Remote bednet use monitoring to describe patterns of use and exposure to female Anopheles mosquitoes in an Ugandan cohort.

Background: Long lasting insecticide-treated bednets (LLINs) are the most widely used tool for preventing malaria. There has been a plateau in progress in the highest burden African countries since 2015, leading to questions about the effectiveness of LLINs. In this study, remote LLIN use monitors were deployed in a cohort in Eastern Uganda to explore how LLIN use interacts with mosquito exposure. Methods: The SmartNet study included 20 households from May to October 2019. SmartNet devices recorded, every 15 min, whether an LLIN was unfurled or folded up. Unannounced visits were used to assess SmartNet accuracy. Risk factors associated with poor LLIN use were assessed using generalized linear equations. Female Anopheles exposure was estimated by combining hourly probabilities of exposure from human landing catches and measures of density from biweekly CDC light traps in participants rooms. Mosquito exposure averted by LLINs was quantified using SmartNet measurements and age-related differences were estimated using generalized linear equations, adjusting for relevant covariates and household clustering. Results: 96 individuals contributed 5,640 SmartNet observation nights. In 126 unannounced visits, SmartNet had an area under the curve of 0.869 in classifying whether the LLIN was up or down. The rate of non-use was 13.5% of nights (95% CI: 12.6-14.3%). Compared to children under 5, non-use was 1.8 times higher (95% CI: 1.6-2.1; p < 0.001) in children 5-15 years and 2.6 times higher (95% CI: 2.2-3.1; p < 0.001) in participants aged 15-<30years. There was no difference between children under 5 years and adults > 30 years. LLIN use averted 50.3% of female Anopheles mosquito exposure (95% CI: 40.0-60.0%), with decreasing point estimates of efficacy across age groups: from 61.7% (95% CI: 42.6-80.7%) in children under 5 years to 48.0% (95% CI: 29.1-66.8%) in adults over 30. Conclusions: Objective monitors are accurate and can feasibly be deployed to obtain data about LLIN use. LLINs provided protection from only 50% of female Anopheles mosquito exposure in this cohort and protection was dependent upon age. In assessing the role of LLINs in malaria prevention it is crucial to consider the dynamics between mosquito exposure and LLIN use behaviors.

House design and risk of malaria, acute respiratory infection and gastrointestinal illness in Uganda: A cohort study.

House construction is rapidly modernizing across Africa but the potential benefits for human health are poorly understood. We hypothesised that improvements to housing would be associated with reductions in malaria, acute respiratory infection (ARI) and gastrointestinal illness in an area of low malaria endemicity in Uganda. Data were analysed from a cohort study of male and female child and adult residents (n = 531) of 80 randomly-selected households in Nagongera sub-county, followed for 24 months (October 4, 2017 to October 31, 2019). Houses were classified as modern (brick walls, metal roof and closed eaves) or traditional (all other homes). Light trap collections of mosquitoes were done every two weeks in all sleeping rooms. Every four weeks, we measured malaria infection (using microscopy and qPCR to detect malaria parasites), incidence of malaria, ARI and gastrointestinal illness. We collected 15,780 adult female Anopheles over 7,631 nights. We collected 13,277 blood samples of which 10.2% (1,347) were positive for malaria parasites. Over 958 person years we diagnosed 38 episodes of uncomplicated malaria (incidence 0.04 episodes per person-year at risk), 2,553 episodes of ARI (incidence 2.7 episodes per person-year) and 387 episodes of gastrointestinal illness (incidence 0.4 episodes per person-year). Modern houses were associated with a 53% lower human biting rate compared to traditional houses (adjusted incidence rate ratio [aIRR] 0.47, 95% confidence interval [CI] 0.32-0.67, p<0.001) and a 24% lower incidence of gastrointestinal illness (aIRR 0.76, 95% CI 0.59-0.98, p = 0.04) but no changes in malaria prevalence, malaria incidence nor ARI incidence. House improvements may reduce mosquito-biting rates and gastrointestinal illness among children and adults. For the health sector to leverage Africa's housing modernization, research is urgently needed to identify the healthiest house designs and to assess their effectiveness across a range of epidemiological settings in sub-Saharan Africa.

Non-adherence to long-lasting insecticide treated bednet use following successful malaria control in Tororo, Uganda.

Indoor residual spraying (IRS) and long-lasting insecticide-treated bednets (LLINs) are common tools for reducing malaria transmission. We studied a cohort in Uganda with universal access to LLINs after 5 years of sustained IRS to explore LLIN adherence when malaria transmission has been greatly reduced. Eighty households and 526 individuals in Nagongera, Uganda were followed from October 2017 -October 2019. Every two weeks, mosquitoes were collected from sleeping rooms and LLIN adherence the prior night assessed. Episodes of malaria were diagnosed using passive surveillance. Risk factors for LLIN non-adherence were evaluated using multi-level mixed logistic regression. An age-matched case-control design was used to measure the association between LLIN non-adherence and malaria. Across all time periods, and particularly in the last 6 months, non-adherence was higher among both children <5 years (OR 3.31, 95% CI: 2.30-4.75; p<0.001) and school-aged children 5-17 years (OR 6.88, 95% CI: 5.01-9.45; p<0.001) compared to adults. In the first 18 months, collection of fewer mosquitoes was associated with non-adherence (OR 3.25, 95% CI: 2.92-3.63; p<0.001), and, in the last 6 months, residents of poorer households were less adherent (OR 5.1, 95% CI: 1.17-22.2; p = 0.03). Any reported non-adherence over the prior two months was associated with a 15-fold increase in the odds of having malaria (OR 15.0, 95% CI: 1.95 to 114.9; p = 0.009). Knowledge about LLIN use was high, and the most frequently reported barriers to use included heat and low perceived risk of malaria. Children, particularly school-aged, participants exposed to fewer mosquitoes, and those from poorer households, were less likely to use LLINs. Non-adherence to LLINs was associated with an increased risk of malaria. Strategies, such as behavior change communications, should be prioritized to ensure consistent LLIN use even when malaria transmission has been greatly reduced.

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. RESULTS: We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. CONCLUSIONS: These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.