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A Prospective Evaluation of a Three-Gene Host Response Signature to Classify Tuberculosis Severity in Children.
Get PDFBACKGROUND: Children with non-severe TB may benefit from short-course treatment, but point-of-care tools are needed to stratify disease severity. We prospectively evaluated the Cepheid Xpert MTB-Host Response (HR) prototype cartridge for distinguishing TB severity in children with pulmonary TB (PTB) in The Gambia and Uganda. METHODS: We included children <15 with microbiologically confirmed or clinically diagnosed unconfirmed PTB. Severity was defined using the World Health Organization (WHO) guidelines for a four-month, drug-susceptible regimen. Capillary or venous blood was tested with the HR cartridge for PCR-based detection of 3 mRNA genes and calculation of a TB score from cycle thresholds. We generated receiver operating characteristic curves with the TB score to classify severe TB and assessed if Xpert-HR could achieve the WHO target accuracy for treatment optimization (≥90% sensitivity, ≥70% specificity). RESULTS: Among 106 children, the median age was 4 years (IQR 1-7), 56.6% were female, and 13.2% were living with HIV. In all children with PTB, Xpert-HR achieved an AUC of 0.67 (95% CI 0.55-0.78), with 89.3% sensitivity (95% CI 71.8-97.7) and 29.5% specificity (95% CI 19.7-40.9, cutoff ≤ -0.60). By confirmation status, Xpert-HR approached the target accuracy in children with Confirmed TB, with 62.5% specificity (95% CI 24.5-91.5) at 91.7% sensitivity (95% CI 61.5-99.8, cut-off ≤ -1.349). Among children with Unconfirmed TB, specificity was lower (24.3%, 95% CI 14.8-36.0) at 93.8% sensitivity (95% CI 69.8-99.8, cutoff ≤ -0.450). Target accuracy was almost achieved in children 5-9 regardless of confirmation status (100% sensitivity [95% CI 71.5-100], 66.7% specificity [95% CI 43.0-85.4], cutoff ≤ -1.35), but specificity (28.2%, 95% CI 18.6-39.5) was lower for children < 5 (92.9% sensitivity, 95% CI 76.5-99.1, cutoff ≤ -0.550). CONCLUSIONS: Xpert-HR approached the target accuracy to stratify PTB severity in older children and those with Confirmed TB but had lower specificity in children with Unconfirmed TB. Child-specific signatures may be needed to improve performance in younger children with paucibacillary disease
For girls and women (4GW) HPV RCT protocol: a crowdsourced, pragmatic stepped-wedge cluster randomized trial to improve uptake of HPV vaccination and screening among mother-daughter dyads in Nigeria.
Get PDFBACKGROUND: Expanding human papillomavirus (HPV) vaccination for girls and HPV self-collection for women can reduce the global burden of cervical cancer. However, HPV vaccination and self-collection services are rarely implemented simultaneously in mother-daughter dyads, leaving a critical gap in cervical cancer prevention. From 2023 to 2024, a community-engaged model for combined HPV vaccination and screening was co-designed using crowdsourcing open calls and designathons with mother-daughter teams and pilot-tested by trained research facilitators. This study explores the impact of this crowdsourced, community-engaged mother-daughter campaign and implementation strategy bundle on HPV vaccination among girls and HPV screening among their mothers in Nigeria over 6 months in 18 Nigerian local government areas (LGAs). METHODS: A hybrid effectiveness-implementation type II pragmatic stepped-wedge cluster randomized control trial has been employed to the effectiveness of an implementation strategy bundle; a crowdsourced, tailored, community-engaged, mother-daughter HPV campaign on increasing uptake of HPV vaccination among girls aged 9-14 and HPV screening uptake among women aged 30-49 in Nigeria. The mother-daughter campaign will be tailored to local sites and conducted among 612 mother-daughter dyads (1,224 participants) recruited from 18 LGAs in six geopolitical zones of Nigeria. Trained community health workers will collect baseline data and implement a mother-daughter campaign that will provide education on cervical cancer control and access to onsite services for HPV vaccination and screening in a private area while engaging mothers and daughters simultaneously to increase uptake of the services. A mixed-methods evaluative and iterative assessment will be conducted using Proctor's Implementation Outcomes Framework and the PEN- 3 cultural model. The primary outcomes are the uptake of HPV preventive measures-HPV vaccination (one dose) among girls (ascertained by onsite clinical records of vaccine uptake) and HPV self-collection completion among mothers (ascertained by laboratory receipt of self-collected specimens) within six months of trial enrollment. Pre-post effectiveness and cost of study components are embedded in the implementation and sustainment phases, compared to pre-implementation data assessed for each LGA. DISCUSSION: This study is a unique dyadic intervention focused on both girls and their mothers or female caregivers to drive cervical cancer control in Africa. Findings have the potential to inform local and global policies aimed at reducing the cervical cancer burden in African countries like Nigeria, eliminating missed opportunities by closing the research-to-translation gap. The protocol was registered with clinicaltrials.gov under registration NCT06728085
Feasibility of Tiyanjane: A Family–School–Community Intervention Promoting Parental Involvement in the Education of Children with Disabilities in Malawi
Get PDFEvidence-based and theory-informed interventions focusing on parents of children with disabilities in low-income countries are scarce. This study examined the feasibility of Tiyanjane, a 12-week pilot intervention developed to promote parental involvement in the education of children with disabilities in Malawi. A mixed-method approach was employed based on five aspects of Bowen’s feasibility framework: acceptability, demand, implementation, practicality, and limited efficacy. Twenty-one participants (13 caregivers, four teachers, and four local leaders) participated in the study. Standardised measures, namely the Parent and Family Adjustment Scale (PAFAS) and the Multidimensional Scale of Perceived Social Support (MSPSS), were employed to evaluate changes in parental practices, adjustments, and perceived social support. Qualitative data were collected using focus groups and in-depth interviews to assess the feasibility of the intervention. Tiyanjane showed promise in promoting parental involvement in the education of children with disabilities. The intervention demonstrated high fidelity, achieving 100% retention and 95% attendance. Local resources, commitment from participants and facilitators, and strong family school–community ties enabled the practicality and execution of the intervention. Significant improvements were observed in the PAFAS and MSPSS scores across the assessed post-intervention outcomes. Minor logistical issues including resource and implementation challenges were reported. Tiyanjane was feasible for the facilitators and participants in the Malawian context. Further studies are needed to assess the programme’s adaptation, integration, and expansion in other contexts before scaling up
Developing guidelines for culturally relevant informed consent: an example from Lebanon.
Get PDFThis study addresses the prominent gap in literature and practice by exploring the facilitators and barriers to informed consent and developing culturally relevant informed consent guidelines in Lebanon. Utilizing a Design Thinking (DT) framework combined with Participatory Action Research (PAR), the study aimed to: i) explore what constitutes culturally relevant informed consent in this context, according to both researchers and affected communities; and ii) use these insights to create a guideline aimed at enhancing informed consent processes for vulnerable populations involved in mental health research. The study revealed that motivations for participation, trust-building, and timing are critical yet often overlooked aspects in informed consent processes. Language and literacy barriers, along with power imbalances, present significant challenges that can be mitigated by involving community members and trained interpreters. Trust-building, especially in long-term studies, requires sustained relationships and recognizing participants' intrinsic value. Timing and clarity in consent forms, along with concise and straightforward communication, are essential for genuine informed consent. The study also highlighted the impact of gender, nationality, and community support in research participation, underscoring the need for culturally sensitive research practices. Recommendations include using audio-visual methods and the "Teach Back Method" to enhance understanding and engagement. This research emphasizes the importance of inclusive and participant-centric approaches in informed consent processes. The collaborative development of the guideline ensured diverse perspectives, leading to a comprehensive and relevant outcome. Future research should focus on testing the guideline
Safety and efficacy of praziquantel 40 mg/kg versus 80 mg/kg in preschool-aged children with intestinal schistosomiasis in Uganda: a 2 × 2 factorial, double-blind, placebo-controlled, phase 2 randomised trial.
Get PDFBACKGROUND: Optimal dosing of praziquantel for schistosomiasis for children younger than 5 years is not established and some studies suggest this age group might need a higher dosing per kilogram. Our aim was to assess the safety and efficacy of a split dose of 80 mg/kg of praziquantel tablets given in a single day to preschool children versus the recommended single dose of 40 mg/kg for treatment of Schistosoma mansoni. METHODS: We did a 2 × 2 factorial design, placebo-controlled, phase 2 randomised trial in Uganda. Children aged 12-47 months infected with Schistosoma mansoni were randomly assigned in a 1:1:1:1 ratio to receive crushed praziquantel tablets at single standard (40 mg/kg) versus double standard dosing (80 mg/kg delivered as two 40 mg/kg doses 3 hours apart) and same dose or placebo at 6 months. Coprimary outcomes were parasitological cure and egg reduction rate at 4 weeks. Secondary outcomes included antigenic cure at 4 weeks, adverse events and clinical toxicity 12 h after treatment, and key morbidity markers at 6 months and 12 months. This trial is registered with ClinicalTrials.gov (NCT03640377). FINDINGS: Between Feb 18 and Dec 14, 2021, 354 children were randomly assigned to either praziquantel 40 mg/kg at baseline and placebo at 6 months (n=88); 40 mg/kg at baseline and 40 mg/kg at 6 months (n=86); 80 mg/kg at baseline and placebo at 6 months (m=89); or 80 mg/kg at baseline and 80 mg/kg at 6 months (n=91). 181 (51%) of 354 participants were boys. The median age was 36 months (28-42). Cure rate at 4 weeks was 67% in the 40 mg/kg group and 90% in the 80 mg/kg group (absolute difference 23% [95% CI 14-31]; p<0·001); for egg reduction rate the difference was 2% (95% CI 1-3; p<0·001) based on geometric mean and 22% (5-59; p<0·001) based on arithmetic mean. There were no differences in adverse event rates between the trial groups. At 12 months, biannual versus annual treatment reduced prevalence of faecal occult blood and 80 mg/kg dose reduced prevalence of faecal calprotectin. No severe adverse events related to the study drug were reported. INTERPRETATION: Two 40 mg/kg doses given 3 hours apart are safe, well tolerated, and more effective in achieving parasitic cure than the current proposed single 40 mg/kg dose. Until a paediatric formulation of praziquantel is available in endemic areas, the use of crushed tablets with this dosing strategy can be recommended for young children living in S mansoni endemic areas. In addition, twice-a-year treatment compared with once-a-year treatment affected some intestinal morbidity markers. FUNDING: US National Institutes of Health's National Institute of Child Health and Human Development. TRANSLATION: For the Alur translation of the abstract see Supplementary Materials section
Sex differences in the risk of Mycobacterium tuberculosis infection: a systematic review and meta-analysis of population-based immunoreactivity surveys.
Get PDFBACKGROUND: Tuberculosis killed 1·25 million people globally in 2023. Men have a 1·7 times higher tuberculosis incidence than women, but it is not known to what extent this discrepancy is driven by greater exposure to Mycobacterium tuberculosis. We aimed to analyse the effect of age and sex on M tuberculosis immunoreactivity. METHODS: In this systematic review and meta-analysis, we reviewed Embase, Global Health databases, Science Citation Index Expanded, and Global Index Medicus for population-based M tuberculosis immunoreactivity (with interferon-γ release assay or skin test) surveys done in high tuberculosis incidence settings from Jan 1, 1993, to Dec 31, 2022, with a sample size of at least 150 people. We included cross-sectional surveys, baseline surveys for interventional or cohort studies, and control groups of case-control studies with population-representative groups. We extracted data on M tuberculosis immunoreactivity prevalence, disaggregated by sex and age group. We constructed Bayesian hierarchical models, first of immunoreactivity prevalence by age and sex and second of the male-to-female (M:F) prevalence ratio by age. We analysed the effect of covariables including region, tuberculosis incidence, and study year. This study was registered on PROSPERO (CRD42022360483). FINDINGS: We screened 26 517 studies, of which 167 met our inclusion criteria. Sex-disaggregated results were available from 80 studies (81 surveys), from 38 different countries, comprising data from 478 968 participants. We found little sex difference in M tuberculosis immunoreactivity in childhood (M:F prevalence ratio for children younger than 10 years was 0·95; 95% credible interval 0·90-1·01). However, from adolescence onwards, men experienced higher immunoreactivity conversion than women (1·4 times higher by age 30 years). This higher conversion rate cumulatively drove a higher immunoreactivity prevalence in men, with a prevalence ratio of 1·07 (95% credible interval 1·01-1·13) in those aged 10-19 years, 1·13 (1·06-1·20) in those aged 20-39 years, and 1·28 (1·19-1·37) for those aged 40 years and older. Adult men had consistently higher M tuberculosis prevalence across different settings, with low between-study heterogeneity in M:F prevalence ratio. INTERPRETATION: Men have higher M tuberculosis immunoreactivity risk than women, which is likely to be a key driver of the sex differences in global tuberculosis morbidity and mortality. This difference could be due to higher exposure through social and behavioural differences in time spent in congregate indoor spaces where tuberculosis transmission occurs, further amplified by longer duration of infectiousness in men, and age-assortative and sex-assortative mixing. Public health interventions addressing men's determinants of M tuberculosis exposure will be crucial to ending the tuberculosis epidemic. FUNDING: Wellcome Trust and UK Foreign, Commonwealth & Development Office
Contact data and SARS-CoV-2: Retrospective analysis of the estimated impact of the first UK lockdown.
Get PDFTo combat the spread of SARS-CoV-2 in March 2020 the United Kingdom (UK) announced a series of restrictions on social interaction, culminating with the introduction of lockdown measures. Estimation of lockdown effectiveness using pandemic models relied on the availability of contact data and choices on how to structure models accordingly. We revisit the Cambridge/Public Health England real-time model (RTM), which was routinely implemented during the pandemic to monitor its development and produce short-term projections. To derive contact matrices, Google Mobility weekly contact data and school attendance data from the Department for Education were combined with information from the POLYMOD study and the UK Time Use Survey. These matrices were combined with susceptibility and transmissibility parameters to estimate effective reproduction numbers, which were taken as indicators of transmission trends. We explore alternative formulations of the RTM, which make fuller use of the available contact data, and assess the impact of each formulation on the conclusions of lockdown effectiveness. Results show that the estimated impact of the lockdown remains unchanged, but also uncover previously uncaptured early epidemic dynamics. This highlights the importance of the timely availability of contact data in understanding transmission dynamics during the early stages of an epidemic and assessing the effectiveness of interventions
Adverse fetal and perinatal outcomes associated with Zika virus infection during pregnancy: an individual participant data meta-analysis
Get PDFBackground: Zika virus (ZIKV) infection during pregnancy is associated with an increased risk of congenital malformations. The prevalence of short and long-term consequences, however, remains uncertain due to heterogeneity across studies. Individual Participant Data Meta-Analysis (IPD-MA) offers an alternative approach to provide more precise and generalisable estimates through data harmonisation across studies, allowing for standardised definitions and exploration of heterogeneity. This project was undertaken to estimate absolute and relative risks of adverse outcomes for individuals with ZIKV infection during pregnancy. Methods: IPD-MA studies and their datasets were identified through a systematic search conducted in 2018 with the following criteria: observational longitudinal or surveillance-based studies investigating ZIKV during pregnancy or at birth, measured fetal, infant, or child outcomes, and included at least 10 participants. Here we used IPD data shared by March 2022 from 18 studies from international health organisations and research networks, comprising 24 unique datasets, in 11 countries. Datasets were harmonised with standardised definitions, using variables related to pregnant individuals, methods used for ZIKV diagnoses, fetal characteristics and outcomes, and pooled for analysis. Frequentist and Bayesian regression methods were applied to estimate outcome prevalence and evaluate the association between maternal ZIKV infection and fetal loss, microcephaly and congenital zika syndrome as primary outcomes. Findings: Data including 9568 pregnant individuals and 9608 newborns, were harmonised. The risk of severe primary microcephaly was significantly higher in ZIKV-positive pregnancies (1.5%, CI 0.8%–2.7%) compared to ZIKV-negative ones (0.3%, CI 0.1%–1.0%), with a relative risk of 4.5 (CI 1.5–13.3) in the one-stage meta-analysis. While some risk estimates were consistent between Bayesian and Frequentist methods, estimates for other outcomes varied, underscoring the influence of both the analytical approach and the definition of ZIKV on the associations. Interpretation: Our findings align with previously published meta-analyses and indicate an added burden to adverse pregnancy outcomes with higher prevalence compared to pre-epidemic population-based average values. Future research should focus on additional outcomes with clear definitions of maternal infection. Women of reproductive age should be informed about the risks of Zika infection during pregnancy to support reproductive planning. Funding: This project was supported by the Wellcome Trust grant number 206532/Z/17/Z, the WHO Health Emergencies Programme Global Arbovirus Initiative, and the WHO Department of Sexual and Reproductive Health and Research, including the Human Reproduction Special Programme (HRP)
Cannabis Use and Self-Reported Bothersome Symptoms in People with HIV.
Get PDFOBJECTIVE: While cannabis use is common among people with HIV (PWH), there have been few studies examining the association of use with health outcomes among PWH. We aimed to evaluate the association between cannabis use and bothersome physical and mental health symptoms using both self-report and a direct biomarker for cannabis use. METHOD: The Medications, Alcohol and Substance use in HIV Study (MASH) is a cross-cohort study focused on polypharmacy and substance use among PWH. Participants were enrolled from October 2018 to May 2022 in the Swiss HIV Cohort Study (SHCS), Kaiser Permanente Northern California (KPNC) HIV Cohort, and 7 sites (Atlanta, GA; Bronx, NY; Washington, DC; Houston, TX; Los Angeles, CA; New York, NY; and Nashville, TN) in the Veterans Aging Cohort Study - HIV (VACS-HIV). Participants submitted self-reported information on the presence/absence of symptoms in the prior 4 weeks, along with bothersome level, using the HIV Symptom Index, which is comprised of 20 symptoms commonly reported in PWH, including fatigue, diarrhea, fever, anxiety, and weight loss, among others. Concurrent self-reported substance use information was also collected, and participants provided nail clippings to be tested for cannabis use. We used logistic regression models, adjusted for age, sex, race/ethnicity, and cohort, to examine associations of self-report and biomarker-identified cannabis use with self-reported bothersome symptoms. RESULTS: The analytic sample included 1,226 PWH who were predominantly male (85%), non-white (64%), with an average age of 57 years; 20% tested positive for cannabis use, and 23% reported recent cannabis use. Agreement between self-report and biomarker cannabis use was substantial (agreement 89%, kappa = 0.67). Put together, 27% either reported cannabis use or tested positive. Of the 20 symptoms included in the HIV Symptom Index, 19 were more prevalent at a bothersome level among those with cannabis use compared to those without. In adjusted models, the patterns of association remained for both self-reported and biomarker-confirmed cannabis use, and they were particularly substantial for memory, depression, anxiety, and nausea. CONCLUSIONS: Cannabis use was common among PWH and was associated with a number of bothersome symptoms. While cannabis use may be used to treat loss of appetite, nausea/vomiting, and weight loss, the associations of cannabis use with depression, anxiety, and memory loss are concerning and deserve investigation
Evidence quality and uncertainties considered in appraisal documents of drugs for rare diseases in England and Germany: a data extraction protocol.
Get PDFINTRODUCTION: Rare disease treatments (RDTs) promise considerable patient benefit but the evidence to demonstrate their value in health technology assessment (HTA) is often limited. HTA outcomes for RDTs vary across countries and there are differences in how uncertainty is dealt with by HTA agencies. Yet, there is limited comparative research assessing how different HTA agencies consider issues affecting evidence quality and uncertainty in RDT appraisals. This protocol describes a systematic and consistent approach for data extraction from RDT appraisal documents produced to inform decisions by HTA agencies. By documenting data extraction rules transparently, we ensure reproducibility and reliability of analyses of the extracted data. METHODS AND ANALYSIS: We will select RDT appraisals issued by the National Institute for Health and Care Excellence (NICE) in England and the Federal Joint Committee (GBA) in Germany, using predefined inclusion criteria. We will extract data from appraisal documents in accordance with the rules set out in this protocol. We will analyse the extracted data to investigate how issues affecting evidence quality and uncertainty as documented in appraisals are considered, highlighting the similarities and differences between countries and identifying factors that are associated with HTA outcomes. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of the London School of Hygiene & Tropical Medicine (reference number 29156). Study results will be submitted for publication in peer-reviewed journals