Detection of persistent Plasmodium spp. infections in Ugandan children after artemether-lumefantrine treatment

During a longitudinal study investigating the dynamics of malaria in Ugandan lakeshore communities, a consistently high malaria prevalence was observed in young children despite regular treatment. To explore the short-term performance of artemether-lumefantrine (AL), a pilot investigation into parasite carriage after treatment(s) was conducted in Bukoba village. A total of 163 children (aged 2–7 years) with a positive blood film and rapid antigen test were treated with AL; only 8·7% of these had elevated axillary temperatures. On day 7 and then on day 17, 40 children (26·3%) and 33 (22·3%) were positive by microscopy, respectively. Real-time PCR analysis demonstrated that multi-species Plasmodium infections were common at baseline, with 41·1% of children positive for Plasmodium falciparum/Plasmodium malariae, 9·2% for P. falciparum/ Plasmodium ovale spp. and 8·0% for all three species. Moreover, on day 17, 39·9% of children infected with falciparum malaria at baseline were again positive for the same species, and 9·2% of those infected with P. malariae at baseline were positive for P. malariae. Here, chronic multi-species malaria infections persisted in children after AL treatment(s). Better point-of-care diagnostics for non-falciparum infections are needed, as well as further investigation of AL performance in asymptomatic individuals

Mandatory anatomy dissection, effect on examination performance

Regular class attendance is evidence of professionalism. This has led to mandatory class attendance in many disciplines including anatomy. However, there is paucity of data on the effect of mandatory class attendance on student performance in resource-limited settings. The objective of this study was to determine the effect of mandatory attendance of anatomy dissections on student’s practical exams. This was an audit of undergraduate first year health professional students performance on the practical summative Steeplechase exam for the anatomy of limbs in two consecutive academic years at Makerere University. The second lot of first year students in the study had all their scheduled anatomy dissection sessions roll called to confirm their attendance that was the intervention arm in the study. The data was analysed with STATA statistical computing software version 13. Some of the tests run on this data included independent samples t test and Regression analysis. The overall performance of students in the academic year varied with roll call and was significantly lower than that in the previous academic year without roll call (mean difference -8.04 95% CI -10.76 to -5.31). Significant reductions in performance were also observed with type of student sponsorship (P<0.01) and the program they were pursuing (P<0.01). Roll calling had the largest effect on student performance demonstrated by the 0.23 standard deviation reduction in performance of students. This study shows that mandatory attendance of anatomy dissections leads to a reduction in the student’s performance on practical anatomy examinationsKeywords: Anatomy dissection, class attendance, examination performanc

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Compatibility of Ugandan Schistosoma mansoni isolates with Biomphalaria snail species from Lake Albert and Lake Victoria.

In order to investigate the capacity of being intermediate host for Schistosoma mansoni, the Ugandan F1 generation of Biomphalaria snail species that were laboratory-bred from parent populations originally collected from either Lake Victoria or Lake Albert was challenged with sympatric and non-sympatric S. mansoni isolates. After a prepatent period of 20 days, a daily 10-hourly snail shedding for cercariae was done to determine the infection rate, cercarial production per hour and survival period of infected snails. The study suggests that when parasite strains from a different geographical origin is used for infection, survival of infected snails increase, leading to an increased transmission potential. Although earlier literature had indicated that the Lake Victoria Biomphalaria sudanica is refractory to S. mansoni, we showed that all Ugandan Biomphalaria spp., including B. sudanica from all locations, were highly susceptible to the S. mansoni isolates. Thus if B. choanomphala, which is an efficient intermediate host in Lake Victoria, is given an opportunity to occupy Lake Albert, it will most likely be compatible with the Albertine S. mansoni parasites. Equally, if B. stanleyi, currently restricted to Lake Albert invades Lake Victoria, it is likely to act as an efficient intermediate host. Future work should concentrate on intraspecific population-level differences in compatibility

Wuchereria bancrofti infection at four primary schools and surrounding communities with no previous blood surveys in northern Uganda: the prevalence after mass drug administrations and a report on suspected non-filarial endemic elephantiasis

Abstract Background A prevalence study of Wuchereria bancrofti infection was carried out in 2014 at 4 study sites in northern Uganda using antigen and microfilaria tests. Each study site consists of a primary school and surrounding communities. These sites are inside the filariasis endemic area and have been covered by mass drug administration under the national elimination programme. However, no prevalence study had been conducted there before the present study. Without information on past and present endemicity levels, our study was meant to be an independent third-party investigation to know the latest filariasis situation. Results A total of 982 people including 570 schoolchildren (7–19 years) and 412 community people (7–25 years) were examined, all of them for filarial antigen and 695 for microfilariae. The study revealed that all subjects were negative by both methods. Conclusions It was considered that annual mass drug administrations together with anti-malarial activities such as indoor residual spraying had contributed to the reduction of the filarial infection. However, based on the past data obtained near our study sites, we cannot exclude the possibility that filarial prevalence rates in our study sites were very low or even zero originally. During the study, we encountered several patients with lower leg edema and pachydermic (elephant skin-like), mossy skin lesion of the foot. Judging from clinical features and bare-footed life-style of people in the area, non-filarial elephantiasis, possibly podoconiosis, was suspected. This elephantiasis has been reported in areas where filariasis is not endemic