tests at ≥1 per 2 years). Reacting cattle were more likely to have been born on the restocked farm before the first test after FMD and less likely to have been purchased from a low frequency tested (LFT) farm (routine bTB tests at 3-4 year intervals) after the first test compared with a baseline of cattle purchased from a LFT farm before the first test. Unconfirmed HBD at the second test was more likely when the first test was a confirmed HBD and when there was a history of bTB in the restocked farm. In contrast to confirmed HBD, cattle purchased from a LFT farm after the first test were at increased risk of reacting at an unconfirmed HBD at the second test. We conclude that a farm history of bTB suggests persistence of bTB on the farm. Confirmed tests indicate exposure to bTB for some time indicated by the increased risk from HFT source and restocked farms and a farm history of bTB. The risks for reactors are related to the farm and herd and duration of exposure to these risks. Therefore, the spread of bTB to naïve herds would be reduced if farmers only introduced cattle known not to have been in herds and on farms exposed to bTB. Management of bTB on farms with bTB is complicated because there is undisclosed infection in cattle and environmental contamination.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection International Journal for Parasitology, 42 (6), pp. 535-548. | Citations: 29 (Scopus) | Show Abstract | Read more

Malaria is a vector-borne infectious disease caused by infection with eukaryotic pathogens termed . Plasmodium. Epidemiological hallmarks of . Plasmodium falciparum malaria are continuous re-infections, over which time the human host may experience several clinical malaria episodes, slow acquisition of partial protection against infection, and its partial decay upon migration away from endemic regions. To overcome the exposure-dependence of naturally acquired immunity and rapidly elicit robust long-term protection are ultimate goals of malaria vaccine development. However, cellular and molecular correlates of naturally acquired immunity against either parasite infection or malarial disease remain elusive. Sero-epidemiological studies consistently suggest that acquired immunity is primarily directed against the asexual blood stages. Here, we review available data on the relationship between immune responses against the . Anopheles mosquito-transmitted sporozoite and exo-erythrocytic liver stages and the incidence of malaria. We discuss current limitations and research opportunities, including the identification of additional sporozoite antigens and the use of systematic immune profiling and functional studies in longitudinal cohorts to look for pre-erythrocytic signatures of naturally acquired immunity. © 2012 Australian Society for Parasitology Inc..

Jones COH, Wasunna B, Sudoi R, Githinji S, Snow RW, Zurovac D. 2012. "Even if you know everything you can forget": health worker perceptions of mobile phone text-messaging to improve malaria case-management in Kenya. PLoS One, 7 (6), pp. e38636. | Citations: 33 (Scopus) | Show Abstract | Read more

This paper presents the results of a qualitative study to investigate the perceptions and experiences of health workers involved in a a cluster-randomized controlled trial of a novel intervention to improve health worker malaria case-management in 107 government health facilities in Kenya. The intervention involved sending text-messages about paediatric outpatient malaria case-management accompanied by "motivating" quotes to health workers' mobile phones. Ten malaria messages were developed reflecting recommendations from the Kenyan national guidelines. Two messages were delivered per day for 5 working days and the process was repeated for 26 weeks (May to October 2009). The accompanying quotes were unique to each message. The intervention was delivered to 119 health workers and there were significant improvements in correct artemether-lumefantrine (AL) management both immediately after the intervention (November 2009) and 6 months later (May 2010). In-depth interviews with 24 health workers were undertaken to investigate the possible drivers of this change. The results suggest high acceptance of all components of the intervention, with the active delivery of information in an on the job setting, the ready availability of new and stored text messages and the perception of being kept 'up to date' as important factors influencing practice. Applying the construct of stages of change we infer that in this intervention the SMS messages were operating primarily at the action and maintenance stages of behaviour change achieving their effect by creating an enabling environment and providing a prompt to action for the implementation of case management practices that had already been accepted as the clinical norm by the health workers. Future trials testing the effectiveness of SMS reminders in creating an enabling environment for the establishment of new norms in clinical practice as well as in providing a prompt to action for the implementation of the new case-management guidelines are justified.

Lipsitch M, Abdullahi O, DʼAmour A, Xie W, Weinberger DM, Tchetgen Tchetgen E, Scott JAG. 2012. Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model. Epidemiology, 23 (4), pp. 510-519. | Citations: 41 (Scopus) | Show Abstract | Read more

BACKGROUND: There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion. METHODS: We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model. RESULTS: Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes. CONCLUSIONS: Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine.

Smith M, Campino S, Gu Y, Clark TG, Otto TD, Maslen G, Manske M, Imwong M, Dondorp AM, Kwiatkowski DP et al. 2012. An In-Solution Hybridisation Method for the Isolation of Pathogen DNA from Human DNA-rich Clinical Samples for Analysis by NGS. Open Genomics J, 5 (1), pp. 18-29. | Citations: 2 (Scopus) | Show Abstract | Read more

Studies on DNA from pathogenic organisms, within clinical samples, are often complicated by the presence of large amounts of host, e.g., human DNA. Isolation of pathogen DNA from these samples would improve the efficiency of next-generation sequencing (NGS) and pathogen identification. Here we describe a solution-based hybridisation method for isolation of pathogen DNA from a mixed population. This straightforward and inexpensive technique uses probes made from whole-genome DNA and off-the-shelf reagents. In this study, Escherichia coli DNA was successfully enriched from a mixture of E.coli and human DNA. After enrichment, genome coverage following NGS was significantly higher and the evenness of coverage and GC content were unaffected. This technique was also applied to samples containing a mixture of human and Plasmodium falciparum DNA. The P.falciparum genome is particularly difficult to sequence due to its high AT content (80.6%) and repetitive nature. Post enrichment, a bias in the recovered DNA was observed, with a poorer representation of the AT-rich non-coding regions. This uneven coverage was also observed in pre-enrichment samples, but to a lesser degree. Despite the coverage bias in enriched samples, SNP (single-nucleotide polymorphism) calling in coding regions was unaffected and the majority of samples had over 90% of their coding region covered at 5× depth. This technique shows significant promise as an effective method to enrich pathogen DNA from samples with heavy human contamination, particularly when applied to GC-neutral genomes.

Salter SJ, Hinds J, Gould KA, Lambertsen L, Hanage WP, Antonio M, Turner P, Hermans PWM, Bootsma HJ, O'Brien KL, Bentley SD. 2012. Variation at the capsule locus, cps, of mistyped and non-typable Streptococcus pneumoniae isolates. Microbiology, 158 (Pt 6), pp. 1560-1569. | Citations: 36 (Scopus) | Show Abstract | Read more

The capsule polysaccharide locus (cps) is the site of the capsule biosynthesis gene cluster in encapsulated Streptococcus pneumoniae. A set of pneumococcal samples and non-pneumococcal streptococci from Denmark, the Gambia, the Netherlands, Thailand, the UK and the USA were sequenced at the cps locus to elucidate serologically mistyped or non-typable isolates. We identified a novel serotype 33B/33C mosaic capsule cluster and previously unseen serotype 22F capsule genes, disrupted and deleted cps clusters, the presence of aliB and nspA genes that are unrelated to capsule production, and similar genes in the non-pneumococcal samples. These data provide greater understanding of diversity at a locus which is crucial to the antigenic diversity of the pathogen and current vaccine strategies.

Gitonga CW, Edwards T, Karanja PN, Noor AM, Snow RW, Brooker SJ. 2012. Plasmodium infection, anaemia and mosquito net use among school children across different settings in Kenya Tropical Medicine and International Health, 17 (7), pp. 858-870. | Citations: 12 (Scopus) | Show Abstract | Read more

Objective To investigate risk factors, including reported net use, for Plasmodium infection and anaemia among school children and to explore variations in effects across different malaria ecologies occurring in Kenya. Methods This study analysed data for 49975 school children in 480 schools surveyed during a national school malaria survey, 2008-2010. Mixed effects logistic regression was used to investigate factors associated with Plasmodium infection and anaemia within different malaria transmission zones. Results Insecticide-treated net (ITN) use was associated with reduction in the odds of Plasmodium infection in coastal and western highlands epidemic zones and among boys in the lakeside high transmission zone. Other risk factors for Plasmodium infection and for anaemia also varied by zone. Plasmodium infection was negatively associated with increasing socio-economic status in all transmission settings, except in the semi-arid north-east zone. Plasmodium infection was a risk factor for anaemia in lakeside high transmission, western highlands epidemic and central low-risk zones, whereas ITN use was only associated with lower levels of anaemia in coastal and central zones and among boys in the lakeside high transmission zone. Conclusions The risk factors for Plasmodium infection and anaemia, including the protective associations with ITN use, vary according to malaria transmission settings in Kenya, and future efforts to control malaria and anaemia should take into account such heterogeneities among school children. © 2012 Blackwell Publishing Ltd.

Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. 2012. Open-Label Randomized Clinical Trial of Atropine Bolus Injection Versus Incremental Boluses Plus Infusion for Organophosphate Poisoning in Bangladesh Journal of Medical Toxicology, 8 (2), pp. 108-117. | Citations: 16 (Scopus) | Show Abstract | Read more

Severe organophosphate compound (OPC) poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine the best therapy. A study was therefore undertaken to determine the optimal dosing regimen for atropine in the treatment of OPC poisoning. An open-label randomized clinical trial was conducted in Chittagong Medical College Hospital, Chittagong, Bangladesh, on 156 hospitalized individuals with OPC poisoning from June to September 2006. The aim was to compare the efficacy and safety of conventional bolus doses with individualized incremental doses of atropine for atropinization followed by continuous atropine infusion for management of OPC poisoning. Inclusion criteria were patients with a clear history of OPC poisoning with clear clinical signs of toxicity, i. e. features of cholinergic crisis. The patients were observed for at least 96 h. Immediate outcome and complications were recorded. Out of 156 patients, 81 patients received conventional bolus dose atropine (group A) and 75 patients received rapidly incremental doses of atropine followed by infusion (group B). The mortality in group 'A' was 22. 5% (18/80) and in group 'B' 8% (6/75) (p < 0. 05). The mean duration of atropinization in group 'A' was 151. 74 min compared to 23. 90 min for group 'B' (p < 0. 001). More patients in group A experienced atropine toxicity than in group 'B' (28. 4% versus 12. 0%, p < 0. 05); intermediate syndrome was more common in group 'A' than in group 'B' (13. 6% versus 4%, p < 0. 05), and respiratory support was required more often for patients in group 'A' than in group 'B' (24. 7% versus 8%, p < 0. 05). Rapid incremental dose atropinization followed by atropine infusion reduces mortality and morbidity from OPC poisoning and shortens the length of hospital stay and recovery. Incremental atropine and infusion should become the treatment of choice for OPC poisoning. Given the paucity of existing evidence, further clinical studies should be performed to determine the optimal dosing regimen of atropine that most rapidly and safely achieves atropinization in these patients. © 2012 American College of Medical Toxicology.

Stone SP, Fuller C, Savage J, Cookson B, Hayward A, Cooper B, Duckworth G, Michie S, Murray M, Jeanes A et al. 2012. Evaluation of the national Cleanyourhands campaign to reduce Staphylococcus aureus bacteraemia and Clostridium difficile infection in hospitals in England and Wales by improved hand hygiene: four year, prospective, ecological, interrupted time series study. BMJ, 344 (may03 2), pp. e3005. | Citations: 133 (Scopus) | Show Abstract | Read more

OBJECTIVE: To evaluate the impact of the Cleanyourhands campaign on rates of hospital procurement of alcohol hand rub and soap, report trends in selected healthcare associated infections, and investigate the association between infections and procurement. DESIGN: Prospective, ecological, interrupted time series study from 1 July 2004 to 30 June 2008. SETTING: 187 acute trusts in England and Wales. INTERVENTION: Installation of bedside alcohol hand rub, materials promoting hand hygiene and institutional engagement, regular hand hygiene audits, rolled out nationally from 1 December 2004. MAIN OUTCOME MEASURES: Quarterly (that is, every three months) rates for each trust of hospital procurement of alcohol hand rub and liquid soap; Staphylococcus aureus bacteraemia (meticillin resistant (MRSA) and meticillin sensitive (MSSA)) and Clostridium difficile infection for each trust. Associations between procurement and infection rates assessed by mixed effect Poisson regression model (which also accounted for effect of bed occupancy, hospital type, and timing of other national interventions targeting these infections). RESULTS: Combined procurement of soap and alcohol hand rub tripled from 21.8 to 59.8 mL per patient bed day; procurement rose in association with each phase of the campaign. Rates fell for MRSA bacteraemia (1.88 to 0.91 cases per 10,000 bed days) and C difficile infection (16.75 to 9.49 cases). MSSA bacteraemia rates did not fall. Increased procurement of soap was independently associated with reduced C difficile infection throughout the study (adjusted incidence rate ratio for 1 mL increase per patient bed day 0.993, 95% confidence interval 0.990 to 0.996; P < 0.0001). Increased procurement of alcohol hand rub was independently associated with reduced MRSA bacteraemia, but only in the last four quarters of the study (0.990, 0.985 to 0.995; P < 0.0001). Publication of the Health Act 2006 was strongly associated with reduced MRSA bacteraemia (0.86, 0.75 to 0.98; P = 0.02) and C difficile infection (0.75, 0.67 to 0.84; P < 0.0001). Trust visits by Department of Health improvement teams were also associated with reduced MRSA bacteraemia (0.91, 0.83 to 0.99; P=0.03) and C difficile infection (0.80, 0.71 to 0.90; P=0.01), for at least two quarters after each visit. CONCLUSIONS: The Cleanyourhands campaign was associated with sustained increases in hospital procurement of alcohol rub and soap, which the results suggest has an important role in reducing rates of some healthcare associated infections. National interventions for infection control undertaken in the context of a high profile political drive can reduce selected healthcare associated infections.

Opiyo N, Shepperd S, Musila N, English M, Fretheim A. 2012. The "Child Health Evidence Week" and GRADE grid may aid transparency in the deliberative process of guideline development. J Clin Epidemiol, 65 (9), pp. 962-969. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To explore the evidence translation process during a 1-week national guideline development workshop ("Child Health Evidence Week") in Kenya. STUDY DESIGN AND SETTING: Nonparticipant observational study of the discussions of a multidisciplinary guideline development panel in Kenya. Discussions were aided by GRADE (Grading of Recommendations Assessment, Development, and Evaluation) grid. RESULTS: Three key thematic categories emerged: 1) "referral to other evidence to support or refute the proposed recommendations;" 2) "assessment of the presented research evidence;" and 3) "assessment of the local applicability of evidence." The types of evidence cited included research evidence and anecdotal evidence based on clinician experiences. Assessment of the research evidence revealed important challenges in the translation of evidence into recommendations, including absence of evidence, low quality or inconclusive evidence, inadequate reporting of key features of the management under consideration, and differences in panelists' interpretation of the research literature. A broad range of factors with potential to affect local applicability of evidence were discussed. CONCLUSION: The process of the "Child Health Evidence Week" combined with the GRADE grid may aid transparency in the deliberative process of guideline development, and provide a mechanism for comprehensive assessment, documentation, and reporting of multiple factors that influence the quality and applicability of guideline recommendations.

Kim J-R, Nandy A, Maji AK, Addy M, Dondorp AM, Day NPJ, Pukrittayakamee S, White NJ, Imwong M. 2012. Genotyping of Plasmodium vivax reveals both short and long latency relapse patterns in Kolkata. PLoS One, 7 (7), pp. e39645. | Citations: 25 (Scopus) | Show Abstract | Read more

BACKGROUND: The Plasmodium vivax that was once prevalent in temperate climatic zones typically had an interval between primary infection and first relapse of 7-10 months, whereas in tropical areas P.vivax infections relapse frequently at intervals of 3-6 weeks. Defining the epidemiology of these two phenotypes from temporal patterns of illness in endemic areas is difficult or impossible, particularly if they overlap. METHODS: A prospective open label comparison of chloroquine (CQ) alone versus CQ plus unobserved primaquine for either 5 days or 14 days was conducted in patients presenting with acute vivax malaria in Kolkata. Patients were followed for 15 months and primary and recurrent infections were genotyped using three polymorphic antigen and up to 8 microsatellite markers. RESULTS: 151 patients were enrolled of whom 47 (31%) had subsequent recurrent infections. Recurrence proportions were similar in the three treatment groups. Parasite genotyping revealed discrete temporal patterns of recurrence allowing differentiation of probable relapse from newly acquired infections. This suggested that 32 of the 47 recurrences were probable relapses of which 22 (69%) were genetically homologous. The majority (81%) of probable relapses occurred within three months (16 homologous, 10 heterologous) and six genetically homologous relapses (19%) were of the long latency (8-10 month interval) phenotype. CONCLUSIONS: With long follow-up to assess temporal patterns of vivax malaria recurrence, genotyping of P.vivax can be used to assess relapse rates. A 14 day unobserved course of primaquine did not prevent relapse. Genotyping indicates that long latency P.vivax is prevalent in West Bengal, and that the first relapses after long latent periods are genetically homologous. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN14027467.

Stuetz W, Carrara VI, McGready R, Lee SJ, Biesalski HK, Nosten FH. 2012. Thiamine diphosphate in whole blood, thiamine and thiamine monophosphate in breast-milk in a refugee population. PLoS One, 7 (6), pp. e36280. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The provision of high doses of thiamine may prevent thiamine deficiency in the post-partum period of displaced persons. METHODOLOGY/PRINCIPAL FINDINGS: The study aimed to evaluate a supplementation regimen of thiamine mononitrate (100 mg daily) at the antenatal clinics in Maela refugee camp. Women were enrolled during antenatal care and followed after delivery. Samples were collected at 12 weeks post partum. Thiamine diphosphate (TDP) in whole blood and thiamine in breast-milk of 636 lactating women were measured. Thiamine in breast-milk consisted of thiamine monophosphate (TMP) in addition to thiamine, with a mean TMP to total thiamine ratio of 63%. Mean whole blood TDP (130 nmol/L) and total thiamine in breast-milk (755 nmol/L) were within the upper range reported for well-nourished women. The prevalence of women with low whole blood TDP (<65 nmol/L) was 5% and with deficient breast-milk total thiamine (<300 nmol/L) was 4%. Whole blood TDP predicted both breast-milk thiamine and TMP (R(2) = 0.36 and 0.10, p<0.001). A ratio of TMP to total thiamine ≥63% was associated with a 7.5 and 4-fold higher risk of low whole blood TDP and deficient total breast-milk thiamine, respectively. Routine provision of daily 100 mg of thiamine mononitrate post-partum compared to the previous weekly 10 mg of thiamine hydrochloride resulted in significantly higher total thiamine in breast-milk. CONCLUSIONS/SIGNIFICANCE: Thiamine supplementation for lactating women in Maela refugee camp is effective and should be continued. TMP and its ratio to total thiamine in breast-milk, reported for the first time in this study, provided useful information on thiamine status and should be included in future studies of breast-milk thiamine.

Klein K, Aarons L, Ter Kuile FO, Nosten F, White NJ, Edstein MD, Teja-Isavadharm P. 2012. Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria. J Pharm Pharmacol, 64 (11), pp. 1603-1613. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

AIMS: To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria. METHODS: Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai-Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption. KEY FINDINGS: The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively. CONCLUSIONS: The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.

Gillrie MR, Lee K, Gowda DC, Davis SP, Monestier M, Cui L, Hien TT, Day NPJ, Ho M. 2012. Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction American Journal of Pathology, 180 (3), pp. 1028-1039. | Citations: 41 (Scopus) | Show Abstract | Read more

Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria. © 2012 American Society for Investigative Pathology.

Ponsford MJ, Medana IM, Prapansilp P, Hien TT, Lee SJ, Dondorp AM, Esiri MM, Day NPJ, White NJ, Turner GDH. 2012. Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis, 205 (4), pp. 663-671. | Citations: 68 (Scopus) | Show Abstract | Read more

The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature.

Lwin KM, Phyo AP, Tarning J, Hanpithakpong W, Ashley EA, Lee SJ, Cheah P, Singhasivanon P, White NJ, Lindegårdh N, Nosten F. 2012. Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother, 56 (3), pp. 1571-1577. | Citations: 37 (Scopus) | Show Abstract | Read more

Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4 g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P < 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P < 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivax and multidrug-resistant P. falciparum malaria are endemic.

Midega JT, Smith DL, Olotu A, Mwangangi JM, Nzovu JG, Wambua J, Nyangweso G, Mbogo CM, Christophides GK, Marsh K, Bejon P. 2012. Wind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya Nature Communications, 3 | Citations: 35 (Scopus) | Show Abstract | Read more

Studies of the fine-scale spatial epidemiology of malaria consistently identify malaria hotspots, comprising clusters of homesteads at high transmission intensity. These hotspots sustain transmission, and may be targeted by malaria-control programmes. Here we describe the spatial relationship between the location of Anopheles larval sites and human malaria infection in a cohort study of 642 children, aged 1-10-years-old. Our data suggest that proximity to larval sites predict human malaria infection, when homesteads are upwind of larval sites, but not when homesteads are downwind of larval sites. We conclude that following oviposition, female Anophelines fly upwind in search for human hosts and, thus, malaria transmission may be disrupted by targeting vector larval sites in close proximity, and downwind to malaria hotspots. © 2012 Macmillan Publishers Limited. All rights reserved.

Moore CE, Hennig BJ, Perrett KP, Hoe JC, Lee SJ, Fletcher H, Brocklebank D, O'Connor D, Snape MD, Hall AJ et al. 2012. Single nucleotide polymorphisms in the toll-like receptor 3 and CD44 genes are associated with persistence of vaccine-induced immunity to the serogroup C meningococcal conjugate vaccine Clinical and Vaccine Immunology, 19 (3), pp. 295-303. | Citations: 11 (Scopus) | Show Abstract | Read more

The rate of decay of antibody concentration following serogroup C meningococcal (MenC) polysaccharide-protein conjugate vaccination varies between individuals. This depends partly on vaccination age but may be influenced by human genetics. We studied 721 single nucleotide polymorphisms (SNPs) across 131 candidate genes in a first cohort of 905 Caucasians (11 to 21 years old; mean time after vaccination, 4.9 years) and 30 SNPs across 17 genes in a replication study using 155 children, aged 6 to 12 years (mean time after vaccination, 6.7 years), and 196 infants (1 year old; mean time after vaccination, 8 months). Individuals were classified as responders or nonresponders for total MenC IgG concentration and MenC serum bactericidal antibody (SBA) measurements. Associated genes were examined further for quantitative outcome measures. Fifty-nine SNPs in 37 genes were associated with IgG persistence (adjusted for age at measurement), and 56 SNPs in 36 genes were associated with SBA persistence (adjusted for age at measurement and vaccine used). Three SNPs each within the Toll-like receptor 3 (TLR3) (rs3775291, rs3775292, and rs5743312) and CD44 (rs11033013, rs353644, and rs996076) genes were associated with IgG (adjusted for age at measurement) or SBA (adjusted for age at measurement and vaccine used) persistence in the initial genetic study (P, 0.02 to 0.04). Single SNPs within the TLR3 (rs7657186) (P = 0.004 [unadjusted]) and CD44 (rs12419062) (P = 0.01 [unadjusted] ) genes were associated with IgG persistence in the replication study. These results suggest that genetic polymorphisms in the TLR3 and CD44 genes are associated with the persistence of the immune response to MenC vaccines 1 to 6 years after vaccination. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Miller CE, Batra R, Cooper BS, Patel AK, Klein J, Otter JA, Kypraios T, French GL, Tosas O, Edgeworth JD. 2012. An association between bacterial genotype combined with a high-vancomycin minimum inhibitory concentration and risk of endocarditis in methicillin-resistant staphylococcus aureus bloodstream infection Clinical Infectious Diseases, 54 (5), pp. 591-600. | Citations: 28 (Scopus) | Show Abstract | Read more

Introduction. Antimicrobial resistance and bacterial virulence factors may increase the risk of hematogenous complications during methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI). This study reports on the impact of increasing vancomycin minimum inhibitory concentrations (V-MICs) and MRSA clone type on risk of hematogenous complications from MRSA BSI during implementation of an effective MRSA control program. Methods. In sum, spa typing, staphylococcal cassette chromosome mec allotyping, and vancomycin and teicoplanin MICs were performed on 821 consecutive MRSA bloodstream isolates from 1999 to 2009. Prospectively collected data, including focus of infection, were available for 695 clinically significant cases. Logistic and multinomial logistic regression was used to determine the association between clone type, vancomycin MIC (V-MIC), and focus of infection. Results. MRSA BSIs decreased by ∼90% during the 11 years. Typing placed isolates into 3 clonal complex (CC) groups that had different population median V-MICs (CC30, 0.5 μg/mL [n = 349]; CC22, 0.75 μg/mL [n = 272] ; non-CC22/30, 1.5 μg/mL [n = 199]). There was a progressive increase in the proportion of isolates with a V-MIC above baseline median in each clonal group and a disproportionate fall in the clone group with lowest median V-MIC (CC30). In contrast, there were no increases in teicoplanin MICs. High V-MIC CC22 isolates (1.5-2 μg/mL) were strongly associated with endocarditis (odds ratio, 12; 95% confidence interval, 3.72-38.9) and with a septic metastasis after catheter-related BSI (odds ratio, 106; 95% confidence interval, 12.6-883) compared with other clone type/V-MIC combinations.Conclusions.An interaction between clone type and V-MIC can influence the risk of endocarditis associated with MRSA BSI, implying involvement of both therapeutic and host-pathogen factors. © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

McGready R, Boel M, Rijken MJ, Ashley EA, Cho T, Moo O, Paw MK, Pimanpanarak M, Hkirijareon L, Carrara VI et al. 2012. Effect of early detection and treatment on malaria related maternal mortality on the north-western border of Thailand 1986-2010. PLoS One, 7 (7), pp. e40244. | Citations: 39 (Scopus) | Show Abstract | Read more

INTRODUCTION: Maternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand. METHODS AND FINDINGS: All medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12(th) May 1986 to 31(st) December 2010 were reviewed, and maternal death records were analyzed for causality. There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once. Three were suicide and excluded from the analysis as incidental deaths. The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150-230) per 100,000 live births. In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200-780) in 1986-90 to 79 (40-170) in 2006-10, p<0.05. In migrants from adjacent Myanmar the decline in MMR was less significant: 588 (100-3260) to 252 (150-430) from 1996-2000 to 2006-2010. Mortality from P. falciparum malaria in pregnancy dropped sharply with the introduction of systematic screening and treatment and continued to decline with the reduction in the incidence of malaria in the communities. P. vivax was not a cause of maternal death in this population. Infection (non-puerperal sepsis and P. falciparum malaria) accounted for 39.7 (27/68) % of all deaths. CONCLUSIONS: Frequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from P. falciparum malaria. No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai-Myanmar border.

Noor AM, Alegana VA, Patil AP, Moloney G, Borle M, Yusuf F, Amran J, Snow RW. 2012. Mapping the receptivity of malaria risk to plan the future of control in Somalia. BMJ Open, 2 (4), pp. e001160-e001160. | Citations: 10 (Scopus) | Show Abstract | Read more

OBJECTIVES: To measure the receptive risks of malaria in Somalia and compare decisions on intervention scale-up based on this map and the more widely used contemporary risk maps. DESIGN: Cross-sectional community Plasmodium falciparum parasite rate (PfPR) data for the period 2007-2010 corrected to a standard age range of 2 to <10 years (PfPR(2-10)) and used within a Bayesian space-time geostatistical framework to predict the contemporary (2010) mean PfPR(2-10) and the maximum annual mean PfPR(2-10) (receptive) from the highest predicted PfPR(2-10) value over the study period as an estimate of receptivity. SETTING: Randomly sampled communities in Somalia. PARTICIPANTS: Randomly sampled individuals of all ages. MAIN OUTCOME MEASURE: Cartographic descriptions of malaria receptivity and contemporary risks in Somalia at the district level. RESULTS: The contemporary annual PfPR(2-10) map estimated that all districts (n=74) and population (n=8.4 million) in Somalia were under hypoendemic transmission (≤10% PfPR(2-10)). Of these, 23% of the districts, home to 13% of the population, were under transmission of <1% PfPR(2-10). About 58% of the districts and 55% of the population were in the risk class of 1% to <5% PfPR(2-10). In contrast, the receptivity map estimated 65% of the districts and 69% of the population were under mesoendemic transmission (>10%-50% PfPR(2-10)) and the rest as hypoendemic. CONCLUSION: Compared with maps of receptive risks, contemporary maps of transmission mask disparities of malaria risk necessary to prioritise and sustain future control. As malaria risk declines across Africa, efforts must be invested in measuring receptivity for efficient control planning.

Stoesser N, Pocock J, Moore CE, Soeng S, Chhat HP, Sar P, Limmathurotsakul D, Day N, Thy V, Sar V, Parry CM. 2012. Pediatric suppurative parotitis in cambodia between 2007 and 2011 Pediatric Infectious Disease Journal, 31 (8), pp. 865-868. | Citations: 16 (Scopus) | Show Abstract | Read more

The causes of suppurative parotitis in Cambodian children are not known. We describe 39 cases at the Angkor Hospital for Children, Siem Reap, between January 2007 and July 2011 (0.07/1000 hospital attendances). The median age was 5.7 years with no neonates affected. Burkholderia pseudomallei was cultured in 29 (74%) cases. No deaths occurred; 1 child developed facial nerve palsy. © 2012 by Lippincott Williams & Wilkins.

Crook DW, Walker AS, Kean Y, Weiss K, Cornely OA, Miller MA, Esposito R, Louie TJ, Stoesser NE, Young BC et al. 2012. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis, 55 Suppl 2 (suppl_2), pp. S93-103. | Citations: 116 (Scopus) | Show Abstract | Read more

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

Van Vinh Chau N, Simmons CP, Wills B. 2012. Dengue New England Journal of Medicine, 367 (2), pp. 180-181. | Read more

Irimu GW, Gathara D, Zurovac D, Kihara H, Maina C, Mwangi J, Mbori-Ngacha D, Todd J, Greene A, English M. 2012. Performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital: before and after a training intervention. PLoS One, 7 (7), pp. e39964. | Citations: 24 (Scopus) | Show Abstract | Read more

BACKGROUND: Implementation of WHO case management guidelines for serious common childhood illnesses remains a challenge in hospitals in low-income countries. The impact of locally adapted clinical practice guidelines (CPGs) on the quality-of-care of patients in tertiary hospitals has rarely been evaluated. METHODS AND FINDINGS: We conducted, in Kenyatta National Hospital, an uncontrolled before and after study with an attempt to explore intervention dose-effect relationships, as CPGs were disseminated and training was progressively implemented. The emergency triage, assessment and treatment plus admission care (ETAT+) training and locally adapted CPGs targeted common, serious childhood illnesses. We compared performance in the pre-intervention (2005) and post-intervention periods (2009) using quality indicators for three diseases: pneumonia, dehydration and severe malnutrition. The indicators spanned four domains in the continuum of care namely assessment, classification, treatment, and follow-up care in the initial 48 hours of admission. In the pre-intervention period patients' care was largely inconsistent with the guidelines, with nine of the 15 key indicators having performance of below 10%. The intervention produced a marked improvement in guideline adherence with an absolute effect size of over 20% observed in seven of the 15 key indicators; three of which had an effect size of over 50%. However, for all the five indicators that required sustained team effort performance continued to be poor, at less than 10%, in the post-intervention period. Data from the five-year period (2005-09) suggest some dose dependency though the adoption rate of the best-practices varied across diseases and over time. CONCLUSION: Active dissemination of locally adapted clinical guidelines for common serious childhood illnesses can achieve a significant impact on documented clinical practices, particularly for tasks that rely on competence of individual clinicians. However, more attention must be given to broader implementation strategies that also target institutional and organisational aspects of service delivery to further enhance quality-of-care.

Mahavanakul W, Nickerson EK, Srisomang P, Teparrukkul P, Lorvinitnun P, Wongyingsinn M, Chierakul W, Hongsuwan M, West TE, Day NP et al. 2012. Correction: Feasibility of Modified Surviving Sepsis Campaign Guidelines in a Resource-Restricted Setting Based on a Cohort Study of Severe S. Aureus Sepsis. PLoS One, 7 (5), | Show Abstract | Read more

[This corrects the article on p. e29858 in vol. 7.].

Maude RR, Maude RJ, Ghose A, Amin MR, Islam MB, Ali M, Bari MS, Majumder MI, Wuthiekanan V, Dondorp AM et al. 2012. Seroepidemiological surveillance of Burkholderia pseudomallei in Bangladesh Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (9), pp. 576-578. | Citations: 7 (Scopus) | Show Abstract | Read more

Melioidosis (. Burkholderia pseudomallei infection) has yet to be demonstrated systematically in Bangladesh. A prospective, cross-sectional serological survey was conducted in 2010 at six Bangladeshi hospitals. Age, gender, occupation and residential address were recorded. Of 1244 patients, 359 (28.9%) were positive for . B. pseudomallei by indirect haemagglutination assay. Farmers had an increased risk of seropositivity (risk ratio. =. 1.4, 95% CI 1.0-1.8; p. =. 0.03). There was no clear geographic clustering of seropositives. Melioidosis should be considered as a possible cause of febrile illness in Bangladesh. Further studies are needed to establish the incidence of clinical disease and distribution of environmental risk. © 2012 Royal Society of Tropical Medicine and Hygiene.

Chue AL, Carrara VI, Paw MK, Pimanpanarak M, Wiladphaingern J, van Vugt M, Lee SJ, Nosten F, McGready R. 2012. Is areca innocent? The effect of areca (betel) nut chewing in a population of pregnant women on the Thai-Myanmar border. Int Health, 4-172 (3), pp. 204-209. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

Eight manuscripts have specifically examined the effects of areca (betel) nut use in pregnant women, seven of which have documented adverse effects on birth weight, newborn neurological status, gender ratio and pregnancy outcomes such as anaemia and miscarriage following areca nut use during pregnancy. A retrospective cohort analysis of migrant and refugee pregnant women attending antenatal clinics along the Thai-Myanmar border (July 1997 to November 2006) was conducted to examine the adverse effects of areca nut use routinely recorded on enrolment. Of 7685 women, 2284 (29.7%) never used areca or smoked (cheroots), 2484 (32.3%) only used areca, 438 (5.7%) only smoked cheroots and 2479 (32.3%) used both areca and cheroots. Pieces of ripe areca nut in a leaf with lime, without tobacco, were used particularly among older multigravid women. Adverse pregnancy effects were not observed in areca nut users compared with non-users. Smoking, but not areca nut use, had a dose-related effect on miscarriage. Areca nut use in conjunction with smoking reduced the adverse effects of smoking on birth weight, further supporting a lack of effect of areca nut. Areca (betel) nut-related adverse pregnancy outcomes were not observed in this population, whereas smoking was clearly harmful. Differences from previous reports may result from the amount or types of areca nut, or quid content, consumed between countries. Smoking, but not areca nut, reduction is likely to improve pregnancy outcomes on the Thai-Myanmar border.

Tanganuchitcharnchai A, Smythe L, Dohnt M, Hartskeerl R, Vongsouvath M, Davong V, Lattana O, Newton PN, Blacksell SD. 2012. Evaluation of the Standard Diagnostics Leptospira IgM ELISA for diagnosis of acute leptospirosis in Lao PDR Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (9), pp. 563-566. | Citations: 6 (Scopus) | Show Abstract | Read more

The diagnostic utility of the Standard Diagnostics . Leptospira IgM ELISA for detection of acute leptospirosis was assessed in febrile adults admitted in Vientiane, Laos. Using the cut-off suggested by the manufacturer [optical density (OD) ≥0.75], the assay demonstrated limited diagnostic capacity with a sensitivity of 95% and a specificity of 41% compared with the . Leptospira microscopic agglutination test, which is the serological gold standard. However, re-evaluation of the diagnostic cut-off to an OD of 1.7 demonstrated improved diagnostic accuracy overall (sensitivity 70%; specificity 78%). © 2012 Royal Society of Tropical Medicine and Hygiene.

Stuetz W, Carrara VI, McGready R, Lee SJ, Erhardt JG, Breuer J, Biesalski HK, Nosten FH. 2012. Micronutrient status in lactating mothers before and after introduction of fortified flour: Cross-sectional surveys in Maela refugee camp European Journal of Nutrition, 51 (4), pp. 425-434. | Citations: 22 (Scopus) | Show Abstract | Read more

Background Deficiency of micronutrients is common in refugee populations. Objectives Identify deficiencies and whether provided supplements and wheat flour fortified with 10 micronutrients impacts upon status among breast-feeding women from Maela refugee camp. Methods Two sequential cross-sectional studies were conducted in different groups of lactating mothers at 12 weeks postpartum. The first survey was before and the second 4-5 months after micronutrient fortified flour (MFF) had been provided to the camp (in addition to the regular food basket). Iron status and micronutrients were measured in serum, whole blood, and in breast milk samples. Results Iron and zinc deficiency and anemia were highly prevalent while low serum retinol and thiamine deficiency were rarely detected. Iron and zinc deficiency were associated with anemia, and their proportions were significantly lower after the introduction of MFF (21 vs. 35% with soluble transferrin receptor (sTfR) > 8.5 mg/L, P = 0.042, and 50 vs. 73% with serum zinc < 0.66 mg/L, P = 0.001). Serum sTfR, whole-blood thiamine diphosphate (TDP) and serum β-carotene were significant predictors (P < 0.001) of milk iron, thiamine and β-carotene, respectively. Lower prevalence of iron deficiency in the MFF group was associated with significantly higher iron and thiamine in breast milk. Conclusions High whole-blood TDP and breast milk thiamine reflected good compliance to provided thiamine; high prevalence of iron deficiency suggested insufficient dietary iron and low acceptance to ferrous sulfate supplements. MFF as an additional food ration in Maela refugee camp seemed to have an effect in reducing both iron and zinc deficiency postpartum. © Springer-Verlag 2012.

Holt KE, Baker S, Weill F-X, Holmes EC, Kitchen A, Yu J, Sangal V, Brown DJ, Coia JE, Kim DW et al. 2012. Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe. Nat Genet, 44 (9), pp. 1056-1059. | Citations: 97 (Web of Science Lite) | Show Abstract | Read more

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery(1,2), spreading efficiently via low-dose fecal-oral transmission(3,4). Historically, S. sonnei has been predominantly responsible for dysentery in developed countries but is now emerging as a problem in the developing world, seeming to replace the more diverse Shigella flexneri in areas undergoing economic development and improvements in water quality(4-6). Classical approaches have shown that S. sonnei is genetically conserved and clonal(7). We report here whole-genome sequencing of 132 globally distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and that diversified into several distinct lineages with unique characteristics. Our analysis suggests that the majority of this diversification occurred in Europe and was followed by more recent establishment of local pathogen populations on other continents, predominantly due to the pandemic spread of a single, rapidly evolving, multidrug-resistant lineage.

Taylor WRJ, Hanson J, Turner GDH, White NJ, Dondorp AM. 2012. Respiratory manifestations of malaria. Chest, 142 (2), pp. 492-505. | Citations: 78 (Scopus) | Show Abstract | Read more

Respiratory distress develops in up to 25% of adults and 40% of children with severe falciparum malaria. Its diverse causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary edema, concomitant pneumonia, and severe anemia. Patients with severe falciparum, vivax, and knowlesi malaria may develop acute lung injury (ALI) and ARDS, often several days after antimalarial drug treatment. ARDS rates, best characterized for severe Plasmodium falciparum, are 5% to 25% in adults and up to 29% in pregnant women; ARDS is rare in young children. ARDS pathophysiology centers on inflammatory-mediated increased capillary permeability or endothelial damage leading to diffuse alveolar damage that can continue after parasite clearance. The role of parasite sequestration in the pulmonary microvasculature is unclear, because sequestration occurs intensely in P falciparum, less so in P knowlesi, and has not been shown convincingly in P vivax. Because early markers of ALI/ARDS are lacking, fluid resuscitation in severe malaria should follow the old adage to "keep them dry." Bacteremia and hospital-acquired pneumonia can complicate severe malaria and may contribute to ALI/ARDS. Mechanical ventilation can save life in ALI/ARDS. Basic critical care facilities are increasingly available in tropical countries. The use of lung-protective ventilation has helped to reduce mortality from malaria-induced ALI/ARDS, but permissive hypercapnia in unconscious patients is not recommended because increased intracranial pressure and cerebral swelling may occur in cerebral malaria. The best antimalarial treatment of severe malaria is IV artesunate.

Sullivan PS, Carballo-Diéguez A, Coates T, Goodreau SM, McGowan I, Sanders EJ, Smith A, Goswami P, Sanchez J. 2012. Successes and challenges of HIV prevention in men who have sex with men The Lancet, 380 (9839), pp. 388-399. | Citations: 190 (Scopus) | Show Abstract | Read more

Men who have sex with men (MSM) have been substantially affected by HIV epidemics worldwide. Epidemics in MSM are re-emerging in many high-income countries and gaining greater recognition in many low-income and middle-income countries. Better HIV prevention strategies are urgently needed. Our review of HIV prevention strategies for MSM identified several important themes. At the beginning of the epidemic, stand-alone behavioural interventions mostly aimed to reduce unprotected anal intercourse, which, although somewhat efficacious, did not reduce HIV transmission. Biomedical prevention strategies reduce the incidence of HIV infection. Delivery of barrier and biomedical interventions with coordinated behavioural and structural strategies could optimise the effectiveness of prevention. Modelling suggests that, with sufficient coverage, available interventions are sufficient to avert at least a quarter of new HIV infections in MSM in diverse countries. Scale-up of HIV prevention programmes for MSM is difficult because of homophobia and bias, suboptimum access to HIV testing and care, and financial constraints.

Barasa EW, Ayieko P, Cleary S, English M. 2012. Out-of-pocket costs for paediatric admissions in district hospitals in Kenya Tropical Medicine and International Health, 17 (8), pp. 958-961. | Citations: 4 (Scopus) | Show Abstract | Read more

Objective To describe out-of-pocket costs of inpatient care for children under 5years of age in district hospitals in Kenya. Methods A total of 256 caretakers of admitted children were interviewed in 2-week surveys conducted in eight hospitals in four provinces in Kenya. Caretakers were asked to report care seeking behaviour and expenditure related to accessing inpatient care. Family socio-economic status was assessed through reported expenditure in the previous month. Results Seventy eight percent of caretakers were required to pay user charges to access inpatient care for children. User charges (mean, US$ 8.1; 95% CI, 6.4-9.7) were 59% of total out-of-pocket costs, while transport costs (mean, US$ 4.9; 95% CI, 3.9-6.0) and medicine costs (mean, US$ 0.7; 95% CI, 0.5-1.0) were 36% and 5%, respectively. The mean total out-of-pocket cost per paediatric admission was US$ 14.1 (95% CI, 11.9-16.2). Out-of-pocket expenditures on health were catastrophic for 25.4% (95% CI, 18.4-33.3) of caretakers interviewed. Out-of-pocket expenditures were regressive, with a greater burden being experienced by households with lower socio-economic status. Conclusion Despite a policy of user fee exemption for children under 5years of age in Kenya, our findings show that high unofficial user fees are still charged in district hospitals. Financing mechanisms that will offer financial risk protection to children seeking care need to be developed to remove barriers to child survival. © 2012 Blackwell Publishing Ltd.

Baird JK. 2012. Chemotherapeutics challenges in developing effective treatments for the endemic malarias INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, 2 pp. 256-261. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

The endemic malarias threaten the several billion people residing where transmission occurs. Chemotherapeutic strategy pitted against these threats hinges upon species- and stage-specific treatments guided by diagnosis and screening against sometime dangerous contraindications. This approach suits malaria as it occurs among travelers in the developed, non-endemic world. However, limiting treatment to that which diagnosis affirms may not be rational in endemic zones. Most of the endemic malarias remain out of diagnostic reach, either by inaccessibility of the parasite stage, insensitivity of the technology, or unavailability of diagnostic services. The partial and fragmented chemotherapeutic attack of malaria guided by confirmed diagnostics leaves most of the endemic malarias unchallenged. Development of elimination therapy, a single course of treatment aimed at all species and stages, would significantly advance progress against the major killers known collectively as malaria. © 2012.

Vien LTM, Minh NNQ, Thuong TC, Khuong HD, Nga TVT, Thompson C, Campbell JI, de Jong M, Farrar JJ, Schultsz C et al. 2012. The co-selection of fluoroquinolone resistance genes in the gut flora of Vietnamese children. PLoS One, 7 (8), pp. e42919. | Citations: 23 (Scopus) | Show Abstract | Read more

Antimicrobial consumption is one of the major contributing factors facilitating the development and maintenance of bacteria exhibiting antimicrobial resistance. Plasmid-mediated quinolone resistance (PMQR) genes, such as the qnr family, can be horizontally transferred and contribute to reduced susceptibility to fluoroquinolones. We performed an observational study, investigating the copy number of PMQR after antimicrobial therapy. We enrolled 300 children resident in Ho Chi Minh City receiving antimicrobial therapy for acute respiratory tract infections (ARIs). Rectal swabs were taken on enrollment and seven days subsequently, counts for Enterobacteriaceae were performed and qnrA, qnrB and qnrS were quantified by using real-time PCR on metagenomic stool DNA. On enrollment, we found no association between age, gender or location of the participants and the prevalence of qnrA, qnrB or qnrS. Yet, all three loci demonstrated a proportional increase in the number of samples testing positive between day 0 and day 7. Furthermore, qnrB demonstrated a significant increase in copy number between paired samples (p<0.001; Wilcoxon rank-sum), associated with non-fluoroquinolone combination antimicrobial therapy. To our knowledge, this is the first study describing an association between the use of non-fluoroquinolone antimicrobials and the increasing relative prevalence and quantity of qnr genes. Our work outlines a potential mechanism for the selection and maintenance of PMQR genes and predicts a strong effect of co-selection of these resistance determinants through the use of unrelated and potentially unnecessary antimicrobial regimes.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Erratum to ''Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection" [Int. J. Parasitol. 42 (2012) 535-548] (DOI:10.1016/j.ijpara.2012.03.011) International Journal for Parasitology,

Graham SM, Holte SE, Dragavon JA, Ramko KM, Mandaliya KN, McClelland RS, Peshu NM, Sanders EJ, Krieger JN, Coombs RW. 2012. HIV-1 RNA may decline more slowly in semen than in blood following initiation of efavirenz-based antiretroviral therapy. PLoS One, 7 (8), pp. e43086. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: Antiretroviral therapy (ART) decreases HIV-1 RNA levels in semen and reduces sexual transmission from HIV-1-infected men. Our objective was to study the time course and magnitude of seminal HIV-1 RNA decay after initiation of efavirenz-based ART among 13 antiretroviral-naïve Kenyan men. METHODS: HIV-1 RNA was quantified (lower limit of detection, 120 copies/mL) in blood and semen at baseline and over the first month of ART. Median log(10) HIV-1 RNA was compared at each time-point using Wilcoxon Signed Rank tests. Perelson's two-phase viral decay model and nonlinear random effects were used to compare decay rates in blood and semen. RESULTS: Median baseline HIV-1 RNA was 4.40 log(10) copies/mL in blood (range, 3.20-5.08 log(10) copies/mL) and 3.69 log(10) copies/mL in semen (range, <2.08-4.90 log(10) copies/mL). The median reduction in HIV-1 RNA by day 28 was 1.90 log(10) copies/mL in blood (range, 0.56-2.68 log(10) copies/mL) and 1.36 log(10) copies/mL in semen (range, 0-2.66 log(10) copies/mL). ART led to a decrease from baseline by day 7 in blood and day 14 in semen (p = 0.005 and p = 0.006, respectively). The initial modeled decay rate was slower in semen than in blood (p = 0.06). There was no difference in second-phase decay rates between blood and semen. CONCLUSIONS: Efavirenz-based ART reduced HIV-1 RNA levels more slowly in semen than in blood. Although this difference was of borderline significance in this small study, our observations suggest that there is suboptimal suppression of seminal HIV-1 RNA for some men in the early weeks of treatment.

Taylor WR, Nguyen K, Nguyen D, Nguyen H, Horby P, Nguyen HL, Lien T, Tran G, Tran N, Nguyen HM et al. 2012. The spectrum of central nervous system infections in an adult referral hospital in Hanoi, Vietnam. PLoS One, 7 (8), pp. e42099. | Citations: 18 (Scopus) | Show Abstract | Read more

OBJECTIVES: To determine prospectively the causative pathogens of central nervous system (CNS) infections in patients admitted to a tertiary referral hospital in Hanoi, Vietnam. METHODS: From May 2007 to December 2008, cerebrospinal fluid (CSF) samples from 352 adults with suspected meningitis or encephalitis underwent routine testing, staining (Gram, Ziehl-Nielsen, India ink), bacterial culture and polymerase chain reaction targeting Neisseria meningitidis, Streptococcus pneumoniae, S. suis, Haemophilus influenzae type b, Herpes simplex virus (HSV), Varicella Zoster virus (VZV), enterovirus, and 16S ribosomal RNA. Blood cultures and clinically indicated radiology were also performed. Patients were classified as having confirmed or suspected bacterial (BM), tuberculous (TBM), cryptococcal (CRM), eosinophilic (EOM) meningitis, aseptic encephalitis/meningitis (AEM), neurocysticercosis and others. RESULTS: 352 (male: 66%) patients were recruited: median age 34 years (range 13-85). 95/352 (27.3%) diagnoses were laboratory confirmed and one by cranial radiology: BM (n = 62), TBM (n = 9), AEM (n = 19), CRM (n = 5), and neurocysticercosis (n = 1, cranial radiology). S. suis predominated as the cause of BM [48/62 (77.4%)]; Listeria monocytogenese (n = 1), S. pasteurianus (n = 1) and N. meningitidis (n = 2) were infrequent. AEM viruses were: HSV (n = 12), VZV (n = 5) and enterovirus (n = 2). 5 patients had EOM. Of 262/352 (74.4%) patients with full clinical data, 209 (79.8%) were hospital referrals and 186 (71%) had been on antimicrobials. 21 (8%) patients died: TBM (15.2%), AEM (10%), and BM (2.8%). CONCLUSIONS: Most infections lacked microbiological confirmation. S. suis was the most common cause of BM in this setting. Improved diagnostics are needed for meningoencephalitic syndromes to inform treatment and prevention strategies.

Acestor N, Cooksey R, Newton PN, Ménard D, Guerin PJ, Nakagawa J, Christophel E, González IJ, Bell D. 2012. Mapping the aetiology of non-malarial febrile illness in Southeast Asia through a systematic review--terra incognita impairing treatment policies. PLoS One, 7 (9), pp. e44269. | Citations: 52 (Scopus) | Show Abstract | Read more

BACKGROUND: An increasing use of point of care diagnostic tests that exclude malaria, coupled with a declining malaria burden in many endemic countries, is highlighting the lack of ability of many health systems to manage other causes of febrile disease. A lack of knowledge of distribution of these pathogens, and a lack of screening and point-of-care diagnostics to identify them, prevents effective management of these generally treatable contributors to disease burden. While prospective data collection is vital, an untapped body of knowledge already exists in the published health literature. METHODS: Focusing on the Mekong region of Southeast Asia, published data from 1986 to 2011 was screened to for frequency of isolation of pathogens implicated in aetiology of non-malarial febrile illness. Eligibility criteria included English-language peer-reviewed studies recording major pathogens for which specific management is likely to be warranted. Of 1,252 identified papers, 146 met inclusion criteria and were analyzed and data mapped. RESULTS: Data tended to be clustered around specific areas where research institutions operate, and where resources to conduct studies are greater. The most frequently reported pathogen was dengue virus (n = 70), followed by Orientia tsutsugamushi and Rickettsia species (scrub typhus/murine typhus/spotted fever group n = 58), Leptospira spp. (n = 35), Salmonella enterica serovar Typhi and Paratyphi (enteric fever n = 24), Burkholderia pseudomallei (melioidosis n = 14), and Japanese encephalitis virus (n = 18). Wide tracts with very little published data on aetiology of fever are apparent. DISCUSSION AND CONCLUSIONS: This mapping demonstrates a very heterogeneous distribution of information on the causes of fever in the Mekong countries. Further directed data collection to address gaps in the evidence-base, and expansion to a global database of pathogen distribution, is readily achievable, and would help define wider priorities for research and development to improve syndromic management of fever, prioritize diagnostic development, and guide empirical therapy.

Kauss T, Gaudin K, Gaubert A, Ba B, Tagliaferri S, Fawaz F, Fabre J-L, Boiron J-M, Lafarge X, White NJ et al. 2012. Screening paediatric rectal forms of azithromycin as an alternative to oral or injectable treatment. Int J Pharm, 436 (1-2), pp. 624-630. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

The aim of this study was to identify a candidate formulation for further development of a home or near-home administrable paediatric rectal form of a broad-spectrum antibiotic - specially intended for (emergency) use in tropical rural settings, in particular for children who cannot take medications orally and far from health facilities where injectable treatments can be given. Azithromycin, a broad-spectrum macrolide used orally or intravenously for the treatment of respiratory tract, skin and soft tissue infections, was selected because of its pharmacokinetic and therapeutic properties. Azithromycin in vitro solubility and stability in physiologically relevant conditions were studied. Various pharmaceutical forms, i.e. rectal suspension, two different rectal gels, polyethylene glycol (PEG) suppository and hard gelatin capsule (HGC) were assessed for in vitro dissolution and in vivo bioavailability in the rabbit. Azithromycin PEG suppository appears to be a promising candidate.

Thao VP, Le T, Toeroek EM, Yen NTB, Chau TTH, Jurriaans S, van Doorn HR, de Jong MD, Farrar JJ, Dunstan SJ. 2012. HIV-1 drug resistance in antiretroviral-naive individuals with HIV-1-associated tuberculous meningitis initiating antiretroviral therapy in Vietnam (vol 17, pg 905, 2012) ANTIVIRAL THERAPY, 17 (5), pp. 937-937. | Citations: 1 (Scopus) | Read more

Holt KE, Baker S, Weill FX, Holmes EC, Kitchen A, Yu J, Sangal V, Brown DJ, Coia JE, Kim DW et al. 2012. Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe Nature Genetics, 44 (9), pp. 1056-1059. | Citations: 103 (Scopus) | Show Abstract | Read more

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery, spreading efficiently via low-dose fecal-oral transmission. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries but is now emerging as a problem in the developing world, seeming to replace the more diverse Shigella flexneri in areas undergoing economic development and improvements in water quality. Classical approaches have shown that S. sonnei is genetically conserved and clonal. We report here whole-genome sequencing of 132 globally distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and that diversified into several distinct lineages with unique characteristics. Our analysis suggests that the majority of this diversification occurred in Europe and was followed by more recent establishment of local pathogen populations on other continents, predominantly due to the pandemic spread of a single, rapidly evolving, multidrug-resistant lineage. © 2012 Nature America, Inc. All rights reserved.

Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P et al. 2012. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: A modelling study The Lancet Infectious Diseases, 12 (9), pp. 687-695. | Citations: 439 (Scopus) | Show Abstract | Read more

Background: 18 500 laboratory-confirmed deaths caused by the 2009 pandemic influenza A H1N1 were reported worldwide for the period April, 2009, to August, 2010. This number is likely to be only a fraction of the true number of the deaths associated with 2009 pandemic influenza A H1N1. We aimed to estimate the global number of deaths during the first 12 months of virus circulation in each country. Methods: We calculated crude respiratory mortality rates associated with the 2009 pandemic influenza A H1N1 strain by age (0-17 years, 18-64 years, and > 64 years) using the cumulative (12 months) virus-associated symptomatic attack rates from 12 countries and symptomatic case fatality ratios (sCFR) from five high-income countries. To adjust crude mortality rates for differences between countries in risk of death from influenza, we developed a respiratory mortality multiplier equal to the ratio of the median lower respiratory tract infection mortality rate in each WHO region mortality stratum to the median in countries with very low mortality. We calculated cardiovascular disease mortality rates associated with 2009 pandemic influenza A H1N1 infection with the ratio of excess deaths from cardiovascular and respiratory diseases during the pandemic in five countries and multiplied these values by the crude respiratory disease mortality rate associated with the virus. Respiratory and cardiovascular mortality rates associated with 2009 pandemic influenza A H1N1 were multiplied by age to calculate the number of associated deaths. Findings: We estimate that globally there were 201 200 respiratory deaths (range 105 700-395 600) with an additional 83 300 cardiovascular deaths (46 000-179 900) associated with 2009 pandemic influenza A H1N1. 80% of the respiratory and cardiovascular deaths were in people younger than 65 years and 51% occurred in southeast Asia and Africa. Interpretation: Our estimate of respiratory and cardiovascular mortality associated with the 2009 pandemic influenza A H1N1 was 15 times higher than reported laboratory-confirmed deaths. Although no estimates of sCFRs were available from Africa and southeast Asia, a disproportionate number of estimated pandemic deaths might have occurred in these regions. Therefore, efforts to prevent influenza need to effectively target these regions in future pandemics. Funding: None. © 2012 Elsevier Ltd.

Baird JK. 2012. Primaquine toxicity forestalls effective therapeutic management of the endemic malarias. Int J Parasitol, 42 (12), pp. 1049-1054. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

Treatment of acutely ill patients, informed by a diagnosis of the species of Plasmodium involved, has long dominated strategic thinking in malaria chemotherapeutics. This bias for both acute illness and access to diagnosis resulted in therapeutic strategies poorly suited to malaria as it occurs in endemic zones. Most of those malarias do not provoke illness and occur beyond diagnostic reach for technical or practical reasons. Therapies effective against all species and stages would likely prove more practical in endemic zones, especially if safely administered without laboratory screening for contraindications. The primary impediment to such therapies is the mild to severe hemolytic toxicity of primaquine in patients with glucose-6-phosphate dehydrogenase deficiency. Primaquine is the only treatment licensed for therapy against relapse caused by dormant liver stages occurring in some species, and against the sexual blood stages responsible for transmission to mosquitoes in all species. Despite being licensed over 50 years ago, no alternative drugs have been developed, and safer dosing regimens of primaquine have not been explored. These failures forestalled the emergence of therapies practical for use in endemic zones, especially in the context of eliminating transmission.

Baird JK. 2012. Elimination therapy for the endemic malarias Current Infectious Disease Reports, 14 (3), pp. 227-237. | Citations: 8 (Scopus) | Show Abstract | Read more

Most malaria diagnosed outside endemic zones occurs in patients experiencing the consequences of what was likely a single infectious bite by an anopheline mosquito. A single species of parasite is nearly always involved and expert opinion on malaria chemotherapy uniformly prescribes species- and stage-specific treatments. However the vast majority of people experiencing malaria, those resident in endemic zones, do so repeatedly and very often with the involvement of two or more species and stages of parasite. Silent forms of these infections-asymptomatic and beyond the reach of diagnostics-may accumulate to form substantial and unchallenged reservoirs of infection. In such settings treating only the species and stage of malaria revealed by diagnosis and not others may not be sensible or appropriate. Developing therapeutic strategies that address all species and stages independently of diagnostic evidence may substantially improve the effectiveness of the control and elimination of endemic malaria. © The Author(s) 2012.

Green LE, Carrique-Mas JJ, Mason SA, Medley GF. 2012. Patterns of delayed detection and persistence of bovine tuberculosis in confirmed and unconfirmed herd breakdowns in cattle and cattle herds in Great Britain Preventive Veterinary Medicine, 106 (3-4), pp. 266-274. | Citations: 7 (Scopus) | Show Abstract | Read more

Approximately 1500/6000 cattle farms that were depopulated during the foot and mouth epidemic in GB in 2001 had been repopulated and subjected to two unrestricted (herd considered free from bovine tuberculosis (bTB)) herd tests. Factors associated with herd breakdown(s) (HBD) and individual cattle reactor status at the second test were investigated. There were 96 HBD in total, with a 3-fold increased risk of HBD in herds that had had a HBD at the first test after restocking. Two mixed effect models were used to investigate factors associated with 324/246,060 reactor cattle at the second bTB test; 228 reactors were at confirmed HBD and 96 at unconfirmed HBD; 253 (79%) reactors at the second test were present and test negative at the first test. In confirmed HBD, the odds of cattle reacting were higher if the restocked farm had a history of bTB before 2001 and if the source and restocked farms were high frequency tested (HFT) farms (routine bTB tests at ≥1 per 2 years). Reacting cattle were more likely to have been born on the restocked farm before the first test after FMD and less likely to have been purchased from a low frequency tested (LFT) farm (routine bTB tests at 3-4 year intervals) after the first test compared with a baseline of cattle purchased from a LFT farm before the first test. Unconfirmed HBD at the second test was more likely when the first test was a confirmed HBD and when there was a history of bTB in the restocked farm. In contrast to confirmed HBD, cattle purchased from a LFT farm after the first test were at increased risk of reacting at an unconfirmed HBD at the second test.We conclude that a farm history of bTB suggests persistence of bTB on the farm. Confirmed tests indicate exposure to bTB for some time indicated by the increased risk from HFT source and restocked farms and a farm history of bTB. The risks for reactors are related to the farm and herd and duration of exposure to these risks. Therefore, the spread of bTB to naïve herds would be reduced if farmers only introduced cattle known not to have been in herds and on farms exposed to bTB. Management of bTB on farms with bTB is complicated because there is undisclosed infection in cattle and environmental contamination. © 2012 Elsevier B.V.

Sarovich DS, Price EP, Limmathurotsakul D, Cook JM, Von Schulze AT, Wolken SR, Keim P, Peacock SJ, Pearson T. 2012. Development of ceftazidime resistance in an acute Burkholderia pseudomallei infection. Infect Drug Resist, 5 (1), pp. 129-132. | Citations: 21 (Scopus) | Show Abstract | Read more

Burkholderia pseudomallei, a bacterium that causes the disease melioidosis, is intrinsically resistant to many antibiotics. First-line antibiotic therapy for treating melioidosis is usually the synthetic β-lactam, ceftazidime (CAZ), as almost all B. pseudomallei strains are susceptible to this drug. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, which can lead to mortality if therapy is not switched to a different drug in a timely manner. Serial B. pseudomallei isolates obtained from an acute Thai melioidosis patient infected by a CAZ susceptible strain, who ultimately succumbed to infection despite being on CAZ therapy for the duration of their infection, were analyzed. Isolates that developed CAZ resistance due to a proline to serine change at position 167 in the β-lactamase PenA were identified. Importantly, these CAZ resistant isolates remained sensitive to the alternative melioidosis treatments; namely, amoxicillin-clavulanate, imipenem, and meropenem. Lastly, real-time polymerase chain reaction-based assays capable of rapidly identifying CAZ resistance in B. pseudomallei isolates at the position 167 mutation site were developed. The ability to rapidly identify the emergence of CAZ resistant B. pseudomallei populations in melioidosis patients will allow timely alterations in treatment strategies, thereby improving patient outcomes for this serious disease.

Maude RR, Vatcharapreechasakul T, Ariyaprasert P, Maude RJ, Hongsuwan M, Yuentrakul P, Limmathurotsakul D, Koh GCKW, Chaowagul W, Day NPJ, Peacock SJ. 2012. Prospective observational study of the frequency and features of intra-abdominal abscesses in patients with melioidosis in northeast Thailand Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (10), pp. 629-631. | Citations: 6 (Scopus) | Show Abstract | Read more

Retrospective case series from Thailand have reported the presence of intra-abdominal abscesses in around half of patients with melioidosis, a much higher rate than our clinical experience would suggest. We performed a prospective, observational study of 230 adult patients with culture-confirmed melioidosis in which all patients underwent abdominal ultrasound. One or more abscesses were detected in the liver and/or spleen in 77 (33%) cases. These were often multiple (70%, 31/44 in hepatic abscesses and 88%, 50/57 in splenic abscesses) and clinically silent (27% of cases with abscesses presenting with abdominal pain). The mortality rate at 4 weeks post-discharge was lower in patients who were abscess-positive vs abscess-negative (10%, 8/77 vs 20%, 31/153). © 2012 Royal Society of Tropical Medicine and Hygiene.

Turner P, Melchiorre S, Moschioni M, Barocchi MA, Turner C, Watthanaworawit W, Kaewcharernnet N, Nosten F, Goldblatt D. 2012. Assessment of Streptococcus pneumoniae pilus islet-1 prevalence in carried and transmitted isolates from mother-infant pairs on the Thailand-Burma border Clinical Microbiology and Infection, 18 (10), pp. 970-975. | Citations: 7 (Scopus) | Show Abstract | Read more

Streptococcus pneumoniae pilus islet-1 (PI-1)-encoded pilus enhances in vitro adhesion to the respiratory epithelium and may contribute to pneumococcal nasopharyngeal colonization and transmission. The pilus subunits are regarded as potential protein vaccine candidates. In this study, we sought to determine PI-1 prevalence in carried pneumococcal isolates and explore its relationship with transmissibility or carriage duration. We studied 896 pneumococcal isolates collected during a longitudinal carriage study that included monthly nasopharyngeal swabbing of 234 infants and their mothers between the ages of 1 and 24 months. These were cultured according to the WHO pneumococcal carriage detection protocol. PI-1 PCR and genotyping by multilocus sequence typing were performed on isolates chosen according to specific carriage and transmission definitions. Overall, 35.2% of the isolates were PI-1-positive, but PI-1 presence was restricted to ten of the 34 serotypes studied and was most frequently associated with serotypes 19F and 23F; 47.5% of transmitted and 43.3% of non-transmitted isolates were PI-1-positive (OR 1.2; 95% CI 0.8-1.7; p0.4). The duration of first-ever infant pneumococcal carriage was significantly longer with PI-1-positive organisms, but this difference was not significant at the individual serotype level. In conclusion, PI-1 is commonly found in pneumococcal carriage isolates, but does not appear to be associated with pneumococcal transmissibility or carriage duration. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

Blacksell SD, Lee SJ, Chanthongthip A, Taojaikong T, Thongpaseuth S, Hübscher T, Newton PN. 2012. Short report: Comparison of performance of serum and plasma in panbio dengue and Japanese encephalitis virus enzyme-linked immunosorbent assays American Journal of Tropical Medicine and Hygiene, 87 (3), pp. 573-575. | Citations: 4 (Scopus) | Show Abstract | Read more

We examined the comparative performance of serum and plasma (in dipotassium EDTA) in Panbio Dengue enzyme-linked immunosorbent assays (ELISAs) for detection of non-structural protein 1 (NS1), IgM, and IgG, and a dengue/Japanese encephalitis virus (JEV) combination IgM ELISA in a prospective series of 201 patients with suspected dengue in Laos. Paired comparisons of medians from serum and plasma samples were not significantly different for Dengue IgM, and NS1 which had the highest number of discordant pairs (both 2%; P = 0.13 and P = 0.25, respectively). Comparison of qualitative final diagnostic interpretations for serum and plasma samples were not significantly different: only 1.5% (3 of 201 for Dengue/JEV IgM and Dengue IgG) and 2.0% (4 of 201; IgM and NS1) showed discordant pairs. These results demonstrate that plasma containing EDTA is suitable for use in these ELISAs. Copyright © 2012 by The American Society of Tropical Medicine and Hygiene.

Pratt B, Zion D, Lwin KM, Cheah PY, Nosten F, Loff B. 2012. Closing the translation gap for justice requirements in international research Journal of Medical Ethics, 38 (9), pp. 552-558. | Citations: 7 (Scopus) | Show Abstract | Read more

Bioethicists have long debated the content of sponsors and researchers? obligations of justice in international clinical research. However, there has been little empirical investigation as to whether and how obligations of responsiveness, ancillary care, post-trial benefits and research capacity strengthening are upheld in low- and middle-income country settings. In this paper, the authors argue that research ethics guidelines need to be more informed by international research practice. Practical guidance on how to fulfil these obligations is needed if research groups and other actors are to successfully translate them into practice because doing so is often a complicated, context-specific process. Case study research methods offer one avenue for collecting data to develop this guidance. The authors describe how such methods have been used in relation to the Shoklo Malaria Research Unit's vivax malaria treatment (VHX) trial (NCT01074905). Relying on the VHX trial example, the paper shows how information can be gathered from not only international clinical researchers?but also trial participants, community advisory board members and research funder representatives in order to: (1) measure evidence of responsiveness, provision of ancillary care, access to post-trial benefits and research capacity strengthening in international clinical research; and (2) identify the contextual factors and roles and responsibilities that were instrumental in the fulfilment of these ethical obligations. Such empirical work is necessary to inform the articulation of obligations of justice in international research and to develop guidance on how to fulfil them in order to facilitate better adherence to guidelines' requirements.

Boel ME, Rijken MJ, Pimanpanarak M, Keereecharoen NL, Proux S, Nosten F, McGready R. 2012. No association of phenotypic ABO blood group and malaria during pregnancy. Am J Trop Med Hyg, 87 (3), pp. 447-449. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

In a few small studies an association between blood group O and placental malaria has been described. The relationship between blood group and malaria in pregnancy (Plasmodium vivax and Plasmodium falciparum) was analyzed in 1,468 women from three longitudinal cohort studies in which weekly malaria screening was done systematically during pregnancy. One-third of women (447 of 1,468) had at least one malaria infection in pregnancy. The ABO blood group phenotype was not associated with the species of infection, frequency of malaria attacks, symptoms of malaria, hematocrit, or parasitemia during pregnancy.

Marfurt J, Chalfein F, Prayoga P, Wabiser F, Wirjanata G, Sebayang B, Piera KA, Wittlin S, Haynes RK, Möhrle JJ et al. 2012. Comparative ex vivo activity of novel endoperoxides in multidrug-resistant plasmodium falciparum and P. vivax. Antimicrob Agents Chemother, 56 (10), pp. 5258-5263. | Citations: 25 (Scopus) | Show Abstract | Read more

The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC(50)s) in both species (median IC(50)s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum, the same was not apparent in P. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax. The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

Abdullahi O, Karani A, Tigoi CC, Mugo D, Kungu S, Wanjiru E, Jomo J, Musyimi R, Lipsitch M, Scott JAG. 2012. Rates of acquisition and clearance of pneumococcal serotypes in the nasopharynges of children in Kilifi District, Kenya. J Infect Dis, 206 (7), pp. 1020-1029. | Citations: 35 (Scopus) | Show Abstract | Read more

BACKGROUND: To understand and model the impact of pneumococcal conjugate vaccines at the population level, we need to know the transmission dynamics of individual pneumococcal serotypes. We estimated serotype-specific clearance and acquisition rates of nasopharyngeal colonization among Kenyan children. METHODS: Children aged 3-59 months who were identified as carriers in a cross-sectional survey were followed-up approximately 1, 2, 4, 8, 16, and 32 days later and monthly thereafter until culture of 2 consecutive swabs yielded an alternative serotype or no pneumococcus. Serotype-specific clearance rates were estimated by exponential regression of interval-censored carriage durations. Duration was estimated as the reciprocal of the clearance rate, and acquisition rates were estimated on the basis of prevalence and duration, assuming an equilibrium state. RESULTS: Of 2840 children sampled between October 2006 and December 2008, 1868 were carriers. The clearance rate was 0.032 episodes/day (95% confidence interval [CI], .030-.034), for a carriage duration of 31.3 days, and the rate varied by serotype (P< .0005). Carriage durations for the 28 serotypes with ≥ 10 carriers ranged from 6.7 to 50 days. Clearance rates increased with year of age, adjusted for serotype (hazard ratio, 1.21; 95% CI, 1.15-1.27). The acquisition rate was 0.061 episodes/day (95% CI, .055-.067), which did not vary with age. Serotype-specific acquisition rates varied from 0.0002 to 0.0022 episodes/day. Serotype-specific acquisition rates correlated with prevalence (r=0.91; P< .00005) and with acquisition rates measured in a separate study involving 1404 newborns in Kilifi (r=0.87; P< .00005). CONCLUSIONS: The large sample size and short swabbing intervals provide a precise description of the prevalence, duration, and acquisition of carriage of 28 pneumococcal serotypes. In Kilifi, young children experience approximately 8 episodes of carriage per year. The declining prevalence with age is attributable to increasing clearance rates.

Siritantikorn S, Jintaworn S, Noisakran S, Suputtamongkol Y, Paris DH, Blacksell SD. 2012. Application of ImageJ program to the enumeration of Orientia tsutsugamushi organisms cultured in vitro Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (10), pp. 632-635. | Citations: 7 (Scopus) | Show Abstract | Read more

The ImageJ program was applied to the enumeration of Orientia tsutsugamushi organisms in cell culture using indirect immunofluorescence assay (IFA). The highest correlation (r = 0.984) was observed between manual counting methods and the ImageJ program (MaxEntropy threshold algorithm). This software-based methodology is cheaper, more standardised and better reproducible than a manual-based approach. © 2012 Royal Society of Tropical Medicine and Hygiene.

Tham NT, Hang VTT, Khanh TH, Viet DC, Hien TT, Farrar J, Chau NVV, van Doorn HR. 2012. Comparison of the Roche RealTime ready Influenza A/H1N1 Detection Set with CDC A/H1N1pdm09 RT-PCR on samples from three hospitals in Ho Chi Minh City, Vietnam Diagnostic Microbiology and Infectious Disease, 74 (2), pp. 131-136. | Citations: 6 (Scopus) | Show Abstract | Read more

Real-time polymerase chain reaction (PCR) can be considered the gold standard for detection of influenza viruses due to its high sensitivity and specificity. Roche has developed the RealTime ready Influenza A/H1N1 Detection Set, consisting of a generic influenza virus A PCR targeting the M2 gene (M2 PCR) and a specific PCR targeting the hemagglutinin (HA) of A/H1N1-pdm09 (HA PCR, 2009 H1N1), with the intention to make a reliable, rapid, and simple test to detect and quantify 2009 H1N1 in clinical samples. We evaluated this kit against the US Centers for Disease Control and Prevention (USCDC)/World Health Organization real-time PCR for influenza virus using 419 nose and throat swabs from 210 patients collected in 3 large hospitals in Ho Chi Minh City, Vietnam. In the per-patient analysis, when compared to CDC PCR, the sensitivity and specificity of the M2 PCR were 85.8% and 97.6%, respectively; the sensitivity and specificity of HA PCR were 88.2% and 100%, respectively. In the per-sample analysis, the sensitivity and specificity in nose swabs were higher than those in throat swabs for both M2 and HA PCRs. The viral loads as determined with the M2 and HA PCRs correlated well with the Ct values of the CDC PCR. Compared with the CDC PCR, the kit has a reasonable sensitivity and very good specificity for the detection and quantification of influenza A virus and A/H1N1-pdm09. However, given the current status of 2009 H1N1, a kit that can detect all circulating seasonal influenza viruses would be preferable. © 2012 Elsevier Inc.

Davies A, Mbete B, Fegan G, Molyneux S, Kinyanjui S. 2012. Seeing ‘With my Own Eyes’: Strengthening Interactions between Researchers and Schools* IDS Bulletin, 43 (5), pp. 61-67. | Citations: 2 (Scopus) | Show Abstract | Read more

We describe a participatory action research (PAR) project aimed at initiating a schools project as a component of the wider Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme's (KWTRP) community engagement strategy in Kilifi. Students and teachers from three nearby secondary schools, and scientists from KWTRP, were involved in designing and implementing a set of interventions aimed at promoting school awareness of locally conducted research, and positive attitudes towards school science and health research. The project was evaluated using a mixture of pre- and post-intervention surveys and discussions with teachers, students, researchers and other stakeholders throughout the duration of the project. The project did appear to fill some knowledge gaps about research and contribute to enhancing students' educational experiences, as intended. However, the project also provided a forum where teachers and students could express their concerns and question research practices, and unexpectedly promoted learning among researchers themselves. Further work is needed to learn more about the potential of school engagement to provide benefits for research institutes, individual researchers and local schools. © 2012 Institute of Development Studies.

Kerlin DH, Boyce K, Marfurt J, Simpson JA, Kenangalem E, Cheng Q, Price RN, Gatton ML. 2012. An analytical method for assessing stage-specific drug activity in Plasmodium vivax malaria: implications for ex vivo drug susceptibility testing. PLoS Negl Trop Dis, 6 (8), pp. e1772. | Citations: 14 (Scopus) | Show Abstract | Read more

The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT), originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC(50)) values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC(50) for CQ. Our findings indicate that EC(50) values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.

Pindolia DK, Garcia AJ, Wesolowski A, Smith DL, Buckee CO, Noor AM, Snow RW, Tatem AJ. 2012. Human movement data for malaria control and elimination strategic planning. Malar J, 11 (1), pp. 205. | Citations: 54 (Web of Science Lite) | Show Abstract | Read more

Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements.

Douglas NM, Anstey NM, Buffet PA, Poespoprodjo JR, Yeo TW, White NJ, Price RN. 2012. The anaemia of Plasmodium vivax malaria. Malar J, 11 (1), pp. 135. | Citations: 78 (Scopus) | Show Abstract | Read more

Plasmodium vivax threatens nearly half the world's population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment.

Ariana P. 2012. Challenging Our Understanding of Health: Indigenous Perspectives from the Highlands of Chiapas, Mexico Oxford Development Studies, 40 (3), pp. 405-421. | Citations: 2 (Scopus) | Show Abstract | Read more

In the context of development, considerable attention is paid to population health, usually interpreted according to mortality rates or burden of disease estimates. However, health is more complex than such physical indices can convey. This is particularly evident among many contemporary indigenous communities whose concepts of well-being extend well beyond conventional biomedical measures. Such misalignment of perspectives can have implications for how the health effects of development are determined. To gauge the relevance of alternative perspectives, indigenous notions of health among Highland communities in Chiapas, Mexico are examined. This paper begins with a historical account of health and healing rituals in the region, then describes current beliefs and practices among a set of Highland communities. © 2012 Copyright Oxford Department of International Development.

White LJ, Newton PN, Maude RJ, Pan-ngum W, Fried JR, Mayxay M, Maude RR, Day NPJ. 2012. Defining disease heterogeneity to guide the empirical treatment of febrile illness in resource poor settings. PLoS One, 7 (9), pp. e44545. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria incidence is in decline in many parts of SE Asia leading to a decreasing proportion of febrile illness that is attributable to malaria. However in the absence of rapid, affordable and accurate diagnostic tests, the non-malaria causes of these illnesses cannot be reliably identified. Studies on the aetiology of febrile illness have indicated that the causes are likely to vary by geographical location within countries (i.e. be spatially heterogeneous) and that national empirical treatment policies based on the aetiology measured in a single location could lead to inappropriate treatment. METHODS: Using data from Vientiane as a reference for the incidence of major febrile illnesses in the Lao People's Democratic Republic (Laos) and estimated incidences, plausible incidence in other Lao provinces were generated using a mathematical model for a range of national and local scale variations. For a range of treatment protocols, the mean number of appropriate treatments was predicted and the potential impact of a spatially explicit national empirical treatment protocol assessed. FINDINGS: The model predicted a negative correlation between number of appropriate treatments and the level of spatial heterogeneity. A spatially explicit national treatment protocol was predicted to increase the number of appropriate treatments by 50% for intermediate levels of spatial heterogeneity. CONCLUSIONS: The results suggest that given even only moderate spatial variation, a spatially explicit treatment algorithm will result in a significant improvement in the outcome of undifferentiated fevers in Laos and other similar resource poor settings.

Nosten F, Phillips-Howard PA, ter Kuile FO. 2012. Other 4-methanolquinolines, amyl alcohols and phentathrenes: Mefloquine, lumefantrine and halofantrine Milestones in Drug Therapy, 41 pp. 95-111. | Show Abstract | Read more

This chapter describes mefloquine, pyronaridine, halofantrine, piperaquine and lumefantrine under the broader title of the 4-methanolquinolines, amyl alcohols and phentathrenes. We provide a brief resume of each drug, in terms of their chemical properties, formulae, pharmacokinetics, clinical indications for use, and their efficacy and safety. Recognizing the limited number of antimalarials available, and in the developmental pipeline, attention is focussed on describing the history of each drug and how their indications have evolved as data on safety in human populations accumulates over time, and how patterns of use have changed with growing multiple drug resistance. Their combined use with the artemisinin derivatives is briefly described and readers are recommended to consult other chapters in this book which more fully describe such combinations. © Springer Basel AG 2012.

Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S et al. 2012. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma Nature Genetics, 44 (10), pp. 1142-1146. | Citations: 87 (Scopus) | Show Abstract | Read more

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10 -12 ), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10 -10 ) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10 -9 ). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG. © 2012 Nature America, Inc. All rights reserved.

Offeddu V, Thathy V, Marsh K, Matuschewski K. 2012. Erratum to ‘‘Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection” [Int. J. Parasitol. 42 (2012) 535–548] International Journal for Parasitology, 42 (10), pp. 961-961. | Read more

Trung DT, Thao TT, Dung NM, Ngoc TV, Hien TT, Chau NV, Wolbers M, Tam DT, Farrar J, Simmons C, Wills B. 2012. Clinical features of dengue in a large Vietnamese cohort: intrinsically lower platelet counts and greater risk for bleeding in adults than children. PLoS neglected tropical diseases, 6 (6), | Citations: 9 (Scopus) | Show Abstract | Read more

As dengue spreads to new geographical regions and the force of infection changes in existing endemic areas, a greater breadth of clinical presentations is being recognised. Clinical experience suggests that adults manifest a pattern of complications different from those observed in children, but few reports have described the age-related spectrum of disease in contemporaneous groups of patients recruited at the same geographical location. Using detailed prospectively collected information from ongoing studies that encompass the full spectrum of hospitalised dengue cases admitted to a single hospital in southern Vietnam, we compared clinical and laboratory features, management, and outcome for 647 adults and 881 children with confirmed dengue. Signs of vascular leakage and shock were more frequent and more severe in children than adults, while bleeding manifestations and organ involvement were more common in adults. Additionally, adults experienced significantly more severe thrombocytopenia. Secondary infection but not serotype was independently associated with greater thrombocytopenia, although with a smaller effect than age-group. The effect of age-group on platelet count was also apparent in the values obtained several weeks after recovery, indicating that healthy adults have intrinsically lower counts compared to children. There are clear distinctions between adults and children in the pattern of complications seen in association with dengue infection, and these depend partly on intrinsic age-dependent physiological differences. Knowledge of such differences is important to inform research on disease pathogenesis, as well as to encourage development of management guidelines that are appropriate to the age-groups at risk.

Herbert K, Plugge E, Foster C, Doll H. 2012. Authors' reply The Lancet, 380 (9849), pp. 1227-1228.

Shaikh S, Memon H, Iohano B, Shaikh A, Ahmed I, Baird JK. 2012. Severe disease in children hospitalized with a diagnosis of Plasmodium vivax in south-eastern Pakistan. Malar J, 11 (1), pp. 144. | Citations: 21 (Scopus) | Show Abstract | Read more

BACKGROUND: Infection by Plasmodium vivax has been considered rarely threatening to life, but recent studies challenge this notion. This study documented the frequency and character of severe illness in paediatric patients admitted to a hospital in south-eastern Pakistan with a laboratory-confirmed diagnosis of vivax malaria. METHODS: An observational study of all 180 paediatric patients admitted with any diagnosis of malaria during 2010 was conducted: 128 P. vivax; 48 Plasmodium falciparum; and four mixed infections of these species. Patients were classified as having severe illness with any of the following indicators: Glascow coma scale <11; ≥2 convulsions; haemoglobin <5g/dL; thrombocytes <50,000/mL; blood glucose <45mg%; >70 breaths/min; or intravenous anti-malarial therapy. Additionally, 64 patients with a diagnosis of vivax malaria were treated during 2009, and the 21 of these having severe illness were included in analyses of the frequency and character of severe illness with that diagnosis. RESULTS: During 2010, 39 (31%) or 37 (77%) patients with a diagnosis of P. vivax or P. falciparum were classified as having severe disease. Including the 2009 records of 64 patients having vivax malaria, a total of 60 (31%) patients with severe illness and a diagnosis of P. vivax were available. Altered mental status (Glascow coma scale score <11; or ≥2 convulsions) dominated at 54% of the 83 indicators of severe illness manifest among the patients with vivax malaria, as was true among the 37 children with a diagnosis of falciparum malaria and being severely ill; 58% of the 72 indicators of severe disease documented among them. No statistically significant difference appeared in frequencies of any other severe disease indicators between patients diagnosed with vivax or falciparum malaria. Despite such similarities, a diagnosis of falciparum malaria nonetheless came with 3.8-fold (95% CI = 1.8-8.1) higher risk of presenting with severe illness, and 8.0-fold (95% CI = 2.1-31) greater likelihood of presenting with three or more severe disease indicators. Two patients did not survive hospitalization, one each with a diagnosis of falciparum or vivax malaria. CONCLUSIONS: Vivax malaria caused a substantial burden of potentially life-threatening morbidity on a paediatric ward in a hospital in south-eastern Pakistan.

Dongol S, Thompson CN, Clare S, Nga TVT, Duy PT, Karkey A, Arjyal A, Koirala S, Khatri NS, Maskey P et al. 2012. The microbiological and clinical characteristics of invasive salmonella in gallbladders from cholecystectomy patients in kathmandu, Nepal. PLoS One, 7 (10), pp. e47342. | Citations: 25 (Web of Science Lite) | Show Abstract | Read more

Gallbladder carriage of invasive Salmonella is considered fundamental in sustaining typhoid fever transmission. Bile and tissue was obtained from 1,377 individuals undergoing cholecystectomy in Kathmandu to investigate the prevalence, characteristics and relevance of invasive Salmonella in the gallbladder in an endemic area. Twenty percent of bile samples contained a Gram-negative organism, with Salmonella Typhi and Salmonella Paratyphi A isolated from 24 and 22 individuals, respectively. Gallbladders that contained Salmonella were more likely to show evidence of acute inflammation with extensive neutrophil infiltrate than those without Salmonella, corresponding with higher neutrophil and lower lymphocyte counts in the blood of Salmonella positive individuals. Antimicrobial resistance in the invasive Salmonella isolates was limited, indicating that gallbladder colonization is unlikely to be driven by antimicrobial resistance. The overall role of invasive Salmonella carriage in the gallbladder is not understood; here we show that 3.5% of individuals undergoing cholecystectomy in this setting have a high concentration of antimicrobial sensitive, invasive Salmonella in their bile. We predict that such individuals will become increasingly important if current transmission mechanisms are disturbed; prospectively identifying these individuals is, therefore, paramount for rapid local and regional elimination.

Klein K, Aarons L, Ter Kuile FO, Nosten F, White NJ, Edstein MD, Teja-Isavadharm P. 2012. Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria Journal of Pharmacy and Pharmacology, 64 (11), pp. 1603-1613. | Citations: 1 (Scopus) | Show Abstract | Read more

Aims To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria. Methods Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai-Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non-linear mixed effects modelling with a two-compartment model with first-order absorption. Key findings The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre-treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively. Conclusions The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters. © 2012 Royal Pharmaceutical Society.

Wesolowski A, Eagle N, Tatem AJ, Smith DL, Noor AM, Snow RW, Buckee CO. 2012. Quantifying the impact of human mobility on malaria. Science, 338 (6104), pp. 267-270. | Citations: 238 (Scopus) | Show Abstract | Read more

Human movements contribute to the transmission of malaria on spatial scales that exceed the limits of mosquito dispersal. Identifying the sources and sinks of imported infections due to human travel and locating high-risk sites of parasite importation could greatly improve malaria control programs. Here, we use spatially explicit mobile phone data and malaria prevalence information from Kenya to identify the dynamics of human carriers that drive parasite importation between regions. Our analysis identifies importation routes that contribute to malaria epidemiology on regional spatial scales.

Ginsburg AS, Van Cleve WC, Thompson MIW, English M. 2012. Oxygen and pulse oximetry in childhood pneumonia: a survey of healthcare providers in resource-limited settings. J Trop Pediatr, 58 (5), pp. 389-393. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

Globally, pneumonia is the leading cause of death in children <5 years of age. Hypoxemia, a frequent complication of pneumonia, is a risk factor for death. To better understand the availability of oxygen and pulse oximetry, barriers to use and provider perceptions and practices regarding their role in childhood pneumonia, we conducted a survey using a convenience sampling strategy targeting clinicians working in resource-limited countries. Most respondents were physicians from public district and provincial hospitals with access to oxygen and pulse oximetry; however, reported therapeutic use for childhood pneumonia was low. Common barriers included insufficient supply, competition for use, lack of policies, guidelines and training and perceived high cost. Despite the frequency of hypoxemia, the inaccuracy of clinical predictors, the poor outcome hypoxemia portends and the effectiveness of pulse oximetry and oxygen in childhood pneumonia, our data indicate that these tools may be underused in resource-limited settings.

Price RN, Auburn S, Marfurt J, Cheng Q. 2012. Phenotypic and genotypic characterisation of drug-resistant Plasmodium vivax Trends in Parasitology, 28 (11), pp. 522-529. | Citations: 25 (Scopus) | Show Abstract | Read more

In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance. © 2012 Elsevier Ltd.

Whitehorn J, Van Vinh Chau N, Truong NT, Tai LTH, Van Hao N, Hien TT, Wolbers M, Merson L, Dung NTP, Peeling R et al. 2012. Lovastatin for adult patients with dengue: protocol for a randomised controlled trial. Trials, 13 (1), pp. 203. | Citations: 29 (Scopus) | Show Abstract | Read more

BACKGROUND: Dengue is the most important vector-borne viral infection of man, with approximately 2 billion people living in areas at risk. Infection results in a range of manifestations from asymptomatic infection through to life-threatening shock and haemorrhage. One of the hallmarks of severe dengue is vascular endothelial disruption. There is currently no specific therapy and clinical management is limited to supportive care. Statins are a class of drug initially developed for lipid lowering. There has been considerable recent interest in their effects beyond lipid lowering. These include anti-inflammatory effects at the endothelium. In addition, it is possible that lovastatin may have an anti-viral effect against dengue. Observational data suggest that the use of statins may improve outcomes for such conditions as sepsis and pneumonia. This paper describes the protocol for a randomised controlled trial investigating a short course of lovastatin therapy in adult patients with dengue. METHODS/DESIGN: A randomised, double-blind, placebo-controlled trial will investigate the effects of lovastatin therapy in the treatment of dengue. The trial will be conducted in two phases with an escalation of dose between phases if an interim safety review is satisfactory. This is an exploratory study focusing on safety and there are no data on which to base a sample size calculation. A target sample size of 300 patients in the second phase, enrolled over two dengue seasons, was chosen based on clinical judgement and feasibility considerations. In a previous randomised trial in dengue, about 10% and 30% of patients experienced at least one serious adverse event or adverse event, respectively. With 300 patients, we will have 80% power to detect an increase of 12% (from 10% to 22%) or 16% (from 30% to 46%) in the frequency of adverse events. Furthermore, this sample size ensures some power to explore the efficacy of statins. DISCUSSION: The development of a dengue therapeutic that can attenuate disease would be an enormous advance in global health. The favourable effects of statins on the endothelium, their good safety profile and their low cost make lovastatin an attractive therapeutic candidate. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN03147572.

Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, Zhou C, Mao S, Anderson JM, Lindegardh N et al. 2012. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: A parasite clearance rate study The Lancet Infectious Diseases, 12 (11), pp. 851-858. | Citations: 181 (Scopus) | Show Abstract | Read more

Background: Artemisinin-resistant . Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods: Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of . G6PD, which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to . P falciparum: age, sex, and place of residence. This study is registered with . ClinicalTrials.gov, number . NCT00341003. Findings: We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54-6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean parasite heritability of half-life was 0·40 (SD 0·17). Interpretation: Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. © 2012 Elsevier Ltd.

Arrow KJ, Danzon PM, Gelband H, Jamison D, Laxminarayan R, Mills A, Mwabu G, Panosian C, Peto R, White NJ. 2012. The Affordable Medicines Facility--malaria: killing it slowly. Lancet, 380 (9857), pp. 1889-1890. | Citations: 5 (Web of Science Lite) | Read more

Gertsch JH, Corbett B, Holck PS, Mulcahy A, Watts M, Stillwagon NT, Casto AM, Abramson CH, Vaughan CPA, Macguire C et al. 2012. Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness. Wilderness Environ Med, 23 (4), pp. 307-315. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). METHODS: Double-blind, randomized, placebo-controlled trial. RESULTS: Two hundred ninety-four healthy Western trekkers were recruited on the Everest approach at 4280 m or 4358 m and randomly assigned to receive either 600 mg of ibuprofen or placebo 3 times daily before and during ascent to 4928 m. One hundred eighty-three of 294 participants completed the trial. Of the participants who did not complete the trial, 62 were lost to follow-up and another 49 broke trial protocol. In an intent-to-treat analysis (232 participants), ibuprofen was found to be more effective than placebo in reducing the incidence of AMS (24.4% vs 40.4%; P = .01) and the incidence of HAH (42.3% vs 60.5%; P < .01). Ibuprofen was also superior to placebo in reducing the severity of HAH (4.9% vs 14.7%; P = .01). The end point of oxygen saturation was also higher in the ibuprofen group (80.8 % vs 82.4%; P = .035). For the 183 participants who completed the trial and conformed to the protocol, the incidence of AMS between placebo and treatment groups was not significant (32.9% vs 22.7%; P = .129 for AMS incidence, 9.6% vs 8.2%; P = .74 for AMS severity, 54.8% vs 42.7%; P = .11 for HAH incidence, and 8.2% vs 3.6%; P = .18 for HAH severity). CONCLUSIONS: Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial. This loss of significance in the subjects who completed the trial may be explained by persons in the placebo group having a higher burden of illness and associated decreased compliance with the protocol. An important limitation of this study may be the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS.

Woodrow CJ, Gardner KB, Bustamante LY. 2012. Questions over high frequency of mutant PfATP6 haplotypes in traveller isolates. Malar J, 11 (1), pp. 186. | Citations: 1 (Scopus) | Show Abstract | Read more

A recent paper in Malaria Journal suggests that a high proportion of Plasmodium falciparum isolates found in travellers returning from a range of African countries carry the PfATP6 A623E S769N haplotype, and that this genotype is associated with artemether resistance. Such a finding would represent a substantial departure from the extensive literature reporting these individual mutations to be very rare, with the double mutation never documented. The number of isolates screened to obtain these double mutants is unstated, but highly relevant, not least because selection of isolates could have introduced significant confounders, such as timing of in vitro testing. An additional concern relates to the location of sequencing primers used to assess these positions. In the absence of clear information on these fundamental questions it would be appropriate to treat the findings with caution.

Seale AC, Berkley JA. 2012. Managing severe infection in infancy in resource poor settings Early Human Development, 88 (12), pp. 957-960. | Citations: 4 (Scopus) | Show Abstract | Read more

Reducing childhood mortality in resource-poor regions depends on effective interventions to decrease neonatal mortality from severe infection, which contributes up to a half of all neonatal deaths. There are key differences in resource-poor, compared to resource-rich, countries in terms of diagnosis, supportive care and treatment. In resource-poor settings, diagnosis is based on identifying clinical syndromes from international guidelines; microbiological investigations are restricted to a few research facilities. Low levels of staffing and equipment limit the provision of basic supportive care, and most facilities cannot provide respiratory support. Empiric antibiotic treatment guidelines are based on few aetiological and antimicrobial susceptibility data. Research on improving health care systems to provide effective supportive care, and implementation of simple pragmatic interventions, such as low-cost respiratory support, are essential, together with improved surveillance to monitor emerging drug resistance and treatment failures. Reductions in mortality will also be achieved through prevention of infection; including emerging vaccination and anti-sepsis strategies. © 2012 Elsevier Ltd.

Ayieko P, Okiro EA, Edwards T, Nyamai R, English M. 2012. Variations in mortality in children admitted with pneumonia to Kenyan hospitals. PLoS One, 7 (11), pp. e47622. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The existing case fatality estimates of inpatient childhood pneumonia in developing countries are largely from periods preceding routine use of conjugate vaccines for infant immunization and such primary studies rarely explore hospital variations in mortality. We analysed case fatality rates of children admitted to nine Kenyan hospitals with pneumonia during the era of routine infant immunization with Hib conjugate vaccine to determine if significant variations exist between hospitals. METHODS: Pneumonia admissions and outcomes in paediatric wards are described using data collected over two time periods: a one-year period (2007-2008) in nine hospitals, and data from a 9.25-year period (1999-March 2008) in one of the participating hospitals. Hospital case fatality rates for inpatient pneumonia during 2007 to 2008 were modeled using a fixed effect binomial regression model with a logit link. Using an interrupted time series design, data from one hospital were analysed for trends in pneumonia mortality during the period between 1997 and March 2008. RESULTS: Overall, 195 (5.9%) children admitted to all 9 hospitals with pneumonia from March 2007 to March 2008 died in hospital. After adjusting for child's sex, comorbidity, and hospital effect, mortality was significantly associated with child's age (p<0.001) and pneumonia severity (p<0.001). There was evidence of significant variations in mortality between hospitals (LR χ(2) =52.19; p<0.001). Pneumonia mortality remained stable in the periods before (trend -0.03, 95% CI -0.1 to 0.02) and after Hib introduction (trend 0.04, 95% CI -0.04 to 0.11). CONCLUSIONS: There are important variations in hospital-pneumonia case fatality in Kenya and these variations are not attributed to temporal changes. Such variations in mortality are not addressed by existing epidemiological models and need to be considered in allocating resources to improve child health.

Turner C, Turner P, Cararra V, Eh Lwe N, Watthanaworawit W, Day NP, White NJ, Goldblatt D, Nosten F. 2012. A high burden of respiratory syncytial virus associated pneumonia in children less than two years of age in a South East Asian refugee population. PLoS One, 7 (11), pp. e50100. | Citations: 9 (Scopus) | Show Abstract | Read more

BACKGROUND: Pneumonia is a major cause of childhood mortality and morbidity approximately 1.6 million deaths and 150 million episodes occur annually in children <5 years. Respiratory syncytial virus (RSV) may be responsible for up to 25% of cases and 12% of deaths making it an important potential vaccine target, although data from South East Asia is scarce. METHODS: We followed a birth cohort of Burmese refugee children, born over a one year period, for two years. Pneumonia episodes were diagnosed using WHO criteria. A chest radiograph, nasopharyngeal aspirate and non-specific markers of infection were taken during each episode. RESULTS: The incidence of RSV-associated pneumonia was 0.24 (95% CI 0.22-0.26) episodes per child year. All children with pneumonia received antibiotic treatment, following WHO guidelines. The highest incidence was in the 2-12 month age group. The commonest diagnosis in a child with RSV-associated pneumonia was non-severe pneumonia (239/362:66.0%), however the incidence of RSV-associated severe or very severe pneumonia was 0.08 (95% CI 0.01-0.10) episodes per child year. Birth in the wet season increased the risk of severe disease in children who had their first episode of RSV-associated pneumonia aged 2-11 months (OR 28.7, 95% CI 6.6-125.0, p<0.001). RSV episodes were highly seasonal being responsible for 80.0% of all the pneumonia episodes occurring each October and November over the study period. CONCLUSIONS: There was a high incidence of RSV associated pneumonia in this refugee population. Interventions to prevent RSV infection have the potential to reduce the incidence of clinically diagnosed pneumonia and hence unnecessary antibiotic usage in this population.

Douglas NM, John GK, von Seidlein L, Anstey NM, Price RN. 2012. Chemotherapeutic strategies for reducing transmission of Plasmodium vivax malaria. Adv Parasitol, 80 pp. 271-300. | Citations: 17 (Scopus) | Show Abstract | Read more

Effective use of anti-malarial drugs is key to reducing the transmission potential of Plasmodium vivax. In patients presenting with symptomatic disease, treatment with potent and relatively slowly eliminated blood schizontocidal regimens administered concurrently with a supervised course of 7 mg/kg primaquine over 7-14 days has potential to exert the greatest transmission-blocking benefit. Given the spread of chloroquine-resistant P. vivax strains, the artemisinin combination therapies dihydroartemisinin + piperaquine and artesunate + mefloquine are currently the most assured means of preventing P. vivax recrudescence. Preliminary evidence suggests that, like chloroquine, these combinations potentiate the hypnozoitocidal effect of primaquine, but further supportive evidence is required. In view of the high rate of P. vivax relapse following falciparum infections in co-endemic regions, there is a strong argument for broadening current radical cure policy to include the administration of hypnozoitocidal doses of primaquine to patients with Plasmodium falciparum malaria. The most important reservoir for P. vivax transmission is likely to be very low-density, asymptomatic infections, the majority of which will arise from liver-stage relapses. Therefore, judicious mass administration of hypnozoitocidal therapy will reduce transmission of P. vivax to a greater extent than strategies focused on treatment of symptomatic patients. An efficacious hypnozoitocidal agent with a short curative treatment course would be particularly useful in mass drug administration campaigns.

Anstey NM, Douglas NM, Poespoprodjo JR, Price RN. 2012. Plasmodium vivax: clinical spectrum, risk factors and pathogenesis. Adv Parasitol, 80 pp. 151-201. | Citations: 91 (Scopus) | Show Abstract | Read more

Vivax malaria was historically described as 'benign tertian malaria' because individual clinical episodes were less likely to cause severe illness than Plasmodium falciparum. Despite this, Plasmodium vivax was, and remains, responsible for major morbidity and significant mortality in vivax-endemic areas. Single infections causing febrile illness in otherwise healthy individuals rarely progress to severe disease. Nevertheless, in the presence of co-morbidities, P. vivax can cause severe illness and fatal outcomes. Recurrent or chronic infections in endemic areas can cause severe anaemia and malnutrition, particularly in early childhood. Other severe manifestations include acute lung injury, acute kidney injury and uncommonly, coma. Multiorgan failure and shock are described but further studies are needed to investigate the role of bacterial and other co-infections in these syndromes. In pregnancy, P. vivax infection can cause maternal anaemia, miscarriage, low birth weight and congenital malaria. Compared to P. falciparum, P. vivax has a greater capacity to elicit an inflammatory response, resulting in a lower pyrogenic threshold. Conversely, cytoadherence of P. vivax to endothelial cells is less frequent and parasite sequestration is not thought to be a significant cause of severe illness in vivax malaria. With a predilection for young red cells, P. vivax does not result in the high parasite biomass associated with severe disease in P. falciparum, but a four to fivefold greater removal of uninfected red cells from the circulation relative to P. falciparum is associated with a similar risk of severe anaemia. Mechanisms underlying the pathogenesis of severe vivax syndromes remain incompletely understood.

Baird KJ, Maguire JD, Price RN. 2012. Diagnosis and treatment of Plasmodium vivax malaria. Adv Parasitol, 80 pp. 203-270. | Citations: 37 (Scopus) | Show Abstract | Read more

Infection by Plasmodium vivax poses unique challenges for diagnosis and treatment. Relatively low numbers of parasites in peripheral circulation may be difficult to confirm, and patients infected by dormant liver stages cannot be diagnosed before activation and the ensuing relapse. Radical cure thus requires therapy aimed at both the blood stages of the parasite (blood schizontocidal) and prevention of subsequent relapses (hypnozoitocidal). Chloroquine and primaquine have been the companion therapies of choice for the treatment of vivax malaria since the 1950s. Confirmed resistance to chloroquine occurs in much of the vivax endemic world and demands the investigation of alternative blood schizontocidal companions in radical cure. Such a shift in practice necessitates investigation of the safety and efficacy of primaquine when administered with those therapies, and the toxicity profile of such combination treatments, particularly in patients with glucose-6-phosphate dehydrogenase deficiency. These clinical studies are confounded by the frequency and timing of relapse among strains of P. vivax, and potentially by differing susceptibilities to primaquine. The inability to maintain this parasite in continuous in vitro culture greatly hinders new drug discovery. Development of safe and effective chemotherapies for vivax malaria for the coming decades requires overcoming these challenges.

White NJ, Imwong M. 2012. Relapse. Adv Parasitol, 80 pp. 113-150. | Citations: 48 (Web of Science Lite) | Show Abstract | Read more

Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. P. vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites), which can be prevented currently only by 8-aminoquinoline anti-malarials. Tropical P. vivax infections relapse at approximately 3-week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics, P. vivax infections are characterized by either a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria therapeutic assessment, control, and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between P. vivax relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas, a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

Paris DH, Chansamouth V, Nawtaisong P, Löwenberg EC, Phetsouvanh R, Blacksell SD, Lee SJ, Dondorp AM, van der Poll T, Newton PN et al. 2012. Coagulation and inflammation in scrub typhus and murine typhus-a prospective comparative study from Laos Clinical Microbiology and Infection, 18 (12), pp. 1221-1228. | Citations: 14 (Scopus) | Show Abstract | Read more

Scrub typhus (caused by Orientia tsutsugamushi) and murine typhus (caused by Rickettsia typhi) cause up to 28% of febrile episodes in Thailand and Laos. The current understanding of coagulation and inflammation in the pathogenesis of these clinically very similar vasculotropic diseases is limited. This study compared human in vivo changes in 15 coagulation, inflammation and endothelial activation markers in prospectively collected admission and follow-up samples of 121 patients (55 scrub typhus, 55 murine typhus, and 11 typhus-like illness) and 51 healthy controls from Laos. As compared with controls, all but one of the markers assessed were significantly affected in typhus patients; however, the activation patterns differed significantly between scrub and murine typhus patients. The levels of markers of coagulation activation and all inflammatory cytokines, except for interleukin-12, were significantly higher in patients with scrub typhus than in those with murine typhus. In patients with murine typhus, however, the levels of endothelium-derived markers were significantly higher. Anticoagulant factors were inhibited in both typhus patient groups. This is the first study demonstrating that, in scrub typhus, in vivo coagulation activation is prominent and is related to a strong proinflammatory response, whereas in murine typhus, changes in coagulant and fibrinolytic pathways are suggestive of endothelial cell perturbation. These data suggest that, although late-stage endothelial infection is common in both diseases, the in vivo pathogenic mechanisms of R. typhi and O. tsutsugamushi could differ in the early phase of infection and may contribute to disease differentiation. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

McGready R, Nosten F. 2012. Proxies and prevention of malaria in pregnancy. Lancet Infect Dis, 12 (12), pp. 902-903. | Citations: 2 (Web of Science Lite) | Read more

Attaran A, Barry D, Basheer S, Bate R, Benton D, Chauvin J, Garrett L, Kickbusch I, Kohler JC, Midha K et al. 2012. How to achieve international action on falsified and substandard medicines. BMJ, 345 (nov13 22), pp. e7381. | Citations: 70 (Scopus) | Read more

Russell B, Suwanarusk R, Malleret B, Costa FTM, Snounou G, Kevin Baird J, Nosten F, Rénia L. 2012. Human ex vivo studies on asexual Plasmodium vivax: The best way forward International Journal for Parasitology, 42 (12), pp. 1063-1070. | Citations: 20 (Scopus) | Show Abstract | Read more

The lack of a continuous culture method for Plasmodium vivax has given the impression that investigations on this important species are severely curtailed. However, the use of new or improved ex vivo methods and tools to study fresh and thawed isolates from vivax malaria patients is currently providing useful data on P. vivax, such as sensitivity to antimalarial drugs, invasion mechanisms and pathobiology. This review discusses a practical framework for conducting ex vivo studies on the asexual erythrocytic stages of P. vivax and considers the synergies between ex vivo defined phenotypes, ex vivo derived 'omic' studies and in vivo clinical studies. © 2012 Australian Society for Parasitology Inc.

Gertsch JH, Corbett B, Holck PS, Mulcahy A, Watts M, Stillwagon NT, Casto AM, Abramson CH, Vaughan CPA, MacGuire C et al. 2012. Altitude sickness in climbers and efficacy of NSAIDs trial (ASCENT): Randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness Wilderness and Environmental Medicine, 23 (4), pp. 307-315. | Citations: 25 (Scopus) | Show Abstract | Read more

Objective: To study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). Methods: Double-blind, randomized, placebo-controlled trial. Results: Two hundred ninety-four healthy Western trekkers were recruited on the Everest approach at 4280 m or 4358 m and randomly assigned to receive either 600 mg of ibuprofen or placebo 3 times daily before and during ascent to 4928 m. One hundred eighty-three of 294 participants completed the trial. Of the participants who did not complete the trial, 62 were lost to follow-up and another 49 broke trial protocol. In an intent-to-treat analysis (232 participants), ibuprofen was found to be more effective than placebo in reducing the incidence of AMS (24.4% vs 40.4%; P =.01) and the incidence of HAH (42.3% vs 60.5%; P < .01). Ibuprofen was also superior to placebo in reducing the severity of HAH (4.9% vs 14.7%; P =.01). The end point of oxygen saturation was also higher in the ibuprofen group (80.8 % vs 82.4%; P =.035). For the 183 participants who completed the trial and conformed to the protocol, the incidence of AMS between placebo and treatment groups was not significant (32.9% vs 22.7%; P =.129 for AMS incidence, 9.6% vs 8.2%; P =.74 for AMS severity, 54.8% vs 42.7%; P =.11 for HAH incidence, and 8.2% vs 3.6%; P =.18 for HAH severity). Conclusions: Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial. This loss of significance in the subjects who completed the trial may be explained by persons in the placebo group having a higher burden of illness and associated decreased compliance with the protocol. An important limitation of this study may be the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS. © 2012 Wilderness Medical Society.

Baird JK. 2012. Primaquine toxicity forestalls effective therapeutic management of the endemic malarias International Journal for Parasitology, 42 (12), pp. 1049-1054. | Citations: 15 (Scopus) | Show Abstract | Read more

Treatment of acutely ill patients, informed by a diagnosis of the species of Plasmodium involved, has long dominated strategic thinking in malaria chemotherapeutics. This bias for both acute illness and access to diagnosis resulted in therapeutic strategies poorly suited to malaria as it occurs in endemic zones. Most of those malarias do not provoke illness and occur beyond diagnostic reach for technical or practical reasons. Therapies effective against all species and stages would likely prove more practical in endemic zones, especially if safely administered without laboratory screening for contraindications. The primary impediment to such therapies is the mild to severe hemolytic toxicity of primaquine in patients with glucose-6-phosphate dehydrogenase deficiency. Primaquine is the only treatment licensed for therapy against relapse caused by dormant liver stages occurring in some species, and against the sexual blood stages responsible for transmission to mosquitoes in all species. Despite being licensed over 50. years ago, no alternative drugs have been developed, and safer dosing regimens of primaquine have not been explored. These failures forestalled the emergence of therapies practical for use in endemic zones, especially in the context of eliminating transmission. © 2012 Australian Society for Parasitology Inc.

Walson J, Singa B, Sangaré L, Naulikha J, Piper B, Richardson B, Otieno PA, Mbogo LW, Berkley JA, John-Stewart G. 2012. Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): a multi-site, randomised trial. Lancet Infect Dis, 12 (12), pp. 925-932. | Citations: 22 (Scopus) | Show Abstract | Read more

BACKGROUND: Co-infection with HIV and helminths is common in sub-Saharan Africa and findings from previous studies have suggested that anthelmintic treatment might delay immunosuppression in people with HIV. We aimed to assess the efficacy of empiric deworming of adults with HIV in delaying HIV disease progression. METHODS: In this non-blinded randomised trial, we enrolled adults (aged ≥18 years) with HIV who did not meet criteria for the initiation of antiretroviral treatment from three sites in Kenya. Using a computer-generated sequence, we randomly assigned (1:1) eligible participants to either empiric albendazole every 3 months plus praziquantel annually (treatment group) or to standard care (control group). Participants were followed up for 24 months. We measured CD4 cell counts every 6 months and plasma HIV RNA annually. The primary endpoints were a CD4 count of less than 350 cells per μL and a composite endpoint consisting of the first occurrence of a CD4 count of less than 350 cells per μL, first reported use of antiretroviral treatment, and non-traumatic deaths. We compared these measures by use of Cox proportional hazards regression and Kaplan-Meier survival analyses. Primary analysis was done by intention to treat. The trial was registered with ClinicalTrials.gov, number NCT0050722. FINDINGS: Between Feb 6, 2008, and June 21, 2011, we enrolled and followed-up 948 participants; 469 were allocated to the treatment group and 479 to the control group. All participants were provided with co-trimoxazole prophylaxis. Median baseline CD4 cell counts and HIV RNA concentrations did not differ between groups. We recorded no statistically significant difference between the treatment and control groups in the number of people reaching a CD4 count of fewer than 350 cells per μL (41·6 events per 100 person-years vs 46·2 events per 100 person-years; hazard ratio 0·89, 95% CI 0·75-1·06, p=0·2) or the composite endpoint (44·0 events per 100 person-years vs 49·8 events per 100 person-years; 0·88, 0·74-1·04, p=0·1). Serious adverse events, none of which thought to be treatment-related, occurred at a similar frequency in both groups. INTERPRETATION: Our findings do not suggest an effect of empiric deworming in the delaying of HIV disease progression in adults with HIV in an area where helminth infection is common. Alternative approaches are needed to delay HIV disease progression in areas where co-infections are common.

Fischer J, Butt C, Dawes H, Foster C, Neale J, Plugge E, Wheeler C, Wright N. 2012. Fitness levels and physical activity among class A drug users entering prison British Journal of Sports Medicine, 46 (16), pp. 1142-1144. | Citations: 4 (Scopus) | Show Abstract | Read more

Physical activity could benefit drug users' physiological and mental health. Previous research has suggested that physical activity levels change when drug users enter prison. Methods Twenty-five class A drug users who were new to prison answered physical activity and drug use cross-sectional questionnaires, took a submaximal fitness test and wore a pedometer for 1 week. Results Participants' mean aerobic capacity was estimated as 49 mls O 2 /kg/min (±12 SD). Their mean selfreported walking distance outside of prison was 4.67 miles on an average day (±4.14 SD). Pedometer data suggest they walked a mean of 1.8 miles/day in prison. Conclusion Many class A drug users entering prison had high levels of fitness and physical activity before admission, often gained from walking. Walking activity reduced when they entered prison, posing a challenge to maintaining healthy activity levels.

Zurovac D, Larson BA, Sudoi RK, Snow RW. 2012. Costs and cost-effectiveness of a mobile phone text-message reminder programmes to improve health workers' adherence to malaria guidelines in Kenya. PLoS One, 7 (12), pp. e52045. | Citations: 31 (Scopus) | Show Abstract | Read more

BACKGROUND: Simple interventions for improving health workers' adherence to malaria case-management guidelines are urgently required across Africa. A recent trial in Kenya showed that text-message reminders sent to health workers' mobile phones improved management of pediatric outpatients by 25 percentage points. In this paper we examine costs and cost-effectiveness of this intervention. METHODS/FINDINGS: We evaluate costs and cost-effectiveness in 2010 USD under three implementation scenarios: (1) as implemented under study conditions in study areas; (2) if the intervention was routinely implemented by the Ministry of Health (MoH) in the same areas; and (3) if the intervention was scaled up nationally. Under study conditions, intervention costs were 19,342 USD, of which 45% were for developing and pretesting text-messages, 12% for developing text-message distribution system, 29% for collecting health workers' phone numbers, and 13% were costs of sending text-messages and monitoring of the system. If the intervention was implemented in the same areas by the MoH, the costs would be 28% lower (13,920 USD) due to lower costs of collecting health workers' numbers. The cost of national scale-up would be 97,350 USD, and the majority of these costs (66%) would be for sending text-messages. The cost per additional child correctly managed was 0.50 USD under study conditions, 0.36 USD if implemented by the MoH in the same area, and estimated at only 0.03 USD if implemented nationally. Even if the effect size was only 5% or the cost on the national scale was 400% higher than estimated, the cost per additional child correctly managed would be only 0.16 USD. CONCLUSIONS: A simple text-messaging intervention improving health worker adherence to malaria guidelines is effective and inexpensive. Further research is justified to optimize delivery of the intervention and expand targets beyond children and malaria disease.

Ibison F, Olotu A, Muema DM, Mwacharo J, Ohuma E, Kimani D, Marsh K, Bejon P, Ndungu FM. 2012. Lack of avidity maturation of merozoite antigen-specific antibodies with increasing exposure to Plasmodium falciparum amongst children and adults exposed to endemic malaria in Kenya. PLoS One, 7 (12), pp. e52939. | Citations: 10 (Scopus) | Show Abstract | Read more

BACKGROUND: Although antibodies are critical for immunity to malaria, their functional attributes that determine protection remain unclear. We tested for associations between antibody avidities to Plasmodium falciparum (Pf) antigens and age, asymptomatic parasitaemia, malaria exposure index (a distance weighted local malaria prevalence) and immunity to febrile malaria during 10-months of prospective follow up. METHODS: Cross-sectional antibody levels and avidities to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1(42) (MSP1) and Merozoite Surface Protein 3 (MSP3) were measured by Enzyme Linked Immunosorbent Assay in 275 children, who had experienced at least one episode of clinical malaria by the time of this study, as determined by active weekly surveillance. RESULTS: Antibody levels to AMA1, MSP1 and MSP3 increased with age. Anti-AMA1 and MSP1 antibody avidities were (respectively) positively and negatively associated with age, while anti-MSP3 antibody avidities did not change. Antibody levels to all three antigens were elevated in the presence of asymptomatic parasitaemia, but their associated avidities were not. Unlike antibody levels, antibody avidities to the three-merozoite antigens did not increase with exposure to Pf malaria. There were no consistent prospective associations between antibody avidities and malaria episodes. CONCLUSION: We found no evidence that antibody avidities to Pf-merozoite antigens are associated with either exposure or immunity to malaria.

Ndungu FM, Mwacharo J, Kimani D, Kai O, Moris P, Jongert E, Vekemans J, Olotu A, Bejon P. 2012. A statistical interaction between circumsporozoite protein-specific T cell and antibody responses and risk of clinical malaria episodes following vaccination with RTS,S/AS01E. PLoS One, 7 (12), pp. e52870. | Citations: 29 (Scopus) | Show Abstract | Read more

The candidate malaria vaccine RTS,S/AS01(E) provides significant but partial protection from clinical malaria. On in vitro circumsporozoite protein (CSP) peptide stimulation and intra-cellular cytokine staining of whole blood taken from 407 5-17 month-old children in a phase IIb trial of RTS,S/AS01(E), we identified significantly increased frequencies of two CSP-specific CD4+ T cells phenotypes among RTS,S/AS01(E) vaccinees (IFNγ-IL2+TNF- and IFNγ-IL2+TNF+ CD4+ T cells), and increased frequency of IFNγ-IL2-TNF+ CD4+ T cells after natural exposure. All these T cells phenotypes were individually associated with reductions in the risk of clinical malaria, but IFNγ-IL2-TNF+ CD4+ T cells independently predicted reduced risk of clinical malaria on multi-variable analysis (HR = 0.29, 95% confidence intervals 0.15-0.54, p<0.0005). Furthermore, there was a strongly significant synergistic interaction between CSP-specific IFNγ-IL2-TNF+ CD4+ T cells and anti-CSP antibodies in determining protection against clinical malaria (p = 0.002). Vaccination strategies that combine potent cellular and antibody responses may enhance protection against malaria.

Rattanavong S, Vongthongchit S, Bounphamala K, Vongphakdy P, Gubler J, Mayxay M, Phetsouvanh R, Elliott I, Logan J, Hill R et al. 2012. Actinomycetoma in SE Asia: the first case from Laos and a review of the literature. BMC Infect Dis, 12 (1), pp. 349. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Mycetoma is a chronic, localized, slowly progressing infection of the cutaneous and subcutaneous tissues caused either by fungi (eumycetoma or implantation mycosis) or by aerobic actinomycetes (actinomycetoma). It is acquired by traumatic implantation, most commonly in the tropics and subtropics, especially in rural agricultural communities. Although well recognized elsewhere in Asia, it has not been reported from the Lao People's Democratic Republic (Laos). CASE PRESENTATION: A 30 year-old female elementary school teacher and rice farmer from northeast Laos was admitted to Mahosot Hospital, Vientiane, with a massive growth on her left foot, without a history of trauma. The swelling had progressed slowly but painlessly over 5 years and multiple draining sinuses had developed. Ten days before admission the foot had increased considerably in size and became very painful, with multiple sinuses and discharge, preventing her from walking. Gram stain and bacterial culture of tissue biopsies revealed a branching filamentous Gram-positive bacterium that was subsequently identified as Actinomadura madurae by 16S rRNA gene amplification and sequencing. She was treated with long-term co-trimoxazole and multiple 3-week cycles of amikacin with a good therapeutic response. CONCLUSION: We report the first patient with actinomycetoma from Laos. The disease should be considered in the differential diagnosis of chronic skin and bone infections in patients from rural SE Asia.

White NJ, Qiao LG, Qi G, Luzzatto L. 2012. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common. Malar J, 11 (1), pp. 418. | Citations: 64 (Scopus) | Show Abstract | Read more

In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission. Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective. This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated.

Fuller C, Michie S, Savage J, McAteer J, Besser S, Charlett A, Hayward A, Cookson BD, Cooper BS, Duckworth G et al. 2012. The Feedback Intervention Trial (FIT)--improving hand-hygiene compliance in UK healthcare workers: a stepped wedge cluster randomised controlled trial. PLoS One, 7 (10), pp. e41617. | Citations: 55 (Scopus) | Show Abstract | Read more

INTRODUCTION: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness. METHODS: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation. PRIMARY OUTCOME: direct blinded hand hygiene compliance (%). RESULTS: All 16 trusts (60 wards) randomised, 33 wards implemented