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A template tool for the evaluation of vaccines for emerging pathogens to be used for pregnant and breast-feeding women.
Get PDFVaccination during pregnancy provides effective protection against pathogens that increase the risk of maternal and infant morbidity and mortality for mothers and their infants. The SARS-CoV-2 pandemic demonstrated the need for the inclusion of pregnant and breast-feeding women in research and development of vaccines for emerging pathogens, such as Ebola, Zika, Lassa fever, Chikungunya, and influenza virus of pandemic potential. The COVID-19 Vaccines Global Access (COVAX) Maternal Immunization Working Group (MIWG), in collaboration with the Coalition for Epidemic Preparedness Innovation and the Safety Platform for Emergency Vaccines (CEPI-SPEAC) developed a standardized template with key considerations to guide the assessment of vaccines against emerging pathogens in pregnant and breast-feeding women. The aim of this tool is to enable key stakeholders to perform an early structured assessment of the overall potential benefit and risk for maternal immunization against an emerging pathogen. It can also be used to support risk management and pharmacovigilance planning, communication strategies, policy development, and acceptance of vaccination during pregnancy in future pandemics
Empagliflozin in resistant hypertension and heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.
Get PDFBACKGROUND AND AIMS: Hypertension has a high prevalence in heart failure with preserved ejection fraction (HFpEF), which can be controlled, uncontrolled, or even resistant. The effects of empagliflozin on systolic blood pressure (SBP), time in target range, incidence of hypertensive urgencies, and studied cardiovascular and renal outcomes in different hypertension categories and after treatment with empagliflozin in the EMPEROR-Preserved trial were explored.
METHODS: A total of 5533 patients were studied and the population was separated into resistant (resHTN), uncontrolled (uctrHTN), and controlled (ctrHTN) hypertension. The effect of SBP on outcomes and treatment effects of empagliflozin were explored. Analyses were done with Cox regression analyses adjusted for demographic and clinical confounders and with a mixed model for repeated measures.
RESULTS: Empagliflozin reduced SBP in resHTN slightly more than in the other categories in the first weeks, while thereafter there were no significant differences. The modest reduction in SBP resulted in a moderate increase in time at target and reduced hypertensive urgencies. The primary endpoint was more prevalent in resHTN (P = .0358), but the treatment effect of empagliflozin on the primary endpoint was similar in resHTN, uctrHTN, and ctrHTN (P for interaction = .92) as was the improvement of the estimated glomerular filtration rate slope (P for interaction = .95) and change in quality of life by empagliflozin.
CONCLUSIONS: In HFpEF, the prevalence of resHTN is high and is associated with frequently higher outcome rates compared with ctrHTN and uctrHTN. The treatment effect was not modified by hypertension categories. This indicates that in HFpEF, moderate modifications of blood pressure do not affect overall outcomes and treatment effects of empagliflozin
Genomic epidemiology of Plasmodium knowlesi reveals putative genetic drivers of adaptation in Malaysia.
Get PDFSabah, Malaysia, has amongst the highest burden of human Plasmodium knowlesi infection in the world, associated with increasing encroachment on the parasite's macaque host habitat. However, the genomic make-up of P. knowlesi in Sabah was previously poorly understood. To inform on local patterns of transmission and putative adaptive drivers, we conduct population-level genetic analyses of P. knowlesi human infections using 52 new whole genomes from Sabah, Malaysia, in combination with publicly available data. We identify the emergence of distinct geographical subpopulations within the macaque-associated clusters using identity-by-descent-based connectivity analysis. Secondly, we report on introgression events between the clusters, which may be linked to differentiation of the subpopulations, and that overlap genes critical for survival in human and mosquito hosts. Using village-level locations from P. knowlesi infections, we also identify associations between several introgressed regions and both intact forest perimeter-area ratio and mosquito vector habitat suitability. Our findings provide further evidence of the complex role of changing ecosystems and sympatric macaque hosts in Malaysia driving distinct genetic changes seen in P. knowlesi populations. Future expanded analyses of evolving P. knowlesi genetics and environmental drivers of transmission will be important to guide public health surveillance and control strategies
So Many Choices: A Guide to Selecting Among Methods to Adjust for Observed Confounders.
Get PDFNon-randomised studies (NRS) typically assume that there are no differences in unobserved baseline characteristics between the treatment groups under comparison. Traditionally regression models have been deployed to estimate treatment effects adjusting for observed confounders but can lead to biased estimates if the model is missspecified, by making incorrect functional form assumptions. A multitude of alternative methods have been developed which can reduce the risk of bias due to model misspecification. Investigators can now choose between many forms of matching, weighting, doubly robust, and machine learning methods. We review key concepts related to functional form assumptions and how those can contribute to bias from model misspecification. We then categorize the three frameworks for modeling treatment effects and the wide variety of estimation methods that can be applied to each framework. We consider why machine learning methods have been widely proposed for estimation and review the strengths and weaknesses of these approaches. We apply a range of these methods in re-analyzing a landmark case study. In the application, we examine how several widely used methods may be subject to bias from model misspecification. We conclude with a set of recommendations for practice
Misclassification of malaria as pneumonia in children in sub-Saharan Africa.
Get PDFBACKGROUND: The World Health Organization (WHO) clinical case definitions for pneumonia were designed to prioritize sensitivity over specificity. In sub-Saharan Africa, the disease that is most likely to be misclassified as pneumonia is Plasmodium falciparum malaria. METHODS: By using chest X-ray positivity as an indicator for pneumonia, we estimated the extent of pneumonia misclassification due to malaria in the Pneumonia Etiology Research for Child Health (PERCH) study. Additionally, we developed a simple model to predict the proportion of pneumonia cases as defined by the WHO that could be attributed to malaria in settings with varying levels of malaria parasitaemia prevalence. RESULTS: In the PERCH study, the prevalence of malaria parasitaemia was low (4.7% among WHO pneumonia cases and 1.4% among controls) and we estimate that only 2.5% of WHO pneumonia cases were misclassified. However, when assuming a prevalence of malaria parasitaemia of 24%, corresponding to the average for malaria-endemic areas in Africa, we estimate that 28% of WHO pneumonia cases are misclassified. Among malaria-slide-positive WHO pneumonia cases in PERCH, lower chest wall indrawing [adjusted odds ratio (aOR) =18.1, 95% confidence interval (95% CI): 1.9, 175.8, P = 0.012], crackles on chest auscultation (aOR = 13.1, 95% CI: 1.4, 127.4, P = 0.027), and nasal flaring (aOR = 5.9, 95% CI: 1.1, 32.8, P = 0.041) were associated with chest X-ray positivity. CONCLUSION: In settings that are typical of sub-Saharan Africa, we predict that one-quarter of WHO-defined pneumonia cases are malaria rather than pneumonia. Among children with WHO pneumonia who also test positive for malaria parasitaemia, clinical features that favour pneumonia include lower chest wall indrawing, nasal flaring, and crackles on chest auscultation
Effects of conditional cash transfers and pre-test and post-test tuberculosis counselling on patient outcomes and loss to follow-up across the continuum of care in South Africa: a randomised controlled trial.
Get PDFBACKGROUND: Economic and behavioural factors lead to poor outcomes in patients with tuberculosis. We investigated the effects of a package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers on patient outcomes in adults undergoing investigation for pulmonary tuberculosis. METHODS: This pragmatic, open-label, individual randomised controlled trial was done in nine clinics in Johannesburg, South Africa. Participants (aged ≥18 years) undergoing investigation for tuberculosis were randomly assigned (1:1) to the intervention group or control group (standard of care) via permuted block randomisation, stratified by clinic; group assignment was concealed using opaque envelopes. The intervention group received pre-test and post-test tuberculosis counselling, and for participants diagnosed with rifampicin-susceptible tuberculosis, a digital payment (R150; approximately US$10) at treatment initiation and each monthly treatment visit. Payments were contingent on timely attendance: 14 days from initial sputum sample collection and within 7 days on either side of their scheduled monthly appointment. The primary endpoint was successful patient outcome (patients who were cured or completed treatment) or unsuccessful patient outcome (pretreatment loss-to-follow-up, on-treatment loss-to-follow-up, development of rifampicin-resistant tuberculosis while on treatment, treatment failure [ie, smear or culture positive at 5 months or later after commencing treatment], or death). The primary outcome was analysed in the modified intention-to-treat population, defined as all randomly assigned participants with rifampicin-susceptible tuberculosis confirmed before the commencement of tuberculosis treatment. Weighted outcome prevalence, relative risks (RRs), and risk differences were calculated using a multivariable Poisson model with robust standard errors. This trial is registered with the Pan African Clinical Trials Registry (PACTR202410708311054) and is completed. FINDINGS: Between Oct 25, 2018, and Dec 9, 2019, 4110 participants were enrolled and randomly assigned, 2059 to the intervention group and 2051 to the control group. 381 (9·3%) participants had microbiologically confirmed rifampicin-susceptible pulmonary tuberculosis (195 [9·5%] of 2059 in the intervention group vs 186 [9·1%] of 2051 in the control group; median age 37 years [IQR 30 to 45], 257 [67·5%] male, 124 [32·5%] female). At study closure, primary outcome data were available for 128 (65·6%) of 195 participants in the intervention group and 139 (74·7%) of 186 participants in the control group. 105 (82·0%) of 128 participants in the intervention group and 93 (66·9%) of 139 participants in the control group had a successful patient outcome; 23 (18·0%) of 128 participants in the intervention group and 46 (33·1%) of 139 participants in the control group had an unsuccessful patient outcome. The weighted regression analysis showed a substantial reduction in the risk of unsuccessful patient outcomes in the intervention group compared with the control group (weighted prevalence 15·9% vs 28·6%; RR in weighted population 0·52, 95% CI 0·33 to 0·82; risk difference in weighted population -14·1 percentage points, 95% CI -23·3 to -4·8). Pretreatment loss to follow-up was lower in the intervention group than in the control group (unweighted population: five [3·9%] of 128 participants vs 22 [15·8%] of 139 participants; risk difference in weighted population -9·6 percentage points, 95% CI -14·9 to -4·2). INTERPRETATION: The package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers significantly reduced the risk of unsuccessful tuberculosis patient outcomes, bringing one of the 90-90-90 targets within reach (ie, achieving 90% tuberculosis treatment success). Furthermore, reduction in pretreatment loss to follow-up is expected to reduce transmission and lower incidence of the disease over time. FUNDING: South African Medical Research Council, UK Medical Research Council, and Newton Fund
Acceptability of and experiences with menstrual hygiene cups among adolescent girls and young women aged 15-24 in two communities in Lusaka, Zambia: an exploratory study nested in the Yathu Yathu trial.
Get PDFBACKGROUND: Menstrual cups could be a sustainable menstrual material for adolescent girls and young women (AGYW) in sub-Saharan Africa. Yathu Yathu was a cluster-randomized trial of community-based delivery of HIV and sexual and reproductive health services to young people in Lusaka, Zambia. Among services available through the intervention were menstrual products, including menstrual cups. We explored knowledge of menstruation and menstrual products, acceptability, and experiences of using cups among AGYW aged 15-24. We share lessons learned on how to distribute cups through community-based strategies to AGYW in urban communities.
METHODS: Through community-based, peer-led spaces (hubs), AGYW could access menstrual products, including pads and menstrual cups. We conducted four focus group discussions, two with AGYW aged 15-19 (n = 9) and 20-21 (n = 8) who had accessed different menstrual products through Yathu Yathu and two with AGYW aged 15-19 (n = 5) and 20-24 (n = 9) who had accessed menstrual cups. Four interviews were conducted with four AGYW (15-19, n = 2; 20-24, n = 2) who had accessed cups, and four with two AGYW who were enrolled in a qualitative cohort. Data were analyzed thematically.
RESULTS: 'Surprise' and 'fear' were initial reactions from most AGYW who saw the cups for the first time at Yathu Yathu hubs. Misconceptions that cups cause cancer and fears that they could get stuck in the vagina, cause sore, vagina enlargement, and loss of virginity were raised by AGYW. The desire to try the cup, use an alternative menstrual product and information gained at the hubs facilitated access. Use of the cup was comfortable, and cups were said to be cost-effective and durable. Advantages over pads included: the absence of odor, easy to maintain, and environmentally friendly: "it is hygienic, and it is even easy to maintain". Challenges included pain, discomfort, and failure to or incorrectly inserting the cup at initial use. When faced with challenges using the cup, AGYW reported going back to the hub for additional information and demonstrations on use.
CONCLUSION: Despite concerns, misconceptions and initial challenges, cups were acceptable among AGYW. Free distribution of cups provides an opportunity to address menstrual health challenges among AGYW. However, as a new product, there is need to increase awareness and provide detailed information on use
Dietary Sugar and Atopic Dermatitis in a Longitudinal Birth Cohort.
Get PDFIMPORTANCE: The association of diet with atopic dermatitis (AD) in children is understudied and may present an opportunity to optimize AD management in a cost-effective and low-risk manner. OBJECTIVE: The aim of this study was to determine the extent to which dietary sugar is associated with AD period prevalence and severity in a longitudinal pediatric cohort. DESIGN SETTING AND PARTICIPANTS: This was a longitudinal cohort study of children from the Avon Longitudinal Study of Parents and Children with food frequency questionnaire data to estimate dietary carbohydrate and sugar at 1, 3, 5, 7, 10, and 13 years. EXPOSURE: The exposure was dietary sugar as a proportion of total caloric intake. MAIN OUTCOME AND MEASURE: The primary outcome was AD based on a maternal- or self-reported questionnaire that asked about disease activity and severity over the past 12 months. Logistic regression models adjusted for sex, race, maternal delivery age, highest parental education level, social class assessed through parental occupation, body mass index, total caloric intake, and maternal history of AD. RESULTS: The study population included 5372 unique participants, 50% of whom were female, and 20-30% of whom reported AD at any time point. No significant associations were found at ages 1, 3, 5, and 7 years. At age 13 years, logistic regression revealed that a 10% increase in dietary sugar as a proportion of total caloric intake was associated with a 22% (95% confidence interval = 7-40%) increase in odds of AD overall. There was a dose-response relationship with disease severity: there was a 19% (95% confidence interval = 0-42%) increase in the odds of mild AD and 32% (95% confidence interval = 5-86%) increase in the odds of moderate-severe AD. When examining subtypes of dietary sugar, the effect was limited to nonmilk extrinsic sugars. CONCLUSIONS AND RELEVANCE: Given the known health benefits, reduction of nonmilk sugars could be studied as a cost-effective and low-risk intervention for AD in late childhood and early adolescence
A noninferiority cluster randomised evaluation of a broflanilide indoor residual spraying insecticide, VECTRON T500, for malaria vector control in Tanzania.
Get PDFEffective malaria vector control is being undermined by the rapid spread of insecticide resistance. VECTRON T500, a new indoor residual spraying (IRS) product containing the active ingredient broflanilide as a 50% wettable powder (WP), was previously shown to be efficacious in experimental hut trials. A two-arm non-inferiority cluster randomized controlled community trial was conducted in Muheza District, Tanga Region, Tanzania. VECTRON T500 was compared to the IRS product Fludora Fusion (clothianidin 50% + deltamethrin 6.25% WP-SB). Sixteen village clusters were pair-matched on baseline vector densities and allocated to reference and intervention arms. Monthly CDC light trapping sampled mosquitoes to estimate vector density, indoor biting, sporozoite and entomological inoculation rate (EIR). The non-inferiority margin of mosquito density was defined as a density ratio of 1.5. Susceptibility to IRS active ingredients was assessed in one of the local vectors, Anopheles gambiae sensu lato (s.l.), using WHO/CDC bottle bioassays. The residual efficacy of both IRS products was monitored for 12 months using susceptible and pyrethroid resistant An. gambiae sensu stricto (s.s.) mosquitoes. This study is registered with ClinicalTrials.gov (NCT05150808). A total of 916 and 844 houses were sprayed with Fludora Fusion and VECTRON T500, respectively, with equitable spray coverage. An. gambiae s.l. was resistant to deltamethrin but susceptible to clothianidin and broflanilide. The density ratio adjusted for baseline Anopheline mosquito density was 0.77 (95% CI: 0.45-1.29). The baseline adjusted sporozoite rate and EIR differences between the two trial arms were 0.84% and 15.61%, respectively. The residual efficacy was > 80% mortality for VECTRON T500 and Fludora Fusion, on both mud and concrete walls, 12 months post spraying. VECTRON T500 was non-inferior to Fludora Fusion in terms of its ability to reduce vector density, sporozoite rate and EIR, providing an additional vector control tool with a new mode of action for malaria prevention and insecticide resistance management
Prospective longitudinal assessment of Albumin-to-Creatinine ratio (ACR) in a clinical cohort of people living with HIV in Gaborone, Botswana.
Get PDFBACKGROUND: People living with HIV (PLWH) in sub-Saharan Africa are vulnerable to end organ dysfunction such as albuminuria, which is associated with an increased risk of cardiovascular and renal events. However, the prevalence of persistent albuminuria among PLWH in Africa is unclear. This observational prospective study assessed for persistence of albuminuria in a cohort of PLWH on longterm antiretroviral therapy (ART) across various HIV service platforms in Gaborone, Botswana. METHODS: A subgroup of ART treated PLWH (n = 867) from a larger cross-sectional study (n = 1537) assessing prevalence of albuminuria among PLWH at a referral hospital HIV clinic and satellite HIV clinics in Gaborone, were invited to participate in a 12-month long albuminuria prospective cohort study between January 2020 and March 2022. During three planned study visits, albumin-creatinine (ACR) was computed using urine albumin measured using immunoturbidimetric assay and urine creatinine using colorimetric assay (Jaffe method), at the Botswana Harvard HIV Reference Laboratory. ACR trajectory groups were identified using growth mixture models, and factors associated with ACR trajectory were analyzed using modified Poisson regression. RESULTS: Among the 623 adults with complete data for all 3 study visits, their baseline median age was 50 (42-57) years with a median HIV disease duration of 13.1 (8.7-16.7) years, and 266 (42.7%) of them were female. Study participants were categorized into two ACR trajectory groups: low increasing ACR, N = 290 (46.5%) and moderate increasing ACR, N = 333 (53.5%) groups. ACR increased by 4.7 mg/g in the slow increasing ACR groups versus 11.5 mg/g in the moderate increasing ACR trajectory group by end of follow-up. Active use of Tenofovir, aRR 1.27 [95% CI 1.02-1.60], p = 0.036, or ACEi/ARB, aRR 1.31 [95% CI 1.07-1.61], p = 0.008, and an elevated baseline ACR, aRR 1.34 [95% CI 1.28-1.41], p < 0.001, were all associated with being in the moderate increasing ACR trajectory group. CONCLUSION: Chronic, treated HIV infection was associated with more than 5 fold increase in ACR over 12 months. Future studies should explore the extent to which modifiable risk factors and HIV specific factors for progressive increase in albuminuria could be aggressively controlled among PLWH