The Uganda housing modification study - association between housing characteristics and malaria burden in a moderate to high transmission setting in Uganda.

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.

Prevalence and Predictors of Tuberculosis Infection in Children and Adolescents in Rural Uganda: A Cross-sectional Study.

BACKGROUND: Much of the latent tuberculosis (TB) reservoir is established in childhood and adolescence. Yet, age-specific data on prevalence and predictors of infection in this population are sparse and needed to guide prevention and case finding. METHODS: From December 2021 to June 2023, we measured TB infection in children 1-17 years in 25 villages in rural Southwestern Uganda. We defined TB infection as a positive QuantiFERON Gold Plus Test (QFT). We estimated overall and age-stratified population-level prevalence and adjusted risk ratios (aRR) of TB infection for individual, household, and community-based predictors, accounting for age, TB contact, and clustering by household. RESULTS: Estimated TB infection prevalence was 9.6% [95% confidence interval (CI): 8.7-10.5%] among the 5789 participants, and prevalence varied slightly with age. Household-level risk factors included crowding (aRR: 1.25, 95% CI: 1.03-1.53), indoor cooking (aRR: 1.62, 95% CI: 1.14-2.30), living with ≥2 persons who drink alcohol (aRR: 1.47, 95% CI: 1.04-2.07). The predominant community-based risk factor was child mobility (aRR: 1.67, 95% CI: 1.24-2.26). In age-stratified analyses, household predictors were important in early childhood but not adolescence, where mobility was predominant (aRR: 1.66, 95% CI: 1.13-2.44). CONCLUSION: We detected a high prevalence of TB infection in children and adolescents in rural Uganda. On a population level, TB risk factors change throughout the early life course, with child mobility a key risk factor in adolescence. Age-specific TB case finding and prevention strategies that address both household and extra-household risk factors are needed to address TB transmission.

Client experiences with "Dynamic Choice Prevention," a model for flexible patient-centred HIV prevention delivery in rural Eastern Africa.

INTRODUCTION: Identifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models. METHODS: In-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes. RESULTS: Individuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure. CONCLUSIONS: Diverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

Seroprevalence of SARS-CoV-2 and risk factors for infection among children in Uganda: a serial cross-sectional study.

Background: Understanding COVID-19's impact on children is vital for public health policy, yet age-specific data is scarce, especially in Uganda. This study examines SARS-CoV-2 seroprevalence and risk factors among Ugandan children at two timepoints, along with COVID-19-related knowledge and practices in households, including adult vaccination status. Methods: Baseline surveys were conducted in 12 communities from April to May 2021 (post-Alpha wave) and follow-up surveys in 32 communities from November 2021 to March 2022 (Omicron wave). Household questionnaires and blood samples were collected to test for malaria by microscopy and for SARS-CoV-2 using a Luminex assay. Seroprevalence was estimated at both the survey and community level. Mixed-effects logistic regression models assessed the association between individual and household factors and SARS-CoV-2 seropositivity in children, adjusting for household clustering. Results: More households reported disruptions in daily life at baseline compared to follow-up, though economic impacts lingered. By the follow-up survey, 52.7% of adults had received at least one COVID-19 vaccine dose. Overall seroprevalence in children was higher at follow-up compared to baseline (71.6% versus 19.2%, p < 0.001). Seroprevalence in children ranged across communities from 6-37% at baseline and 50-90% at follow-up. At baseline, children from the poorest households were more likely to be infected. Increasing age remained the only consistent risk factor for SARS-CoV-2 seroconversion at both timepoints. Conclusions: Results indicate that a larger number of children were infected by the Delta and Omicron waves of COVID-19 compared to the Alpha wave. This study is the largest seroprevalence survey in children in Uganda, providing evidence that most children were infected with SARS-CoV-2 before the vaccine was widely available to pediatric populations. Pediatric infections were vastly underreported by case counts, highlighting the importance of seroprevalence surveys in assessing disease burden when testing and reporting rates are limited and many cases are mild or asymptomatic.

Gravidity influences distinct transcriptional profiles of maternal and fetal placental macrophages at term.

Introduction: Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Maternal reproductive history is associated with differential risk of pregnancy complications. The molecular phenotypes and roles of these distinct monocyte/macrophage populations and the influence of gravidity on these phenotypes has not been systematically investigated. Methods: Here, we used RNA sequencing to study the transcriptional profiles of MIMs and HBCs in normal term pregnancies. Results: Our analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidae compared to primigravidae. In HBCs, multigravidae displayed enrichment of gene pathways involved in cell-cell signaling and differentiation. Discussion: Our results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Furthermore, maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidae to pregnancy complications.

Incident Tuberculosis Infection is Associated with Alcohol use in Adults in Rural Uganda.

Data on alcohol use and incident Tuberculosis (TB) infection are needed. In adults aged 15+ in rural Uganda (N=49,585), estimated risk of incident TB infection was 29.2% with alcohol use vs. 19.2% without (RR: 1.49; 95%CI: 1.40-1.60). There is potential for interventions to interrupt transmission among people who drink alcohol.

Illness Narratives Without the Illness: Biomedical HIV Prevention Narratives from East Africa.

Illness narratives invite practitioners to understand how biomedical and traditional health information is incorporated, integrated, or otherwise internalized into a patient's own sense of self and social identity. Such narratives also reveal cultural values, underlying patterns in society, and the overall life context of the narrator. Most illness narratives have been examined from the perspective of European-derived genres and literary theory, even though theorists from other parts of the globe have developed locally relevant literary theories. Further, illness narratives typically examine only the experience of illness through acute or chronic suffering (and potential recovery). The advent of biomedical disease prevention methods like post- and pre-exposure prophylaxis (PEP and PrEP) for HIV, which require daily pill consumption or regular injections, complicates the notion of an illness narrative by including illness prevention in narrative accounts. This paper has two aims. First, we aim to rectify the Eurocentrism of existing illness narrative theory by incorporating insights from African literary theorists; second, we complicate the category by examining prevention narratives as a subset of illness narratives. We do this by investigating several narratives of HIV prevention from informants enrolled in an HIV prevention trial in Kenya and Uganda in 2022.

LLIN evaluation in Uganda project (LLINEUP2): association between housing construction and malaria burden in 32 districts.

BACKGROUND: Well-built housing limits mosquito entry and can reduce malaria transmission. The association between community-level housing and malaria burden in Uganda was assessed using data from randomly selected households near 64 health facilities in 32 districts. METHODS: Houses were classified as 'improved' (synthetic walls and roofs, eaves closed or absent) or 'less-improved' (all other construction). Associations between housing and parasitaemia were made using mixed effects logistic regression (individual-level) and multivariable fractional response logistic regression (community-level), and between housing and malaria incidence using multivariable Poisson regression. RESULTS: Between November 2021 and March 2022, 4.893 children aged 2-10 years were enrolled from 3.518 houses; of these, 1.389 (39.5%) were classified as improved. Children living in improved houses had 58% lower odds (adjusted odds ratio = 0.42, 95% CI 0.33-0.53, p < 0.0001) of parasitaemia than children living in less-improved houses. Communities with > 67% of houses improved had a 63% lower parasite prevalence (adjusted prevalence ratio 0.37, 95% CI 0.19-0.70, p < 0.0021) and 60% lower malaria incidence (adjusted incidence rate ratio 0.40, 95% CI 0.36-0.44, p < 0.0001) compared to communities with < 39% of houses improved. CONCLUSIONS: Improved housing was strongly associated with lower malaria burden across a range of settings in Uganda and should be utilized for malaria control.

LLIN Evaluation in Uganda Project (LLINEUP)-effects of a vector control trial on Plasmodium infection prevalence and genotypic markers of insecticide resistance in Anopheles vectors from 48 districts of Uganda.

Pyrethroid bednets treated with the synergist piperonyl butoxide (PBO) offer the possibility of improved vector control in mosquito populations with metabolic resistance. In 2017-2019, we conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus PBO (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda. In LLINEUP, and similar trials in Tanzania, PBO LLINs were found to provide greater protection against malaria than conventional LLINs, reducing parasitaemia and vector density. In the LLINEUP trial, we conducted cross-sectional household entomological surveys at baseline and then every 6 months for two years, which we use here to investigate longitudinal changes in mosquito infection rate and genetic markers of resistance. Overall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected (PCR-positive) with Plasmodium falciparum did not change significantly over time, while infection with non-falciparum malaria decreased in An. gambiae s.s., but not An. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The knock-down resistance (kdr) mutation Vgsc-995S declined over time as Vgsc-995F, the alternative resistance mutation at this codon, increased. Vgsc-995F appears to be spreading into Uganda. Distribution of LLINs in Uganda was previously found to be associated with reductions in parasite prevalence and vector density, but here we show that the proportion of infective mosquitoes remained stable across both PBO and non-PBO LLINs, suggesting that the potential for transmission persisted. The increased frequency of markers of pyrethroid resistance indicates that LLIN distribution favoured the evolution of resistance within local vectors and highlights the potential benefits of resistance management strategies.Trial registration: This study is registered with ISRCTN, ISRCTN17516395. Registered 14 February 2017, http://www.isrctn.com/ISRCTN17516395 .

Varied Prevalence of Antimalarial Drug Resistance Markers in Different Populations of Newly Arrived Refugees in Uganda.

Newly arrived refugees offer insights into malaria epidemiology in their countries of origin. We evaluated asymptomatic refugee children within 7 days of arrival in Uganda from South Sudan and the Democratic Republic of Congo (DRC) in 2022 for parasitemia, parasite species, and Plasmodium falciparum drug resistance markers. Asymptomatic P. falciparum infections were common in both populations. Coinfection with P. malariae was more common in DRC refugees. Prevalences of markers of aminoquinoline resistance (PfCRT K76T, PfMDR1 N86Y) were much higher in South Sudan refugees, of antifolate resistance (PfDHFR C59R and I164L, PfDHPS A437G, K540E, and A581G) much higher in DRC refugees, and of artemisinin partial resistance (ART-R; PfK13 C469Y and A675V) moderate in both populations. Prevalences of most mutations differed from those seen in Ugandans attending health centers near the refugee centers. Refugee evaluations yielded insights into varied malaria epidemiology and identified markers of ART-R in 2 previously little-studied countries.

LLIN Evaluation in Uganda Project (LLINEUP): modelling the impact of COVID-19-related disruptions on delivery of long-lasting insecticidal nets on malaria indicators in Uganda.

BACKGROUND: Disruptions in malaria control due to COVID-19 mitigation measures were predicted to increase malaria morbidity and mortality in Africa substantially. In Uganda, long-lasting insecticidal nets (LLINs) are distributed nationwide every 3-4 years, but the 2020-2021 campaign was altered because of COVID-19 restrictions so that the timing of delivery of new nets was different from the original plans made by the National Malaria Control Programme. METHODS: A transmission dynamics modelling exercise was conducted to explore how the altered delivery of LLINs in 2020-2021 impacted malaria burden in Uganda. Data were available on the planned LLIN distribution schedule for 2020-2021, and the actual delivery. The transmission model was used to simulate 100 health sub-districts, and parameterized to match understanding of local mosquito bionomics, net use estimates, and seasonal patterns based on data collected in 2017-2019 during a cluster-randomized trial (LLINEUP). Two scenarios were compared; simulated LLIN distributions matching the actual delivery schedule, and a comparable scenario simulating LLIN distributions as originally planned. Model parameters were otherwise matched between simulations. RESULTS: Approximately 70% of the study population received LLINs later than scheduled in 2020-2021, although some areas received LLINs earlier than planned. The model indicates that malaria incidence in 2020 was substantially higher in areas that received LLINs late. In some areas, early distribution of LLINs appeared less effective than the original distribution schedule, possibly due to attrition of LLINs prior to transmission peaks, and waning LLIN efficacy after distribution. On average, the model simulations predicted broadly similar overall mean malaria incidence in 2021 and 2022. After accounting for differences in cluster population size and LLIN distribution dates, no substantial increase in malaria burden was detected. CONCLUSIONS: The model results suggest that the disruptions in the 2020-2021 LLIN distribution campaign in Uganda did not substantially increase malaria burden in the study areas.

Placental Malaria Induces a Unique Placental Methylation Profile Associated with Fetal Growth Restriction.

Background: Fetal growth restriction (FGR) is associated with perinatal death and other adverse birth outcomes, as well as long term complications including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. FGR has been associated with placental epigenetic reprogramming, which may mediate these long term outcomes. Placental malaria (PM) is the leading cause of FGR globally, but the impact on placental epigenetics is unknown. We hypothesized that methylomic profiling of placentas from non-malarial and malarial FGR would reveal common and distinct mechanistic pathways associated with FGR. Results: We used a methylation array to compare the CpG profiles between FGR from a cohort with no malaria exposure and a cohort of pregnancies complicated by both PM and FGR. Non-malarial FGR was associated with 65 differentially methylated CpGs, whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls. One DMC (cg16389901) was commonly hypomethylated in both groups, corresponding to the promoter region of BMP4 . Comparison of FGR vs. PM-FGR identified 522 DMCs between these two groups, which was not attributable to geographic location or different cellular compositions of these two groups. Conclusion: Placentas from pregnancies with PM-associated FGR showed distinct methylation profiles as compared to non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. There may be distinct long-term health outcomes in FGR pregnancies also complicated by PM.

Effectiveness of a mindfulness and acceptance-based intervention for improving the mental health of adolescents with HIV in Uganda: An open-label trial.

Adolescents with HIV (AWH) face the double burden of dealing with challenges presented by their developmental phase while coping with stigma related to HIV, affecting their mental health. Poor mental health complicates adherence to daily treatment regimens, requiring innovative psychosocial support strategies for use with adolescents. We assessed the effectiveness of a mindfulness and acceptance-based intervention on the mental health of AWH in Uganda. One hundred and twenty-two AWH, mean age 17 ±1.59 (range 15 to 19 years), 57% female, receiving care at a public health facility in Kampala were enrolled in an open-label randomized trial (ClinicalTrials.gov: NCT05010317) with assessments at pre-and post-intervention. The mindfulness and acceptance-based intervention involved weekly 90-minute group sessions for four consecutive weeks facilitated by two experienced trainers. Sessions involved clarifying values, skillfully relating to thoughts, allowing and becoming aware of experiences non-judgmentally, and exploring life through trial and error. The control group received the current standard of care. Three mental health domains (depression, anxiety, and internalized stigma) were compared between the intervention and control groups. A linear mixed effects regression was used to analyze the effect of the intervention across the two time points. Results showed that the intervention was associated with a statistically significant reduction in symptoms of depression (ß = -10.72, 95%CI: 6.25, -15.20; p < .0001), anxiety (ß = -7.55, 95%CI: 2.66, -12.43; p = .0003) and stigma (ß = -1.40, 95%CI: 0.66 to -2.15; p = .0004) over time. Results suggest that mindfulness and acceptance-based interventions have the potential to improve the mental health of AWH.

Exploring HIV risk perception mechanisms among youth in a test-and-treat trial in Kenya and Uganda.

Understanding risk perception and risk-taking among youth can inform targeted prevention efforts. Using a health beliefs model-informed framework, we analysed 8 semi-structured, gender-specific focus group discussions with 93 youth 15-24 years old (48% male, 52% female), drawn from the SEARCH trial in rural Kenya and Uganda in 2017-2018, coinciding with the widespread introduction of PrEP. Highly connected social networks and widespread uptake of antiretrovirals shaped youth HIV risk perception. Amid conflicting information about HIV prevention methods, youth felt exposed to multiple HIV risk factors like the high prevalence of HIV, belief that people with HIV(PWH) purposefully infect others, dislike of condoms, and doubts about PrEP efficacy. Young women also reported minimal sexual autonomy in the context of economic disadvantages, the ubiquity of intergenerational and transactional sex, and peer pressure from other women to have many boyfriends. Young men likewise reported vulnerability to intergenerational sex, but also adopted a sexual conquest mentality. Comprehensive sexuality education and economic empowerment, through credible and trusted sources, may moderate risk-taking. Messaging should leverage youth's social networks to spread fact-based, gender- and age-appropriate information. PrEP should be offered alongside other reproductive health services to address both pregnancy concerns and reduce HIV risk.

Low COVID-19 vaccine uptake in people living with HIV and those with hypertension and diabetes without HIV at Mbarara and Masaka regional referral hospitals: A cross-sectional survey.

Chronic diseases such as HIV, hypertension, and diabetes increase the risk of severe coronavirus disease 2019 (COVID-19) and death. Thus, COVID-19 vaccine uptake data among these priority populations are needed to inform immunization programs. We assessed COVID-19 vaccine uptake among people living with HIV (PLWH) and those with hypertension/diabetes without HIV (PWoH) in Southwestern and Southcentral Uganda and determined factors influencing vaccination. We conducted a cross-sectional study from January to April 2023. We enrolled a random sample of participants aged 18 years and older seeking HIV, hypertension, or diabetes care at two regional referral hospitals (RRHs) in Mbarara and Masaka in Uganda. Using vaccination records abstraction and interviewer-administered questionnaires, we collected data on COVID-19 vaccine uptake, sociodemographic data, and reasons for non-uptake in unvaccinated persons. We compared COVID-19 vaccination uptake between PLWH and PWoH and applied modified Poisson regression to determine sociodemographic factors associated with vaccine uptake. The reasons for non-vaccine uptake were presented as percentages. Of the 1,376 enrolled participants, 65.6% were fully vaccinated against COVID-19. Vaccination coverage was 65% among PWLH versus 67% among PWoH. Higher education attainment and older age were associated with COVID vaccination. Participants with secondary education and those aged ≥50 years achieved >70% coverage. Fear of side effects was the most cited reason (67%) for non-vaccination among 330 unvaccinated participants, followed by vaccine mistrust (24.5%). People with chronic diseases in Southwestern Uganda had slightly lower than 70% COVID-19 vaccine coverage as recommended by WHO. Higher educational attainment and older age were linked to increased vaccine uptake. However, mistrust and fear of vaccine side effects were the main reasons for non-vaccination. To increase COVID-19 vaccine uptake, programs must reach those with lower educational attainment and younger age groups, and address the fear of vaccine side effects and mistrust among persons with underlying diseases in Uganda.

Correction: Limitations of rapid diagnostic tests in malaria surveys in areas with varied transmission intensity in Uganda 2017-2019: Implications for selection and use of HRP2 RDTs.

[This corrects the article DOI: 10.1371/journal.pone.0244457.].

Dramatic resurgence of malaria after 7 years of intensive vector control interventions in Eastern Uganda.

Background: Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015-19 following 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fludora Fusion/SumiShield). To quantify the magnitude of the resurgence, investigate causes, and evaluate the impact of a shift back to IRS with Actellic in 2023, we assessed changes in malaria metrics in regions within and near Tororo District. Methods: Malaria surveillance data from Nagongera Health Center, Tororo District was included from 2011-2023. In addition, a cohort of 667 residents from 84 houses was followed from August 2020 through September 2023 from an area bordering Tororo and neighboring Busia District, where IRS has never been implemented. Cohort participants underwent passive surveillance for clinical malaria and active surveillance for parasitemia every 28 days. Mosquitoes were collected in cohort households every 2 weeks using CDC light traps. Female Anopheles were speciated and tested for sporozoites and phenotypic insecticide resistance. Temporal comparisons of malaria metrics were stratified by geographic regions. Findings: At Nagongera Health Center average monthly malaria cases varied from 419 prior to implementation of IRS; to 56 after 5 years of IRS with Bendiocarb and Actellic; to 1591 after the change in IRS to Fludora Fusion/SumiShield; to 155 after a change back to Actellic. Among cohort participants living away from the border in Tororo, malaria incidence increased over 8-fold (0.36 vs. 2.97 episodes per person year, p<0.0001) and parasite prevalence increased over 4-fold (17% vs. 70%, p<0.0001) from 2021 to 2022 when Fludora Fusion/SumiShield was used. Incidence decreased almost 5-fold (2.97 vs. 0.70, p<0.0001) and prevalence decreased by 39% (70% vs. 43%, p<0.0001) after shifting back to Actellic. There was a similar pattern among those living near the border in Tororo, with increased incidence between 2021 and 2022 (0.93 vs. 2.40, p<0.0001) followed by a decrease after the change to Actellic (2.40 vs. 1.33, p<0.001). Among residents of Busia, malaria incidence did not change significantly over the 3 years of observation. Malaria resurgence in Tororo was temporally correlated with the replacement of An. gambiae s.s. by An. funestus as the primary vector, with a marked decrease in the density of An. funestus following the shift back to IRS with Actellic. In Busia, An. gambiae s.s. remained the primary vector throughout the observation period. Sporozoite rates were approximately 50% higher among An. funestus compared to the other common malaria vectors. Insecticide resistance phenotyping of An. funestus revealed high tolerance to clothianidin, but full susceptibility to Actellic. Conclusions: A dramatic resurgence of malaria in Tororo was temporally associated with a change to clothianidin-based IRS formulations and emergence of An. funestus as the predominant vector. Malaria decreased after a shift back to IRS with Actellic. This study highlights the ability of malaria vectors to rapidly circumvent control efforts and the importance of high-quality surveillance systems to assess the impact of malaria control interventions and generate timely, actionable data.

Monthly Sulfadoxine-Pyrimethamine During Pregnancy Prevents Febrile Respiratory Illnesses: A Secondary Analysis of a Malaria Chemoprevention Trial in Uganda.

Background: Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious antimalarial than sulfadoxine-pyrimethamine (SP); however, SP is associated with higher birthweight, suggesting that SP demonstrates "nonmalarial" effects. Chemoprevention of nonmalarial febrile illnesses (NMFIs) was explored as a possible mechanism. Methods: In this secondary analysis, we leveraged data from 654 pregnant Ugandan women without HIV infection who participated in a randomized controlled trial comparing monthly IPTp-SP with IPTp-DP. Women were enrolled between 12 and 20 gestational weeks and followed through delivery. NMFIs were measured by active and passive surveillance and defined by the absence of malaria parasitemia. We quantified associations among IPTp regimens, incident NMFIs, antibiotic prescriptions, and birthweight. Results: Mean "birthweight for gestational age" Z scores were 0.189 points (95% CI, .045-.333) higher in women randomized to IPTp-SP vs IPTp-DP. Women randomized to IPTp-SP had fewer incident NMFIs (incidence rate ratio, 0.74; 95% CI, .58-.95), mainly respiratory NMFIs (incidence rate ratio, 0.69; 95% CI, .48-1.00), vs IPTp-DP. Counterintuitively, respiratory NMFI incidence was positively correlated with birthweight in multigravidae. In total 75% of respiratory NMFIs were treated with antibiotics. Although overall antibiotic prescriptions were similar between arms, for each antibiotic prescribed, "birthweight for gestational age" Z scores increased by 0.038 points (95% CI, .001-.074). Conclusions: Monthly IPTp-SP was associated with reduced respiratory NMFI incidence, revealing a potential nonmalarial mechanism of SP and supporting current World Health Organization recommendations for IPTp-SP, even in areas with high-grade SP resistance. While maternal respiratory NMFIs are known risk factors of lower birthweight, most women in our study were presumptively treated with antibiotics, masking the potential benefit of SP on birthweight mediated through preventing respiratory NMFIs.