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Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis.
Get PDFGenetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) remain poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify Toll-like receptor 8 (TLR8) as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances the killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant M1V, common in Far Eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signaling may, therefore, both regulate susceptibility to tuberculosis and provide novel drug targets
Study on health seeking behaviour and determinants of undiagnosed hypertension in poor households in the Philippines, part of the RESPOND study (SHARP-RESPOND).
Get PDFHypertension is one of the leading preventable causes of premature death. Although it can be effectively managed with relatively simple interventions, up to 50% of individuals with hypertension in low- and middle-income countries (LMICs) remain undiagnosed. Key factors influencing the health-seeking behaviour of patients with hypertension include household wealth, knowledge about hypertension, perceptions of treatment effectiveness, and access to blood pressure measurement. However, evidence on the facilitators and barriers to hypertension diagnosis in low-income households within LMICs remains inconsistent. This study aims to describe the characteristics and health-seeking behaviours of individuals with undiagnosed hypertension in low-income households in the Philippines and identify the factors influencing undiagnosed hypertension. The study included 516 people with hypertension from low-income households in the Philippines as part of the RESPOND study. Characteristics of participants with undiagnosed hypertension were compared to those with diagnosed hypertension to identify determinants of undiagnosed cases. A follow-up survey one year later gathered data on whether undiagnosed participants had subsequently received a formal diagnosis. In this study, 26.6% of people with hypertension in low-income households were undiagnosed. Over one year, only 25.4% of these undiagnosed individuals received a formal diagnosis. Factors associated with lower odds of undiagnosed hypertension included belief in the effectiveness of Western medicine, recent blood pressure measurement, receipt of health information in the preceding year, presence of comorbidities, and participation in social organisations. Conversely, living in rural areas, employment, and belief in the effectiveness of traditional medicine were linked to higher odds of remaining undiagnosed. A substantial proportion of people with hypertension in low-income households in the Philippines remain undiagnosed. Addressing this issue requires a multifaceted approach targeting the social determinants of health and addressing specific barriers to hypertension diagnosis. Insights from this study can inform strategies to improve hypertension control in other LMICs
Partnership to Develop an Inter-Disciplinary Schistosomiasis Research Training Program in Uganda.
Get PDFThe WHO 2021-2030 roadmap for neglected tropical diseases (NTDs) and the 2022 Kigali Declaration urge academic research institutions to unite in combating NTDs, including schistosomiasis, and emphasize the importance of strategic partnerships to free more than 1 billion people who require interventions against NTDs. We conducted stakeholder meetings to understand the landscape of schistosomiasis research training in Uganda and the existing collaborations with research institutions in sub-Saharan Africa, Europe, the United Kingdom, and the United States. In focus group discussions (involving 33 individuals from four institutions), key challenges were summarized into four emerging themes: 1) limited physical infrastructure for schistosomiasis research and training, 2) a low critical mass of scientists with competencies in schistosomiasis research, 3) a limited scope of current schistosomiasis research, and 4) limited advocacy and community engagement for schistosomiasis control. National and international partnerships, as well as partnerships between academics and implementers, should be harnessed to establish a vibrant network for schistosomiasis research training in resource-limited settings where the disease remains endemic
Two chromosomal reference genome sequences for the malaria mosquito, Anopheles ( Nyssorhynchus) darlingi, Root, 1926 from French Guiana and Peru.
Get PDFWe present two genome assemblies, each generated from individual female Anopheles ( Nyssorhynchus) darlingi (the malaria mosquito; Arthropoda; Insecta; Diptera; Culicidae), from wild populations in French Guiana and Peru. The genome sequences are approximately 180 megabases in span. The majority of each assembly is scaffolded into three chromosomal pseudomolecules with the X sex chromosome assembled. The complete mitochondrial genomes were also assembled and are both 15.4 kilobases in length. The assemblies differ by two inversions in chromosome arm 2R
Who has never tested for HIV following a community-based distribution of HIV self-test kits? Establishing associated predictors in rural Zimbabwe.
Get PDFIn 2023, Zimbabwe attained the 95-95-95 UNAIDS targets. However, some sub-populations are substantially less likely to have tested for HIV. Knowledge of characteristics of these groups is crucial in designing interventions that address their needs. We estimated the prevalence and predictors of "never-having tested for HIV" status following community-based distribution of HIV self-test kits in rural Zimbabwe. We analysed data from a household survey conducted as part of a cluster randomised trial comparing two community-based HIVST distribution models in six rural districts in 2018-19. HIVST distribution was conducted over one month, followed by the household survey after four months. Survey participants aged 16 years and above completed self-administered Audio-Computer-Assisted-Survey-Instrument. Unadjusted and adjusted mixed effect logistic regression was used to identify factors associated with never-having-tested for HIV. Of the 11,076 analysed participants, the median (IQR) age was 32(22,45) years and 54.5% were female. Seventeen percent of participants had never tested for HIV, primarily due to a perceived lack of HIV risk (50%). Never testers were more likely to be: men (adjusted odds ratio [AOR]=1.69;95%Confidence Interval [CI]=1.52-1.87); younger (16-24 years (AOR=3.84; 95%CI=3.23-4.55), 25-34 years (AOR=1.30; 95%CI=1.07-1.59)) and at-least 45 years old: (AOR=2.17; 95%CI=1.80-2.60); having lower levels of education: primary/less (AOR=1.68; 95%CI=1.46-1.98), some secondary (AOR=1.62; 95%CI=1.42-1.86) compared to at least complete secondary, unemployed (AOR=1.39; 95%CI=1.15-1.69); never married (AOR=3.48; 95%CI=2.98-4.07) and previously married (AOR=1.41; 95%CI=1.19-1.68) compared to currently married; having stigmatizing beliefs (AOR=1.42; 95%CI=1.24-1.62); having: low (AOR=1.52, 95%CI=1.32-1.74) and medium (OR=1.53, 95%CI=1.33-1.75) levels of treatment optimism; not participating in household decisions (AOR=1.96; 95%CI=1.70-2.27) and not reporting condomless sex (AOR=2.58; 95%CI=2.31-2.87). The Ministry of Health need to scale up acceptable and targeted interventions to improve HIV testing in different subpopulations which includes but not limited to young people, unmarried, unemployed, those with stigmatizing beliefs and those not participating in decision making
Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Preserved Trial.
No full textBACKGROUND: There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria. METHODS: In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria. RESULTS: The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria). CONCLUSIONS: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951)
Challenges with achieving and maintaining oral cholera vaccine coverage: insights from serial cross-sectional representative surveys in a cholera-endemic community in the Democratic Republic of the Congo.
Get PDFBACKGROUND: We conducted three serial cross-sectional representative surveys after a mass cholera vaccination campaign in Uvira, Democratic Republic of the Congo to (1) estimate the vaccination coverage and explore heterogeneity by geographic and demographic factors; (2) examine barriers and facilitators of vaccine uptake and (3) describe the changes in coverage over time and predict future coverage. METHODS: We collected data on sociodemographics, self-reported vaccination status, population movement and knowledge, attitudes and behaviours related to killed oral cholera vaccines (kOCVs) in August 2021, April 2022 and April 2023, approximately 11, 19 and 30 months postvaccination. We compared the characteristics of participants by vaccination status and explored the potential role of population movement as a cause for low coverage. We used an exponential decay model to predict the proportion of the population vaccinated with ≥1 dose of kOCV over time based on age-specific coverage. RESULTS: We enrolled 8735 participants from 1433 households across all surveys. Coverage in survey 1 (August 2021) was 55% for ≥1 dose of kOCV (95% CI 51 to 60) and 23% for ≥2 doses (95% CI 20 to 27). Vaccine refusal was associated with a lack of confidence in the vaccine's safety, and 29% of unvaccinated adults reported it was unlikely they would accept kOCVs if an additional mass vaccination campaign was conducted in their area. Coverage of ≥1 one dose of kOCV declined on average by 18% per year (95% credible interval 14 to 23) and was 39% (95% CI 36 to 43) by survey 3 (approx. 30 months after second dose campaign). CONCLUSIONS: Our findings suggest that in settings like Uvira, efforts to strengthen vaccine confidence are needed to achieve higher campaign coverage, and vaccine coverage dilution may be reduced by more frequent and coordinated geographic vaccination efforts
Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations.
Get PDFDespite neurobiological overlap, alcohol use disorder (AUD) and body mass index (BMI) show minimal genetic correlation (rg), possibly due to mixed directions of shared variants. Here we applied MiXeR to investigate shared genetic architecture between AUD and BMI, conjunctional false discovery rate to detect shared loci and their directional effect, local analysis of (co)variant association for local rg, functional mapping and annotation to identify lead single-nucleotide polymorphisms, Genotype-Tissue Expression (GTEx) to examine tissue enrichment and BrainXcan to assess associations with brain phenotypes. MiXeR indicated 82.2% polygenic overlap, despite an rg of -0.03. The conjuctional false discovery rate method identified 132 shared lead single-nucleotide polymorphisms, with 53 novel, showing both concordant and discordant effects. GTEx analyses identified overexpression in multiple brain regions. Amygdala and caudate nucleus volumes were associated with AUD and BMI. Opposing variant effects explain the minimal rg between AUD and BMI, with implicated brain regions involved in executive function and reward, clarifying their polygenic overlap and neurobiological mechanisms
Translating Formative Research into Intervention Content: Experiences with Face Washing for Trachoma Control in Rural Ethiopia.
Get PDFFace washing for trachoma, like most public health improvements, necessitates behaviour change, yet traditional educational interventions frequently fail to achieve this goal. Behavioural science frameworks offer guidance to develop alternative types of interventions, helping to translate formative research and insights about the target population and behavioural determinants into more effective strategies. This paper outlines the outputs and decision-making underlying the five-stage process we followed to translate formative research findings into intervention activities and materials: (1) synthesising formative research findings into a creative brief to guide intervention development; (2) selecting behaviour change techniques (BCTs) to address key behavioural targets; (3) selecting an overarching intervention concept; (4) developing intervention content; and (5) finalising the intervention's Theory of Change. This paper presents our experiences and reflections on the intervention design process, using a practical example of a face washing intervention for trachoma control. The intervention was designed for delivery in the Stronger SAFE trial in rural Oromia, Ethiopia (ISCRTN 40760473)
Risk of rifampicin resistance emergence after incomplete first-line tuberculosis treatment.
Get PDFTuberculosis (TB) treatment is lengthy and causes side-effects, making treatment completion challenging. Some patients are “lost to follow-up” (LTFU) before completing treatment. Patients sometimes subsequently return to care if symptoms motivate them, or if health systems and/or personal issues that caused LTFU are resolved. Case–control studies have established that drug-susceptible TB treatment and incomplete adherence were risk factors for relapse with drug-resistant TB, but its frequency and the lengths of incomplete treatment that pose the greatest risk are unknown [1, 2]. We aimed to estimate the risk of recurrent TB, and specifically rifampicin-resistant TB (RIF-R), after rifampicin-susceptible TB (RS-TB) treatment and how these risks vary depending on previous RS-TB treatment length