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Histidine-rich protein 2 (HRP2)-based rapid diagnostic tests detect Plasmodium falciparum malaria and are used throughout sub-Saharan Africa. However, deletions in the pfhrp2 and related pfhrp3 (pfhrp2/3) genes threaten use of these tests. Therapeutic efficacy studies (TESs) enroll persons with symptomatic P. falciparum infection. We screened TES samples collected during 2016-2018 in Ethiopia, Kenya, Rwanda, and Madagascar for HRP2/3, pan-Plasmodium lactate dehydrogenase, and pan-Plasmodium aldolase antigen levels and selected samples with low levels of HRP2/3 for pfhrp2/3 genotyping. We observed deletion of pfhrp3 in samples from all countries except Kenya. Single-gene deletions in pfhrp2 were observed in 1.4% (95% CI 0.2%-4.8%) of Ethiopia samples and in 0.6% (95% CI 0.2%-1.6%) of Madagascar samples, and dual pfhrp2/3 deletions were noted in 2.0% (95% CI 0.4%-5.9%) of Ethiopia samples. Although this study was not powered for precise prevalence estimates, evaluating TES samples revealed a low prevalence of pfhrp2/3 deletions in most sites.

Background Scale up of proven malaria control interventions has not been sufficient to control malaria in Uganda, emphasizing the need to explore innovative new approaches. Improved housing is one such promising strategy. This paper describes housing characteristics and their association with malaria burden in a moderate to high transmission setting in Uganda. Methods Between October and November 2021, a household survey was conducted in 1500 randomly selected households in Jinja and Luuka districts. Information on demographics, housing characteristics, use of malaria prevention measures, and proxy indicators of wealth were collected for each household. A finger-prick blood sample was obtained for thick blood smears for malaria from all children aged 6 months to 14 years in the surveyed households. Febrile children had a malaria rapid diagnostics test (RDT) done; positive cases were managed according to national treatment guidelines. Haemoglobin was assessed in children aged < 5 years. Households were stratified as having modern houses (defined as having finished materials for roofs, walls, and floors and closed eaves) or traditional houses (those not meeting the definition of modern house). Associations between malaria burden and house type were estimated using mixed effects models and adjusted for age, wealth, and bed net use. Results Most (65.5%) of the households surveyed lived in traditional houses. Most of the houses had closed eaves (85.5%), however, the use of other protective features like window/vent screens and installed ceilings was limited (0.4% had screened windows, 2.8% had screened air vents, and 5.2% had ceiling). Overall, 3,443 children were included in the clinical survey, of which 31.4% had a positive smear. RDT test positivity rate was 56.6% among children with fever. Participants living in modern houses had a significantly lower parasite prevalence by microscopy (adjusted prevalence ratio [aPR = 0.80]; 95% confidence interval [CI] 0.71 – 0.90), RDT test positivity rate (aPR = 0.90, 95%CI 0.81 – 0.99), and anaemia (aPR = 0.80, 95%CI 0.65 – 0.97) compared to those in traditional houses. Conclusion The study found that even after adjusting for wealth, higher quality housing had a moderate protective effect against malaria, on top of the protection already afforded by recently distributed nets.

Background Demand for high-quality surveillance data for malaria, and other diseases, is greater than ever before. In Uganda, the primary source of malaria surveillance data is the Health Management Information System (HMIS). However, HMIS data may be incomplete, inaccurate or delayed. Collaborative improvement (CI) is a quality improvement intervention developed in high-income countries, which has been advocated for low-resource settings. In Kayunga, Uganda, a pilot study of CI was conducted in five public health centres, documenting a positive effect on the quality of HMIS and malaria surveillance data. A qualitative evaluation was conducted concurrently to investigate the mechanisms of effect and unintended consequences of the intervention, aiming to inform future implementation of CI. Methods The study intervention targeted health workers, including brief in-service training, plus CI with ‘plan-do-study-act’ (PDSA) cycles emphasizing self-reflection and group action, periodic learning sessions, and coaching from a CI mentor. Health workers collected data on standard HMIS out-patient registers. The qualitative evaluation (July 2015 to September 2016) included ethnographic observations at each health centre (over 12–14 weeks), in-depth interviews with health workers and stakeholders (n = 20), and focus group discussions with health workers (n = 6). Results The results suggest that the intervention did facilitate improvement in data quality, but through unexpected mechanisms. The CI intervention was implemented as planned, but the PDSA cycles were driven largely by the CI mentor, not the health workers. In this context, characterized by a rigid hierarchy within the health system of limited culture of self-reflection and inadequate training and supervision, CI became an effective form of high-quality training with frequent supervisory visits. Health workers appeared motivated to improve data collection habits by their loyalty to the CI mentor and the potential for economic benefits, rather than a desire for self-improvement. Conclusions CI is a promising method of quality improvement and could have a positive impact on malaria surveillance data. However, successful scale-up of CI in similar settings may require deployment of highly skilled mentors. Further research, focusing on the effectiveness of ‘real world’ mentors using robust study designs, will be required to determine whether CI can be translated effectively and sustainably to low-resource settings.

Background Evidence that house design can provide protection from malaria is growing. Housing modifications such as screening windows, doors, and ceilings, and attaching insecticide-impregnated materials to the eaves (the gap between the top of the wall and bottom of the roof), can protect against malaria. To be effective at scale, however, these modifications must be adopted by household residents. There is evidence that housing modifications can be acceptable, but in-depth knowledge on the experiences and interpretation of modifications is lacking. This qualitative study was carried out to provide a holistic account of the relationship between experiences and interpretations of four types of piloted housing modifications and the local context in Jinja, Uganda. Methods Qualitative research was conducted between January to June 2021, before and during the installation of four types of housing modifications. The methods included nine weeks of participant observations in two study villages, nine focus group discussions with primary caregivers and heads of households (11–12 participants each), and nine key informant interviews with stakeholders and study team members. Results Most residents supported the modifications. Experiences and interpretation of the housing modifications were shaped by the different types of housing in the area and the processes through which residents finished their houses, local forms of land and property ownership, and cultural and spiritual beliefs about houses. Conclusions To maximize the uptake and benefit of housing modifications against malaria, programme development needs to take local context into account. Forms of local land and house ownership, preferences, the social significance of housing types, and religious and spiritual ideas shape the responses to housing modifications in Jinja. These factors may be important in other setting. Trial registration  Trial registration number is NCT04622241. The first draft was posted on November 9th 2020.

Background Anti-malarial drug resistance remains a major threat to global malaria control efforts. In Africa, Plasmodium falciparum remains susceptible to artemisinin-based combination therapy (ACT), but the emergence of resistant parasites in multiple countries in Southeast Asia and concerns over emergence and/or spread of resistant parasites in Africa warrants continuous monitoring. The World Health Organization recommends that surveillance for molecular markers of resistance be included within therapeutic efficacy studies (TES). The current study assessed molecular markers associated with resistance to Artemether−lumefantrine (AL) and Dihydroartemisinin−piperaquine (DP) from samples collected from children aged 6–59 months enrolled in a TES conducted in Siaya County, western Kenya from 2016 to 2017. Methods Three hundred and twenty-three samples collected pre-treatment (day-0) and 110 samples collected at the day of recurrent parasitaemia (up to day 42) were tested for the presence of drug resistance markers in the Pfk13 propeller domain, and the Pfmdr1 and Pfcrt genes by Sanger sequencing. Additionally, the Pfpm2 gene copy number was assessed by real-time polymerase chain reaction. Results No mutations previously associated with artemisinin resistance were detected in the Pfk13 propeller region. However, other non-synonymous mutations in the Pfk13 propeller region were detected. The most common mutation found on day-0 and at day of recurrence in the Pfmdr1 multidrug resistance marker was at codon 184 F . Very few mutations were found in the Pfcrt marker (< 5%). Within the DP arm, all recrudescent cases (8 sample pairs) that were tested for Pfpm2 gene copy number had a single gene copy. None of the associations between observed mutations and treatment outcomes were statistically significant. Conclusion The results indicate absence of Pfk13 mutations associated with parasite resistance to artemisinin in this area and a very high proportion of wild-type parasites for Pfcrt . Although the frequency of Pfmdr1 184 F mutations was high in these samples, the association with treatment failure did not reach statistical significance. As the spread of artemisinin-resistant parasites remains a possibility, continued monitoring for molecular markers of ACT resistance is needed to complement clinical data to inform treatment policy in Kenya and other malaria-endemic regions.

Background Surveillance data are essential for malaria control, but quality is often poor. The aim of the study was to evaluate the effectiveness of the novel combination of training plus an innovative quality improvement method—collaborative improvement (CI)—on the quality of malaria surveillance data in Uganda. Methods The intervention (training plus CI, or TCI), including brief in-service training and CI, was delivered in 5 health facilities (HFs) in Kayunga District from November 2015 to August 2016. HF teams monitored data quality, conducted plan-do-study-act cycles to test changes, attended periodic learning sessions, and received CI coaching. An independent evaluation was conducted to assess data completeness, accuracy, and timeliness. Using an interrupted time series design without a separate control group, data were abstracted from 156,707 outpatient department (OPD) records, laboratory registers, and aggregated monthly reports (MR) for 4 time periods: baseline—12 months, TCI scale-up—5 months; CI implementation—9 months; post-intervention—4 months. Monthly OPD register completeness was measured as the proportion of patient records with a malaria diagnosis with: (1) all data fields completed, and (2) all clinically-relevant fields completed. Accuracy was the relative difference between: (1) number of monthly malaria patients reported in OPD register versus MR, and (2) proportion of positive malaria tests reported in the laboratory register versus MR. Data were analysed with segmented linear regression modelling. Results Data completeness increased substantially following TCI. Compared to baseline, all-field completeness increased by 60.1%-points (95% confidence interval [CI]: 46.9–73.2%) at mid-point, and clinically-relevant completeness increased by 61.6%-points (95% CI: 56.6–66.7%). A relative − 57.4%-point (95% confidence interval: − 105.5, − 9.3%) change, indicating an improvement in accuracy of malaria test positivity reporting, but no effect on data accuracy for monthly malaria patients, were observed. Cost per additional malaria patient, for whom complete clinically-relevant data were recorded in the OPD register, was $3.53 (95% confidence interval: $3.03, $4.15). Conclusions TCI improved malaria surveillance completeness considerably, with limited impact on accuracy. Although these results are promising, the intervention’s effectiveness should be evaluated in more HFs, with longer follow-up, ideally in a randomized trial, before recommending CI for wide-scale use.

Penile coital injuries are one of the suggested mechanisms behind the increased risk of HIV among uncircumcised men. We evaluated the prevalence and correlates of self-reported penile coital injuries in a longitudinal community-based cohort of young (18-24 years old), newly circumcised and uncircumcised men in Western Kenya. Self-reported penile coital injuries were assessed at baseline, 6, 12, 18 and 24 months of follow-up, and were defined as scratches, cuts or abrasions during sex, penile soreness during sex, and skin of the penis bleeding during sex. Associations between penile coital injuries, circumcision, sexual satisfaction, and other covariates were estimated with mixed effect models. Between November 2008 and April 2010 3,186 participants were enrolled (1,588 into circumcision group and 1,598 as age-matched controls). Among 2,106 (66%) participants sexually active at baseline, 53% reported any penile injury, including 44% scratches, cuts or abrasions; 32% penile pain/soreness; and 22% penile bleeding. In multivariable modeling, risk was lower for circumcised men than uncircumcised men for scratches, cuts and abrasions (aOR = 0.39; 95% CI 0.34-0.44); penile pain/soreness (aOR = 0.58; 95% CI 0.51-0.65), penile bleeding (aOR = 0.53; 95% CI 0.46-0.62), and any penile coital injuries (aOR = 0.47; 95%CI 0.42-0.53). Other significant risk factors included increasing age, history of STIs and genital sores, and multiple sex partners, while condom use was protective. Coital injuries were significantly associated with lower levels of sexual satisfaction in longitudinal analyses (scratches, cuts or abrasions: aOR = 0.87, 95% CI: 0.76-0.98; penile pain/soreness: aOR = 0.82, 95% CI: 0.72-0.93; and penile bleeding: aOR = 0.65, 95% CI: 0.55-0.76). Self-reported penile coital injuries were common and decreased significantly following circumcision. Improving sexual experience through the removal of a potential source of sexual discomfort may resonate with many men targeted for circumcision services. The role of penile coital injuries in sexual satisfaction, HIV, HSV-2, and as a motivator for seeking circumcision services should be explored further.

Background The WHO recommends single low-dose primaquine (SLDPQ, 0.25 mg/kg body weight) in falciparum-infected patients to block malaria transmission and contribute to eliminating multidrug resistant Plasmodium falciparum from the Greater Mekong Sub region (GMS). However, the anxiety regarding PQ-induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency (G6PDd) has hindered its use. Therefore, we assessed the tolerability of SLDPQ in Cambodia to inform national policy. Methods This open randomised trial of dihydroartemisinin-piperaquine (DHAPP) + SLDPQ vs. DHAPP alone recruited Cambodians aged ≥1 year with acute uncomplicated P. falciparum . Randomisation was 4:1 DHAPP+SLDPQ: DHAPP for G6PDd patients and 1:1 for G6PDn patients, according to the results of the qualitative fluorescent spot test. Definitive G6PD status was determined by genotyping. Day (D) 7 haemoglobin (Hb) concentration was the primary outcome measure. Results One hundred nine patients (88 males, 21 females), aged 4–76 years (median 23) were enrolled; 12 were G6PDd Viangchan (9 hemizygous males, 3 heterozygous females). Mean nadir Hb occurred on D7 [11.6 (range 6.4 ─ 15.6) g/dL] and was significantly lower ( p  = 0.040) in G6PDd ( n  = 9) vs. G6PDn ( n  = 46) DHAPP+SLDPQ recipients: 10.9 vs. 12.05 g/dL, Δ = -1.15 (95% CI: -2.24 ─ -0.05) g/dL. Three G6PDn patients had D7 Hb concentrations < 8 g/dL; D7-D0 Hbs were 6.4 ─ 6.9, 7.4 ─ 7.4, and 7.5 ─ 8.2 g/dL. For all patients, mean (range) D7-D0 Hb decline was -1.45 (-4.8 ─ 2.4) g/dL, associated significantly with higher D0 Hb, higher D0 parasitaemia, and receiving DHAPP; G6PDd was not a factor. No patient required a blood transfusion. Conclusions DHAPP+SLDPQ was associated with modest Hb declines in G6PD Viangchan, a moderately severe variant. Our data augment growing evidence that SLDPQ in SE Asia is well tolerated and appears safe in G6PDd patients. Cambodia is now deploying SLDPQ and this should encourage other GMS countries to follow suit. Trial registration The clinicaltrials.gov reference number is NCT02434952 .

The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1–59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12–23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1–59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22–1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61–1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88–1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5–51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0–18%) in all-cause mortality (excluding injury). In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

Background Innovative, equitable, and sustainable multisectoral solutions are required to address persistently high global malaria deaths, widespread insecticide and antimalarial resistance, and falling funding for malaria control. Housing modification presents a promising option. Alongside a cluster-randomized control trial in Eastern Region, Uganda, we analysed the costs and households’ willingness to pay (WTP) for two housing modification interventions, screening and eave tubes, focusing on equity and scale-up potential. Methods Taking a disaggregated societal perspective, we assessed financial and economic costs of installing two housing modification interventions in approximately 4000 homes (20000 people). We collected WTP data through three cross-sectional household surveys (n = 1500 households each) using modified structured haggling and calculated price elasticity of demand. We used multivariable regressions and concentration indices to analyse how costs and WTP varied by household characteristics. To identify potential financing gaps, we compared WTP to costs and examined variation by household wealth quintiles. Results Screening cost a mean of $116 (societal economic costs; 95%CI $112–120) United States Dollars (2022 USD) per house; eave tubes cost $50 (95%CI $48–52). When annualized over 5 years, screening cost $4.22 per person protected per year and eave tubes cost $3.03. Installation cost more in the wealthiest versus poorest quintiles for both screening ($151 vs $69) and eave tubes ($95 vs $31). Over 75% of respondents were willing to pay something for the interventions, but these values represented only a small fraction of the costs, with a higher fraction in the wealthiest vs poorest quintiles (screening: 12% vs 7%; eave tubes: 18% vs 14%). Conclusions While housing modification has relatively high upfront costs, its annual cost per person protected is comparable to other malaria interventions. Households, especially the poorest, are unwilling or unable to pay the full cost of housing modifications. Equitable scale-up would require additional financing and/or demand-boosting interventions. Trial Registration : NCT04622241 (clinicaltrials.gov).