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The relationship between community prevalence of Plasmodium falciparum and the burden of severe, life-threatening disease remains poorly defined. To examine the three most common severe malaria phenotypes from catchment populations across East Africa, we assembled a dataset of 6506 hospital admissions for malaria in children aged 3 months to 9 years from 2006 to 2020. Admissions were paired with data from community parasite infection surveys. A Bayesian procedure was used to calibrate uncertainties in exposure (parasite prevalence) and outcomes (severe malaria phenotypes). Each 25% increase in prevalence conferred a doubling of severe malaria admission rates. Severe malaria remains a burden predominantly among young children (3 to 59 months) across a wide range of community prevalence typical of East Africa. This study offers a quantitative framework for linking malaria parasite prevalence and severe disease outcomes in children.

Background Pneumonia is among the leading causes of avoidable deaths for young children globally. The main burden of mortality falls on children from poor and rural families who are less likely to obtain the treatment they need, highlighting inequities in access to effective care and treatment. Caretakers’ illness perceptions and care-seeking practices are of major importance for children with pneumonia to receive adequate care. This study qualitatively explores the caretaker concepts of childhood pneumonia in relation to treatment seeking behaviour and health worker management in Moshi urban district, Tanzania. Methods In May - July 2013 data was gathered through different qualitative data collection techniques including five focus group discussions (FGDs) with mothers of children under-five years of age. The FGDs involved free listing of pneumonia symptoms and video presentations of children with respiratory symptoms done, these were triangulated with ten case narratives with mothers of children admitted with pneumonia and eleven in-depth interviews with hospital health workers. Transcripts were coded and analysed using qualitative content analysis. Results Mothers demonstrated good awareness of common childhood illnesses including pneumonia, which was often associated with symptoms such as cough, flu, chest tightness, fever, and difficulty in breathing. Mothers had mixed views on causative factors and treatments options but generally preferred modern medicine for persisting and severe symptoms. However, all respondent reported access to health facilities as a barrier to care, associated with transport, personal safety and economic constraints. Conclusion Local illness concepts and traditional treatment options did not constitute barriers to care for pneumonia symptoms. Poor access to health facilities was the main barrier. Decentralisation of care through community health workers may improve access to care but needs to be combined with strengthened referral systems and accessible hospital care for those in need.

Background The availability of reliable point-of-care tests for malaria has heralded a paradigm shift in the management of febrile illnesses away from presumptive antimalarial therapy. In the absence of a definitive diagnosis, health care providers are more likely to prescribe empirical antimicrobials to those who test negative for malaria. To improve management and guide further test development, better understanding is needed of the true causative agents and their geographic variability. Methods A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in Africa (1980–2015). Literature searches were conducted in English and French languages in six databases: MEDLINE, EMBASE, Global Health (CABI), WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A number of published articles (rather than incidence or prevalence) reporting a given pathogen were presented. Results A total of 16,523 records from 48 African countries were screened, of which 1065 (6.4%) met selection criteria. Bacterial infections were reported in 564 (53.0%) records, viral infections in 374 (35.1%), parasitic infections in 47 (4.4%), fungal infections in nine (0.8%), and 71 (6.7%) publications reported more than one pathogen group. Age range of the study population was not specified in 233 (21.9%) publications. Staphylococcus aureus (18.2%), non-typhoidal Salmonella (17.3%), and Escherichia coli (15.4%) were the commonly reported bacterial infections whereas Rift Valley fever virus (7.4%), yellow fever virus (7.0%), and Ebola virus (6.7%) were the most commonly reported viral infections. Dengue virus infection, previously not thought to be widespread in Africa, was reported in 54 (5.1%) of articles. Conclusions This review summarises the published reports of non-malaria pathogens that may cause febrile illness in Africa. As the threat of antimicrobial resistance looms, knowledge of the distribution of infectious agents causing fever should facilitate priority setting in the development of new diagnostic tools and improved antimicrobial stewardship. Trial registration PROSPERO, CRD42016049281

We conducted a genome-wide association study of host resistance to severePlasmodium falciparummalaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association inATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h2~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.

Objective In sub-Saharan Africa, the use of malaria rapid diagnostic tests (mRDT) has raised awareness of alternative fever causes in children but few studies have included adults. To address this gap, we conducted a study of mRDT-negative fever aetiologies among children and adults in Tanzania. Methods A total of 1028 patients aged 3 months to 50 years with a febrile illness and negative mRDT were enrolled from a Tanzanian hospital outpatient department. All had a physical examination and cultures from blood, nasopharynx/throat and urine. Patients were followed on Days 7 and 14 and children meeting WHO criteria for pneumonia were followed on Day 2 with chest radiology. Results Respiratory symptoms were the most frequent presenting complaint, reported by 20.3% of adults and 64.0% (339/530) of children. Of 38 X-rayed children meeting WHO pneumonia criteria, 47.4% had a normal X-ray. Overall, only 1.3% of 1028 blood cultures were positive. Salmonella typhi was the most prevalent pathogen isolated (7/13, 53.8%) and S. typhi patients reported fever for a median of 7 days (range 2–14). Children with bacteraemia did not present with WHO symptoms requiring antibiotic treatment. Young children and adults had similar prevalences of positive urine cultures (24/428 and 29/498, respectively). Conclusion Few outpatient fevers are caused by blood stream bacterial infection, and most adult bacteraemia would be identified by current clinical guidelines although paediatric bacteraemia may be more difficult to diagnose. While pneumonia may be overdiagnosed, urinary tract infection was relatively common. Our results emphasise the difficulty in identifying African children in need of antibiotics among the majority who do not.

The roles that rapid, point-of-care tests will play in healthcare in low-income settings are likely to expand over the coming years. Yet, very little is known about how they are incorporated into practice, and what it means to use and rely upon them. This paper focuses on the rapid diagnostic test for malaria (mRDT), examining its introduction into low-level public health facilities in Tanzania within an intervention to improve the targeting of costly malaria medication. We interviewed 26 health workers to explore how a participatory training programme, mobile phone messages, posters and leaflets shaped the use and interpretation of the test. Drawing on notions of biopolitics, this paper examines how technologies of the self and mechanisms of surveillance bolstered the role mRDT in clinical decision-making. It shows how the significance of the test interacted with local knowledge, the availability of other medication, and local understandings of good clinical practice. Our findings suggest that in a context in which care is reduced to the provision of medicines, strict adherence to mRDT results may be underpinned by increasing the use of other pharmaceuticals or may leave health workers with patients for whom they are unable to provide care.

The replacement of “presumptive treatment for malaria” by “test before treat” strategies for the management of febrile illness is raising awareness of the importance of knowing more about the causes of illness in children who are suspected to have malaria but return a negative parasitological test. The most common cause of non-malarial febrile illness (NMFI) in African children is respiratory tract infection. Whilst the bacterial causes of NMFI are well known, the increasing use of sensitive techniques such as polymerase chain reaction (PCR) tests is revealing large numbers of viruses that are potential respiratory pathogens. However, many of these organisms are commonly present in the respiratory tract of healthy children so causality and risk factors for pneumonia remain poorly understood. Infection with a combination of viral and bacterial pathogens is increasingly recognised as important in the pathogenesis of pneumonia. Similarly, blood stream infections with organisms typically grown by aerobic culture are well known but a growing number of organisms that can be identified only by PCR, viral culture, or serology are now recognised to be common pathogens in African children. The high mortality of hospitalised children on the first or second day of admission suggests that, unless results are rapidly available, diagnostic tests to identify specific causes of illness will still be of limited use in guiding the potentially life saving decisions relating to initial treatment of children admitted to district hospitals in Africa with severe febrile illness and a negative test for malaria. Malaria control and the introduction of vaccines against Haemophilus influenzae type b and pneumococcal disease are contributing to improved child survival in Africa. However, increased parasitological testing for malaria is associated with increased use of antibiotics to which resistance is already high.

Summary Objective Cough or difficult breathing and an increased respiratory rate for their age are the commonest indications for outpatient antibiotic treatment in African children. We aimed to determine whether respiratory rate was likely to be transiently raised by a number of contextual factors in a busy clinic leading to inaccurate diagnosis. Methods Respiratory rates were recorded in children aged 2–59 months presenting with cough or difficulty breathing to one of the two busy outpatient clinics and then repeated at 10‐min intervals over 1 h in a quiet setting. Results One hundred and sixty‐seven children were enrolled with a mean age of 7.1 (SD ± 2.9) months in infants and 27.6 (SD ± 12.8) months in children aged 12–59 months. The mean respiratory rate declined from 42.3 and 33.6 breaths per minute (bpm) in the clinic to 39.1 and 32.6 bpm after 10 min in a quiet room and to 39.2 and 30.7 bpm (P

Significant selection pressure has been exerted on the genomes of human populations exposed to Plasmodium falciparum infection, resulting in the acquisition of mechanisms of resistance against severe malarial disease. Many host genetic factors, including sickle cell trait, have been associated with reduced risk of developing severe malaria, but do not account for all of the observed phenotypic variation. Identification of novel inherited risk factors relies upon high-resolution genome-wide association studies (GWAS). We present findings of a GWAS of severe malaria performed in a Tanzanian population (n = 914, 15.2 million SNPs). Beyond the expected association with the sickle cell HbS variant, we identify protective associations within two interleukin receptors (IL-23R and IL-12RBR2) and the kelch-like protein KLHL3 (all P0.3). Our approach demonstrates the potential of a joint genotyping-sequencing strategy to identify as-yet unknown susceptibility loci in an African population with well-characterised malaria phenotypes. The regions encompassing these loci are potential targets for the design of much needed interventions for preventing or treating malarial disease., Author summary Malaria, caused by Plasmodium falciparum parasites, is a major cause of mortality and morbidity in endemic countries of sub-Saharan Africa, including Tanzania. Some gene mutations in the human genome, including sickle cell trait, have been associated with reduced risk of developing severe malaria, and have increased in frequency through natural selection over generations. However, new genetic mutations remain to be discovered, and recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine-scale molecular genotyping tools, are facilitating their identification. Here, we present findings of a GWAS of severe malaria performed in a well characterised Tanzanian population (n = 914). We confirm the expected association with the sickle cell trait, but also identify new gene targets in immunological pathways, some under natural selection. Our approach demonstrates the potential of using GWAS to identify as-yet unknown susceptibility genes in endemic populations with well-characterised malaria phenotypes. The genetic mutations are likely to form potential targets for the design of much needed interventions for preventing or treating malarial disease.

Objectives\ud To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia. \ud Design\ud Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study).\ud Setting\ud Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda.\ud Participants\ud 522 480 children and adults with acute febrile illness.\ud Interventions\ud Rapid diagnostic tests for malaria.\ud Main outcome measures\ud Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings.\ud Results\ud Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole.Conclusions Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription.This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined. [Abstract copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.]

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

Objective To assess the role of point‐of‐care (PoC) assessment of C‐reactive protein (CRP) and white blood cell (WBC) count to identify bacterial illness in Tanzanian children with non‐severe non‐malarial fever. Methods From the outpatient department of a district hospital in Tanzania, 428 patients between 3 months and 5 years of age who presented with fever and a negative malaria test were enrolled. All had a physical examination and bacterial cultures from blood and urine. Haemoglobin, CRP and WBC were measured by PoC devices. Results Positive blood cultures were detected in 6/428 (1.4%) children and urine cultures were positive in 24/401 (6.0%). Mean WBC was similar in children with or without bacterial illness (14.0 × 109, 95% CI 12.0–16.0 × 109 vs. 12.0 × 109, 95% CI 11.4–12.7 × 109), while mean CRP was higher in children with bacterial illness (41.0 mg/l, 95% CI 28.3–53.6 vs. 23.8 mg/l, 95% CI 17.8–27.8). In ROC analysis, the optimum cut‐off value for CRP to identify bacterial illness was 19 mg/l but with an area under the curve of only 0.62. Negative predictive values exceeded 80%, while positive predictive values were under 40%. Conclusion WBC and CRP levels had limited value in identifying children with bacterial infections. The positive predictive values for both tests were too low to be used as single tools for treatment decisions.

Objective Measurement of respiratory rate is an important clinical sign in the diagnosis of pneumonia but suffers from interobserver variation. Here, we assess the use of video recordings as a quality assurance tool that could be useful both in research and in training of staff. Methods Respiratory rates (RR) were recorded in children aged 2–59 months presenting with cough or difficulty breathing at two busy outpatient clinics in Tanzania. Measurements were repeated at 10‐min intervals in a quiet environment with simultaneous video recordings that were independently reviewed by two paediatricians. Results Eight hundred and fifty‐nine videos were sent to two paediatricians; 148 (17.2%) were considered unreadable by one or both. For the 711 (82.8%) videos that were readable by both paediatricians, there was perfect agreement for the presence of raised RR with a kappa value (κ) of 0.85 (P < 0.001); and in 476 (66.9%) cases, both paediatricians agreed on the RR within 2 breaths per minute (±2 bpm). A reported illness of 5 days or more was associated with unreadable video recordings (OR = 3.44, CI: 1.5–6.08; P < 0.001). The multilevel model showed that differences between observers accounted for only 13% of the variability in RR. Conclusion Video recordings are reliable tools for quality assurance of RR measurements in children with suspected pneumonia. Videos with a clear view of respiratory movements may also be useful in training primary healthcare staff.

INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells. In the case of Plasmodium falciparum , this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa. This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system. In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors. RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa. To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus. RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region. In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity. By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association. In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria. To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure. The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA. Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant. CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive. Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus. Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria. This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease.

Background. The epidemiology of Salmonella Typhi and invasive nontyphoidal Salmonella (NTS) differs, and prevalence of these pathogens among children in sub-Saharan Africa may vary in relation to malaria transmission intensity. Methods. We compared the prevalence of bacteremia among febrile pediatric inpatients aged 2 months to 13 years recruited at sites of high and low malaria endemicity in Tanzania. Enrollment at Teule Hospital, the high malaria transmission site, was from June 2006 through May 2007, and at Kilimanjaro Christian Medical Centre (KCMC), the low malaria transmission site, from September 2007 through August 2008. Automated blood culture, malaria microscopy with Giemsa-stained blood films, and human immunodeficiency virus testing were performed. Results. At Teule, 3639 children were enrolled compared to 467 at KCMC. Smear-positive malaria was detected in 2195 of 3639 (60.3%) children at Teule and 11 of 460 (2.4%) at KCMC (P < .001). Bacteremia was present in 336 of 3639 (9.2%) children at Teule and 20 of 463 (4.3%) at KCMC (P < .001). NTS was isolated in 162 of 3639 (4.5%) children at Teule and 1 of 463 (0.2%) at KCMC (P < .001). Salmonella Typhi was isolated from 11 (0.3%) children at Teule and 6 (1.3%) at KCMC (P = .008). With NTS excluded, the prevalence of bacteremia at Teule was 5.0% and at KCMC 4.1% (P = .391). Conclusions. Where malaria transmission was intense, invasive NTS was common and Salmonella Typhi was uncommon, whereas the inverse was observed at a low malaria transmission site. The relationship between these pathogens, the environment, and the host is a compelling area for further research.

Parenteral artesunate (ARS) is the drug of choice for the treatment of severe malaria. Pharmacokinetics data on intramuscular ARS are limited with respect to the main treatment group that carries the highest mortality, namely, critically ill children with severe malaria. A population pharmacokinetic study of ARS and dihydroartemisinin (DHA) was conducted from sparse sampling in 70 Tanzanian children of ages 6 months to 11 years. All the children had been admitted with severe falciparum malaria and were treated with intramuscular ARS (2.4 mg/kg at 0, 12, and 24 h). Venous plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling (NONMEM). A one-compartment disposition model accurately described first-dose population pharmacokinetics of ARS and DHA. Body weight significantly affected clearance and apparent volume of distribution (P < 0.001), resulting in lower ARS and DHA exposure levels in smaller children. An adapted dosing regimen including a practical dosing table per weight band is proposed for young children based on the pharmacokinetic model. © 2013 American Society for Clinical Pharmacology and Therapeutics.

Bats carry a variety of paramyxoviruses that impact human and domestic animal health when spillover occurs. Recent studies have shown a great diversity of paramyxoviruses in an urban-roosting population of straw-colored fruit bats in Ghana. Here, we investigate this further through virus isolation and describe two novel rubulaviruses: Achimota virus 1 (AchPV1) and Achimota virus 2 (AchPV2). The viruses form a phylogenetic cluster with each other and other bat-derived rubulaviruses, such as Tuhoko viruses, Menangle virus, and Tioman virus. We developed AchPV1- and AchPV2-specific serological assays and found evidence of infection with both viruses in Eidolon helvum across sub-Saharan Africa and on islands in the Gulf of Guinea. Longitudinal sampling of E. helvum indicates virus persistence within fruit bat populations and suggests spread of AchPVs via horizontal transmission. We also detected possible serological evidence of human infection with AchPV2 in Ghana and Tanzania. It is likely that clinically significant zoonotic spillover of chiropteran paramyxoviruses could be missed throughout much of Africa where health surveillance and diagnostics are poor and comorbidities, such as infection with HIV or Plasmodium sp., are common.

The WHO recommendation for parasitological diagnosis of malaria wherever possible is challenged by evidence of poor-quality microscopy in African hospitals but the reasons are not clear.All 12 of the busier district hospital laboratories from three regions of Tanzania were assessed for quality of the working environment and slide readers read 10 reference slides under exam conditions. Slides that had been routinely read were removed for expert reading.Of 44 slide readers in the study, 39 (88.6%) correctly read90% of the reference slides. Of 206 slides that had been routinely read, 33 (16%) were judged to be unreadable, 104 (51%) were readable with difficulty, and 69 (34%) were easily readable. Compared to expert reading of the same slide, the sensitivity of routine slide results of easily readable slides was 85.7% (95% confidence interval: 77.4-94.0), falling to 44.4% (95% confidence interval: 34.5-54.4) for slides that were 'readable with difficulty'.The commonest cause of inaccurate results was the quality of the slide itself, correction of which is likely to be achievable within existing resources. A minority of slide readers were unable to read slides even under ideal conditions, suggesting the need for a 'slide reading licence' scheme.

Rigorous evidence of "what works" to improve health care is in demand, but methods for the development of interventions have not been scrutinized in the same ways as methods for evaluation. This article presents and examines intervention development processes of eight malaria health care interventions in East and West Africa. A case study approach was used to draw out experiences and insights from multidisciplinary teams who undertook to design and evaluate these studies. Four steps appeared necessary for intervention design: (1) definition of scope, with reference to evaluation possibilities; (2) research to inform design, including evidence and theory reviews and empirical formative research; (3) intervention design, including consideration and selection of approaches and development of activities and materials; and (4) refining and finalizing the intervention, incorporating piloting and pretesting. Alongside these steps, projects produced theories, explicitly or implicitly, about (1) intended pathways of change and (2) how their intervention would be implemented.The work required to design interventions that meet and contribute to current standards of evidence should not be underestimated. Furthermore, the process should be recognized not only as technical but as the result of micro and macro social, political, and economic contexts, which should be acknowledged and documented in order to infer generalizability. Reporting of interventions should go beyond descriptions of final intervention components or techniques to encompass the development process. The role that evaluation possibilities play in intervention design should be brought to the fore in debates over health care improvement.

This comparative study in 1898 children in 2 different African population shows that a pfHRP2-based rapid diagnostic test is a reliable diagnostic for diagnosing severe falciparum malaria in these settings and performs better than routine microscopy or a pLDH based test., Background. Rapid diagnostic tests (RDTs) now play an important role in the diagnosis of falciparum malaria in many countries where the disease is endemic. Although these tests have been extensively evaluated in uncomplicated falciparum malaria, reliable data on their performance for diagnosing potentially lethal severe malaria is lacking. Methods. We compared a Plasmodium falciparum histidine-rich-protein2 (PfHRP2)–based RDT and a Plasmodium lactate dehydrogenase (pLDH)–based RDT with routine microscopy of a peripheral blood slide and expert microscopy as a reference standard for the diagnosis of severe malaria in 1898 children who presented with severe febrile illness at 2 centers in Mozambique and Tanzania. Results. The overall sensitivity, specificity, positive predictive value, and negative predictive values of the PfHRP2-based test were 94.0%, 70.9%, 85.4%, and 86.8%, respectively, and for the pLDH-based test, the values were 88.0%, 88.3%, 93.2%, and 80.3%, respectively. At parasite counts

Background to the debate: Current guidelines recommend that all fever episodes in African children be treated presumptively with antimalarial drugs. But declining malarial transmission in parts of sub-Saharan Africa, declining proportions of fevers due to malaria, and the availability of rapid diagnostic tests mean it may be time for this policy to change. This debate examines whether enough evidence exists to support abandoning presumptive treatment and whether African health systems have the capacity to support a shift toward laboratory-confirmed rather than presumptive diagnosis and treatment of malaria in children under five., Blaise Genton and colleagues argue that we should abandon presumptive antimalarial treatment in children with fever in sub-Saharan Africa, while in a related paper Mike English and colleagues disagree that we have sufficient evidence and health system capacity to do so.

Four predictors were independently associated with an increased risk of death: acidosis, cerebral manifestations of malaria, elevated blood urea nitrogen, or signs of chronic illness. The standard base deficit was found to be the single most relevant predictor of death., 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 (

Background Hypertension is a major contributor to ill health in sub-Saharan Africa. Developing countries need to increase access for screening. This study assesses the feasibility and acceptability of using private sector drug retail outlets to screen for hypertension in Mwanza region, Tanzania. Methods A pilot study took place in eight drug retail outlets from August 2013 to February 2014. Customers ≥18 years were invited for screening. Socio-demographic characteristics, hypertension knowledge, hypertension screening and treatment history were collected. Subjects with systolic blood pressure over 140 mmHg were referred for follow up. Referral slips captured attendance. Mystery client visits and follow up phone calls were conducted to assess service quality. Results A total of 971 customers were screened, one person refused; 109 (11.2%) had blood pressure over 140/90 mmHg and were referred for ongoing assessment; 85/109 (78.0%) were newly diagnosed. Customers reported that the service was acceptable. Service providers were able to follow the protocol. Only 18/85 (21%) newly diagnosed participants visited the referral clinic within two weeks. Conclusions Blood pressure screening was feasible and acceptable to customers of private drug retail outlets. However many who were referred failed to attend at a referral centre and further research is needed in this area.

OBJECTIVE: To describe the contribution of paediatric HIV and of HIV co-infections to admissions to a hospital in Moshi Tanzania using contemporary laboratory methods. METHODS: During 1 year we enrolled consecutively admitted patients aged >/=2 months and

(See the editorial commentary by Levine and Farag, on pages 349-351.) Background. Few studies describe patterns of human immunodeficiency virus (HIV) co-infections in African hospitals in the antiretroviral therapy (ART) era. Methods. We enrolled consecutive admitted patients aged ≥13 years with oral temperature of ≥38.0°C during 1 year in Moshi, Tanzania. A standardized clinical history and physical examination was done and hospital outcome recorded. HIV antibody testing, aerobic and mycobacterial blood cultures, and malaria film were performed. HIV-infected patients also received serum cryptococcal antigen testing and CD4+ T lymphocyte count (CD4 cell count). Results. Of 403 patients enrolled, the median age was 38 years (range, 14–96 years), 217 (53.8%) were female, and 157 (39.0%) were HIV-infected. Of HIV-infected patients, the median CD4 cell count was 98 cells/μL (range, 1–1,105 cells/ μL), 20 (12.7%) were receiving ART, and 29 (18.5%) were receiving trimethoprim-sulfamethoxazole prophylaxis. There were 112 (27.7%) patients who had evidence of invasive disease, including 26 (23.2%) with Salmonella serotype Typhi infection, 24 (21.4%) with Streptococcus pneumoniae infection, 17 (15.2%) with Cryptococcus neoformans infection, 12 (10.7%) with Mycobacterium tuberculosis complex infection, 8 (7.1%) with Plasmodium falciparum infection, and 7 (6.3%) with Escherichia coli infection. HIV infection was associated with M. tuberculosis and C. neoformans bloodstream infection but not with E. coli, S. pneumoniae, or P. falciparum infection. HIV infection appeared to be protective against Salmonella. Typhi bloodstream infection (odds ratio, .12; P = .001). Conclusions. While Salmonella Typhi and S. pneumoniae were the most common causes of invasive infection overall, M. tuberculosis and C. neoformans were the leading causes of bloodstream infection among HIV-infected inpatients in Tanzania in the ART era. We demonstrate a protective effect of HIV against Salmonella. Typhi bloodstream infection in this setting. HIV co-infections continue to account for a large proportion of febrile admissions in Tanzania.

Participation rates in epidemiologic studies in African communities are historically high. We recently performed a pilot prevalence study for neurologic morbidity in Mungushi, Tanzania, where the participation rate was 645/657 subjects (98.2%).1 We questioned whether this high rate was due to a sincere motivation to participate or a fear of refusal of participation. As Western investigators are increasingly performing neuroepidemiologic work in Africa, it is imperative to distinguish between the 2 explanations. Investigators need to tailor the consent process to the local community's needs, and be sensitive to the motivation of the participants whose culture may differ from their own.

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Respiratory infections cause significant mortality in developing countries but are frequently undiagnosed. Reasons for this are unclear. We observed 1,081 outpatient consultations with patients less than five years of age in Tanzania. In 554 patients with cough or difficulty breathing, the absolute percentages examined were 5% for respiratory rate counted, 14% chest exposed, and 25% stethoscope used. Decisions to conduct particular examinations did appear to follow clinical logic, with odds ratios of 4.28 for counting respiratory rate (95% confidence interval [CI] = 1.75-10.47), 2.57 for exposing the chest (95% CI = 1.67-3.95), and 18.91 for using a stethoscope (95% CI = 9.52-37.57) in patients with cough or difficulty breathing. Non-clinical variables, including salary level, were also associated with examinations, and history taking was more common among clinicians originating outside the hospital area. Although respiratory examinations are relatively more common in those with cough or difficulty breathing, the absolute rates are low and related to non-clinical and clinical factors. Copyright © 2008 by The American Society of Tropical Medicine and Hygiene.

BACKGROUND AND OBJECTIVE Children are often admitted to district hospitals in Africa without an adequate record of clinical examination, a problem that could be reduced by greater involvement of nurses in their assessment. We aimed to ascertain whether hospital nurses in a district hospital could conduct paediatric examinations as reliably as clinical staff, when provided with a short structured training session. METHODS Hospital nurses (HN), hospital clinical officers (HCO) and research clinical officers (RCO) repeated examinations on children admitted to the paediatric ward shortly after the first examination by an RCO. Kappa scores were used to compare the agreement on the presence or absence of basic clinical signs by different categories of staff. RESULTS Among 439 paired examinations the agreement between RCOs on clinical signs was slightly higher than for HCOs or HNs; the mean (median) Kappa scores for all signs examined were 0.54 (0.57) for RCO-RCO, 0.49 (0.49) for RCO-HCO and 0.50 (0.49) for RCO-HN. Levels of agreement were lower if children were under the age of 18 months or if they cried during the examination. CONCLUSIONS Nurses with basic training appear to perform as well as clinically trained staff in eliciting essential signs in acutely ill children. Their role in the initial and ongoing assessment of these children should be reviewed in light of the critical shortages in clinically trained staff in African hospitals.

OBJECTIVE In Africa antimalarials are often prescribed when malaria is unlikely, a problem that is becoming critical as more expensive antimalarials replace established drugs. However, little is known about what drives the overuse of antimalarials. We conducted this study to explore to what extent current prescribing behaviour in hospitals is driven by patient demand. METHODS Consultations were observed followed by exit interviews with patients or caretakers. Five district hospitals where microscopy was routinely available were selected in areas of low (n = 3) and high (n = 2) malaria transmission in north-eastern Tanzania. All outpatient consultations during the study period were observed (n = 669). Those sent for a malaria blood slide or treated with antimalarials presumptively were interviewed (n = 326). At the end of the study, clinicians were interviewed for their opinions on the use of antimalarials. Findings Patients were not observed to demand antimalarials from clinicians, but occasionally asked for a malaria slide. Patient satisfaction on exit was similar between those prescribed antimalarials and those not prescribed antimalarials, but more patients or carers expressed satisfaction when the patient had been tested than when not. Clinicians rarely reported perceiving patient demand for antimalarials and asserted that such demand for medication would not affect their prescribing behaviour. CONCLUSIONS Patient demand was not found to be driving the over-prescription of antimalarials found in the hospitals in our setting. To the contrary, the involvement of patients may provide an opportunity to improve prescribing practice if their expectations for testing and treatment in line with test results can be effectively communicated to clinicians.

Salmonella enterica serovar Typhi expresses a capsule of Vi polysaccharide, while most Salmonella serovars, including S. Enteritidis and S. Typhimurium, do not. Both S. Typhi and S. Enteritidis express the lipopolysaccharide O:9 antigen, yet there is little evidence of cross-protection from anti-O:9 antibodies. Vaccines based on Vi polysaccharide have efficacy against typhoid fever, indicating that antibodies against Vi confer protection. Here we investigate the role of Vi capsule and antibodies against Vi and O:9 in antibody-dependent complement- and phagocyte-mediated killing of Salmonella. Using isogenic Vi-expressing and non-Vi-expressing derivatives of S. Typhi and S. Typhimurium, we show that S. Typhi is inherently more sensitive to serum and blood than S. Typhimurium. Vi expression confers increased resistance to both complement- and phagocyte-mediated modalities of antibody-dependent killing in human blood. The Vi capsule is associated with reduced C3 and C5b-9 deposition, and decreased overall antibody binding to S. Typhi. However, purified human anti-Vi antibodies in the presence of complement are able to kill Vi-expressing Salmonella, while killing by anti-O:9 antibodies is inversely related to Vi expression. Human serum depleted of antibodies to antigens other than Vi retains the ability to kill Vi-expressing bacteria. Our findings support a protective role for Vi capsule in preventing complement and phagocyte killing of Salmonella that can be overcome by specific anti-Vi antibodies, but only to a limited extent by anti-O:9 antibodies.