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Development of a malaria vaccine is a high global health priority. This report assessed the effect of waning vaccine-induced immunity and the level of malaria exposure on vaccine efficacy in Kenyan children who received the RTS,S/AS01E vaccine and were followed for 4 years. Malaria remains an important cause of illness and death among children in sub-Saharan Africa. 1 RTS,S is the most advanced candidate malaria vaccine and has entered phase 3 trials. 2 The variation in vaccine efficacy over time will be critical to public health policy decisions concerning the introduction of the vaccine. We previously conducted a phase 2 proof-of-concept trial of RTS,S/AS01E in Kilifi, Kenya, and Korogwe, Tanzania, to evaluate its safety and efficacy against episodes of Plasmodium falciparum malaria in children 5 to 17 months old. 3 At the end of the double-blind phase (mean duration of follow-up, 7.9 months), efficacy against the . . .

As efforts to control malaria are expanded across the world, understanding the role of transmission intensity in determining the burden of clinical malaria is crucial to the prediction and measurement of the effectiveness of interventions to reduce transmission. Furthermore, studies comparing several endemic sites led to speculation that as transmission decreases morbidity and mortality caused by severe malaria might increase. We aimed to assess the epidemiological characteristics of malaria in Kilifi, Kenya, during a period of decreasing transmission intensity. We analyse 18 years (1990–2007) of surveillance data from a paediatric ward in a malaria-endemic region of Kenya. The hospital has a catchment area of 250 000 people. Clinical data and blood-film results for more than 61 000 admissions are reported. Hospital admissions for malaria decreased from 18·43 per 1000 children in 2003 to 3·42 in 2007. Over 18 years of surveillance, the incidence of cerebral malaria initially increased; however, malaria mortality decreased overall because of a decrease in incidence of severe malarial anaemia since 1997 (4·75 to 0·37 per 1000 children) and improved survival among children admitted with non-severe malaria. Parasite prevalence, the mean age of children admitted with malaria, and the proportion of children with cerebral malaria began to change 10 years before hospitalisation for malaria started to fall. Sustained reduction in exposure to infection leads to changes in mean age and presentation of disease similar to those described in multisite studies. Changes in transmission might not lead to immediate reductions in incidence of clinical disease. However, longitudinal data do not indicate that reductions in transmission intensity lead to transient increases in morbidity and mortality. Wellcome Trust, Kenya Medical Research Institute.

Most estimates of the burden of malaria are based on its direct impacts; however, its true burden is likely to be greater because of its wider effects on overall health. Here we estimate the indirect impact of malaria on children’s health in a case-control study, using the sickle cell trait (HbAS), a condition associated with a high degree of specific malaria resistance, as a proxy indicator for an effective intervention. We estimate the odds ratios for HbAS among cases (all children admitted to Kilifi County Hospital during 2000–2004) versus community controls. As expected, HbAS protects strongly against malaria admissions (aOR 0.26; 95%CI 0.22–0.31), but it also protects against other syndromes, including neonatal conditions (aOR 0.79; 0.67–0.93), bacteraemia (aOR 0.69; 0.54–0.88) and severe malnutrition (aOR 0.67; 0.55–0.83). The wider health impacts of malaria should be considered when estimating the potential added benefits of effective malaria interventions. Estimates of the burden of malaria often don't take wider, indirect effects on overall health into consideration. Here, Uyoga et al. estimate the indirect impact of malaria on children’s health in a case-control study, using the sickle cell trait as a proxy indicator for an effective intervention.

Severe falciparum malaria has substantially affected human evolution. Genetic association studies of patients with clinically defined severe malaria and matched population controls have helped characterise human genetic susceptibility to severe malaria, but phenotypic imprecision compromises discovered associations. In areas of high malaria transmission, the diagnosis of severe malaria in young children and, in particular, the distinction from bacterial sepsis are imprecise. We developed a probabilistic diagnostic model of severe malaria using platelet and white count data. Under this model, we re-analysed clinical and genetic data from 2220 Kenyan children with clinically defined severe malaria and 3940 population controls, adjusting for phenotype mis-labelling. Our model, validated by the distribution of sickle trait, estimated that approximately one-third of cases did not have severe malaria. We propose a data-tilting approach for case-control studies with phenotype mis-labelling and show that this reduces false discovery rates and improves statistical power in genome-wide association studies. In areas of sub-Saharan Africa where malaria is common, most people are frequently exposed to the bites of mosquitoes carrying malaria parasites, so they often have malaria parasites in their blood. Young children, who have not yet built up strong immunity against malaria, often fall ill with severe malaria, a life-threatening disease. It is unclear why some children develop severe malaria and die, while other children with high numbers of parasites in their blood do not develop any apparent symptoms. Genetic susceptibility studies are designed to uncover why such differences exist by comparing individuals with severe malaria (referred to as ‘cases’) with individuals drawn from the general population (known as ‘controls’). But severe malaria can be a challenge to diagnose. Since high numbers of malaria parasites can be found in healthy children, it is sometimes difficult to determine whether the parasites are making a child ill, or whether they are a coincidental finding. Consequently, some of the ‘cases’ recruited into these studies may actually have a different disease, such as bacterial sepsis. This ultimately affects how the studies are interpreted, and introduces error and inaccuracy into the data. Watson, Ndila et al. investigated whether measuring blood biomarkers in patients (derived from the complete blood count, including platelet counts and white blood cell counts) could improve the accuracy with which malaria is diagnosed. They developed a new mathematical model that incorporates platelet and white blood cell counts. This model estimates that in a large cohort of 2,220 Kenyan children diagnosed with severe malaria, around one third of enrolled children did not actually have this disease. Further analysis suggests that patients with severe malaria are highly unlikely to have platelet counts higher than 200,000 per microlitre. This defines a cut-off that researchers can use to avoid recruiting patients who do not have severe malaria in future studies. Additionally, the ability to diagnose severe malaria more accurately can make it easier to detect and treat other diseases with similar symptoms in children with high numbers of malaria parasites in their blood. Watson, Ndila et al.’s findings support the recommendation that all children with suspected malaria be given broad spectrum antibiotics, as many misdiagnosed children will likely have bacterial sepsis. It also suggests that using complete blood counts, which are cheap to obtain and increasingly available in low-resource settings, could improve diagnostic accuracy in future clinical studies of severe malaria. This could ultimately improve the ability of these studies to find new treatments for this life-threatening disease.

Globally, men who have sex with men (MSM) continue to bear a high burden of HIV infection. In sub-Saharan Africa, same-sex behaviours have been largely neglected by HIV research up to now. The results from recent studies, however, indicate the widespread existence of MSM groups across Africa, and high rates of HIV infection, HIV risk behaviour, and evidence of behavioural links between MSM and heterosexual networks have been reported. Yet most African MSM have no safe access to relevant HIV/AIDS information and services, and many African states have not begun to recognise or address the needs of these men in the context of national HIV/AIDS prevention and control programmes. The HIV/AIDS community now has considerable challenges in clarifying and addressing the needs of MSM in sub-Saharan Africa; homosexuality is illegal in most countries, and political and social hostility are endemic. An effective response to HIV/AIDS requires improved strategic information about all risk groups, including MSM. The belated response to MSM with HIV infection needs rapid and sustained national and international commitment to the development of appropriate interventions and action to reduce structural and social barriers to make these accessible.

Background Hepatitis B virus (HBV) is one of the most common causes of chronic liver disease and is a growing concern in low-income countries, including Ethiopia. Different studies have been conducted on the prevalence of HBV infection among Ethiopian regions and population segments. Therefore, this systematic review was commenced to summarize these findings, deliver representative pooled data on the prevalence of HBV infection among Ethiopian administrative regions and population segments, and identify possible factors associated with HBV infection. Methods Electronic databases such as PubMed, African Journals Online, and Google Scholar were searched for published articles from July 9, 2019, to February 30, 2024. The data were exported to STATA version 15.1 for meta-analyses. The heterogeneity between the results of the primary studies was accessed using Cochran’s Q chi-square test and quantified with I 2 statistics. A random effect model was used to pool the prevalence of HBV infection. Results The overall pooled prevalence of HBV infection was 6.9% (95% CI: 6.1, 7.7). Among the subgroup analyses, the highest pooled prevalence of HBV infection was obtained from Harar city 9.6% (95% CI: 5.6, 13.5), followed by South Nations and Nationalities People Regions (SNNPR) 8.5% (95% CI: 7.4, 9.7). On the other hand, the pooled prevalence of HBV infection among waste handlers was high 12.6% (95% CI: 2.4, 27.6) followed by female commercial sex workers (FCSW) 10.9% (95% CI: 7.7, 15.2) and human immune deficiency virus (HIV) positive individuals 9.9% (95% CI: 7.2, 12.8). HBV infection was significantly linked to the following factors: those with multiple sexual partners, a family history of chronic liver disease, exposure to bodily fluids, HIV seropositivity, and sharp needle injury had Adjusted Odd Ratio (AOR):3.9 (95% CI: 2.62, 5.76), (AOR: 6.9 (95% CI:3.46, 10.53), (AOR:3.1 (95% CI: 2.01, 3.05), (AOR:7.7 (95% CI: 2.99, 19.93), (AOR:2.1 (95% CI: 1.58, 2.66) times a greater chance of infection, respectively. Conclusions The high pooled prevalence of HBV infection in Ethiopia indicates that the burden of HBV infection continues to be a public health concern. The Ethiopian Ministry of Health should develop a strategic plan for prevention and control of HBV infection transmission including awareness creation, scale-up screening programs, diagnosis, treatment, and care services to reduce the burden of HBV infection and eliminate it as a public health threat.

The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies. On the Kenyan coast we studied the treatment responses in 474 children 6-59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995). The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005-2006 to 87% in 2007-2008 (odds ratio, 5.4, 95%CI, 2.7-11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7-9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005-2006 and 2007-2008 (OR body temperature >37.5°C, 2.8, 1.9-4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof. The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates. Controlled-Trials.com ISRCTN88705995.

Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children due to lower acquired immunity, and this has implications for ongoing control strategies. We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked it to data on residence and insecticide-treated net (ITN) use. This included data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospital between 1 January 1990 and 31 December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the following predictors: location of the residence, calendar time, the child's age, ITN use, and the enhanced vegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissions declined from 0.56 (95% confidence interval [CI] 0.54-0.58) in 1998 to 0.07 (95% CI 0.06-0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22-0.25) in 2014. Older children accounted for most of the increase after 2009 (0.035 [95% CI 0.030-0.040] among young children compared to 0.22 [95% CI 0.21-0.23] in older children). There was a nonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radius of an admitted child's residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis, we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. Following a period of reduced transmission, a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate the increasing burden among older children, and universal ITN coverage is a promising strategy to achieve this goal.

Blood group O is associated with protection against severe malaria and reduced size and stability of P . falciparum- host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO , BO , AA , BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA , BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non- O genotypes ( AA , BB , AB ) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes ( AO , BO ). In the case-control study, compared to OO , the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference ( p = 0.02, Wald test). In vitro experiments with blood group A-preferring P . falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO , whereas AO and BO genotypes rosettes were indistinguishable from OO . Overall, the data show that ABO genotype influences P . falciparum rosetting and support the hypothesis that double dose non- O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.

Background Many parts of Africa have witnessed reductions in Plasmodium falciparum transmission over the last 15 years. Since immunity to malaria is acquired more rapidly at higher transmission, the slower acquisition of immunity at lower transmission may partially offset the benefits of reductions in transmission. We examined the clinical spectrum of disease and predictors of mortality after sustained changes in transmission intensity, using data collected from 1989 to 2016. Methods We conducted a temporal observational analysis of 18,000 children, aged 14 days to 14 years old, who were admitted to Kilifi County Hospital, Kenya, from 1989 to 2016 with malaria. We describe the trends over time of the clinical and laboratory criteria for severe malaria and associated risk of mortality. Results During the time periods 1989–2003, 2004–2008, and 2009–2016, Kilifi County Hospital admitted averages of 657, 310, and 174 cases of severe malaria per year including averages of 48, 14, and 12 malaria-associated deaths per year, respectively. The median ages in years of children admitted with cerebral malaria, severe anaemia, and malaria-associated mortality were 3.0 (95% confidence interval (CI) 2.2–3.9), 1.1 (95% CI 0.9–1.4), and 1.1 (95% CI 0.3–2.2) in the year 1989, rising to 4.9 (95% CI 3.9–5.9), 3.8 (95% CI 2.5–7.1), and 5 (95% CI 3.3–6.3) in the year 2016. The ratio of children with cerebral malaria to severe anaemia rose from 1:2 before 2004 to 3:2 after 2009. Hyperparasitaemia was a risk factor for death after 2009 but not in earlier time periods. Conclusion Despite the evidence of slower acquisition of immunity, continued reductions in the numbers of cases of severe malaria resulted in lower overall mortality. Our temporal data are limited to a single site, albeit potentially applicable to a secular trend present in many parts of Africa.