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Robust evaluation of vaccine effects based on estimation of vaccine efficacy curve.
Get PDFThe Cox model and its extensions assuming proportional hazards is widely used to estimate vaccine efficacy (VE). However, when VE wanes over time, estimates can become sensitive to study duration and timing of vaccine delivery relative to disease seasonality, and may be biased due to sample attrition. Additionally, estimates of vaccine impact such as number of cases averted (NCA) are sensitive to background disease incidence and timing of vaccine delivery. Comparison of the estimates between trials with different implementation features can be misleading. We propose estimation of VE as a function of time in the Cox model framework, using the area under the VE curve as a summary measure of VE, and extension of the method to estimate vaccine impact. We use simulations and re-analysis of a RTS,S/AS01 malaria vaccine trial dataset to demonstrate their properties and applications. Simulation under scenarios with different trial duration, magnitude of sample attrition and timing of vaccine delivery, all assuming vaccine protection wanes over time, demonstrated problems of conventional methods assuming proportional hazard, robustness of the proposed methods, and comparability of the proposed estimates of vaccine efficacy and impact across trials with different implementation features. Furthermore, the proposed NCA estimators are informative in determining the optimal vaccine delivery strategy in regions with highly seasonal disease transmission. The proposed method based on estimation of vaccine efficacy trajectory provides a robust, unbiased, and flexible approach to evaluate vaccine effects
Small countries face specific challenges in health workforce sustainability, but policy responses are a testbed for resilience for all countries.
No full textWhile countries across Europe are facing challenges in building and sustaining a health workforce, small countries (official population of under 2 million people) face specific challenges that go beyond resource constraint. Limited population size constrains training capacity, specialist care provision, and career development opportunities, making these systems highly vulnerable to workforce shortages. Experiences in Cyprus, Luxembourg, North Macedonia, and the Caribbean Netherlands illustrate these dynamics. Cyprus and Luxembourg have expanded in-country medical education and postgraduate training to reduce the need for training abroad. In contrast, North Macedonia trains sufficient health professionals but struggles with outmigration. Island territories face additional logistical and geographic barriers. The Caribbean Netherlands rely on rotations and cross-border care for many healthcare services. Small countries are like a microscope that magnifies both the problems and the policy responses and may thus serve as a testbed for all health systems confronting workforce challenges. Small country experiences underscore the need for collaborative solutions to respond to the health workforce crisis, including enhanced training opportunities, mitigation of migration risks and improved retention. Ensuring resilience of the health workforce in the face of demographic and mobility pressures requires effective planning and integrated strategies addressing remuneration, working conditions, and professional development across all roles and sectors
Validation and clinical application of an LC-MS/MS method designed to simultaneously measure seven second-line TB drugs and two metabolites in human lung tissue.
Get PDFWe developed and validated a novel bioanalytical method for the simultaneous quantification of levofloxacin, linezolid, moxifloxacin, delamanid, bedaquiline, clofazimine, and pretomanid, along with the metabolites of delamanid (DM-6705) and bedaquiline (N-desmethyl-bedaquiline, M2), in human lung tissue samples. Following homogenization by bead beating and extraction by protein precipitation, the analytes were separated on an Agilent 1260 Infinity II HPLC system using a Poroshell 120 C18 EC (2.1 mm×50 mm, 2.7 µm) column with gradient elution, applying a mobile phase consisting of 0.1 % formic acid in water and 0.1 % formic acid in a mixture of acetonitrile and methanol. Detection and quantification of the analytes and their stable isotope labelled internal standards were performed on a Sciex API 5500 QTrap mass spectrometer using positive electrospray ionization and multiple reaction monitoring. Validation according to the guidelines of the FDA and EMA proved the method to be precise, accurate, and robust with no significant influence of matrix components. The application of the method to the analysis of clinical samples demonstrated the feasibility of quantifying the second-line anti-tuberculosis drugs in human lung tissue and the potential to provide insights into the drug distribution across the infection sites in the lung
Identifying care gaps along the HIV treatment failure cascade: A multistate analysis of viral load monitoring, re-suppression, and regimen switches in Zambia.
Get PDFBACKGROUND: Timely response to treatment failure is critical for improved outcomes and viral re-suppression among people living with HIV, but care gaps along the treatment failure cascade can occur due to delays by both clients (e.g., retention and adherence) and health systems (e.g., fidelity to viral load [VL] monitoring guidelines). We used multistate analysis to identify drivers of implementation gaps in the treatment failure cascade, including time to HIV VL monitoring, re-suppression, and regimen switches, in Zambia.
METHODS AND FINDINGS: We used national electronic HIV health records to identify adults on antiretroviral therapy (ART) for more than 6 months who experienced treatment failure (VL ≥ 1,000 copies/ml) at 24 clinics in Lusaka, Zambia, between August 2019 and November 2021. Using multistate analyses, we examined how care evolved after treatment failure, accounting for transitions across the treatment failure cascade over time, such as return visits, repeat VL testing, treatment interruptions (>60 days late for visit), and viral re-suppression. Analyses were stratified by ART regimen at cohort entry: tenofovir disoproxil fumarate/lamivudine or emtricitabine/dolutegravir TDF/XTC/DTG (TLD) and tenofovir disoproxil fumarate/lamivudine or emtricitabine/efavirenz TDF/XTC/EFV (TLE). We repeated analyses to assess switch to second-line therapy among those with consecutively unsuppressed VL test results who were due for regimen switch. Among 179,855 individuals on ART (143,857 with documented VL), 7,916 (4.4%) had a documented elevated VL and drug regimen at the time of treatment failure (52.3% female, median age was 36.7 years (IQR 29.9-43.6), median time on ART 3.3 years (IQR 1.7-6.6), 54.6% on TLD and 45.4% on TLE). Among those with treatment failure, 72.2% (CI 71.3, 73.0%) had returned to clinic 6 months after initial elevated VL was drawn. After one year, 70.1% (CI 69.3, 70.9%) had a repeat VL, 16.6% (CI 15.9, 17.2%) experienced treatment interruption, and 11.4% (CI 10.3, 12.4%) returned to care without repeat VL testing. Among those with a repeat VL, 85.0% (CI 83.9, 86.1%) on TLD and 58.2% (CI 56.8, 59.8%) on TLE had resuppressed. Among those due for second-line switch, 27.9% (CI 24.1, 31.5%) on TLD and 66.6% (CI 64.5, 68.9%) on TLE had changed regimens after one year while 52.4% on TLD had a third VL repeated prior to switch (CI 47.2, 57.4%) (68.0% CI 61.6, 75.2% suppressed of those with repeated VL) compared to 32.1% (CI 29.9, 34.1%) (40.7% CI 36.1, 45.4% suppressed) on TLE. This study was limited by the inability to capture all aspects of care delivery related to treatment failure, such as outreach, enhanced adherence counseling confirmation, and provider rationale for delayed VL rechecking.
CONCLUSION: After treatment failure, we identified substantial delays in returning for adherence counseling, treatment interruptions, and missed opportunities in rechecking VL status or switching to second-line therapy in routine care in Zambia. Among those who did have VL tests rechecked, re-suppression rates were significantly higher among individuals on TLD compared to TLE. To optimize response and outcomes after treatment failure, strategies must prioritize and target both client and health systems behaviors to meet the care needs in the modern era of TLD
Ecological drivers of malaria vector habitat and transmission over 1 year of long-lasting insecticidal net intervention in Côte d'Ivoire.
Get PDFBACKGROUND: Malaria is a mosquito-borne parasitic disease that causes significant morbidity and mortality in at-risk populations, especially in children in sub-Saharan Africa. Despite reductions in malaria burden owing to the scale-up of effective interventions, there are concerns that long-lasting insecticidal net (LLIN) effects may not be sustained owing to widespread insecticide resistance and differential impacts of LLIN on vector species. In this study, we aimed to test the effect of different LLIN products and other environmental factors on the ecological niche of three mosquito vector species using state-of-the-art ecological niche modelling approaches.
METHODS: This study used data from a cluster randomized control trial that took place in Tiébissou, in Central Côte d'Ivoire. Anopheles mosquito density and Plasmodium falciparum vector infection data were available across 33 clusters. We used satellite remote sensing related to land cover, climate, topography and population density across the study area alongside vector species occurrence data to construct ecological niche models for An. coluzzi, An. gambiae s.s. and An. funestus s.s., and for P. falciparum-infected vectors, at baseline and 1-year post-LLIN intervention. We compared the projected habitat and habitat determinants for each species, and assessed the respective contributions of each intervention arm and environmental factors on the probability of species occurrence.
RESULTS: Minimal to considerable overall reductions in suitable habitat across the study area were observed for the three mosquito vector species (less than 1% to more than 60%), and considerable overall reduction was observed for P. falciparum-infected vectors (more than 50%). We did not detect an effect of intervention arm on the probability of occurrence of any vector species, while we found strong significant effects of a combination of land cover, climate, topography and/or population density variables on each of the three mosquito vector species and malaria-infected vectors. Our results suggest environmental factors may have facilitated or restricted changes in the probability of occurrence of vector species and infected vectors in the context of vector control interventions.
CONCLUSIONS: Our study highlights wide ecological differences across malaria vector species and supports the need to consider malaria vector species composition when deploying malaria vector control interventions in endemic settings
Minimum material requirements for hand hygiene in community settings: a systematic review.
Get PDFBACKGROUND: This systematic review assessed the minimum requirements necessary to create an enabling environment for sustained hand hygiene practices: quantity of water and soap, and number, spacing, location, and design of hand hygiene facilities.
METHODS: We searched PubMed, Web of Science, EMBASE, CINAHL, Global Health, Cochrane Library, Global Index Medicus, Scopus, PAIS Index, WHO IRIS, UN Digital Library and World Bank eLibrary, and consulted experts. Eligible studies were published through 29 March 2023, observational, in non-healthcare community settings, and reported on at least one of the five categories: (1) quantity of water, (2) quantity of soap, (3) location of hand hygiene materials, (4) number of users or spacing of facilities and (5) considerations for equitable access. Two reviewers independently extracted data from each study and assessed risk of bias using the Mixed Method Appraisal Tool.
RESULTS: This review identified 37 studies that met inclusion criteria from 27 countries, representing 4 of the 6 WHO regions (Africa, South-East Asia, the Americas and Europe). Household settings were the most represented (59% of studies), followed by institutional or school settings (41%) and public establishments (27%). Of the 37 studies, 12 (32%) assessed the relationship between a material requirement and hand hygiene practices. Despite extensive global research on hand hygiene, we found a lack of evidence linking material requirements with handwashing practices in community settings.
CONCLUSIONS: This review was limited to observational studies, and more data could be derived from experimental studies. Important evidence gaps include the quantity of water and soap needed, the influence of facility location and design on hand hygiene practice, and material needs providing equitable access. Further research is needed to strengthen the evidence base for hand hygiene recommendations and supplement the expert opinion on which many recommendations are currently based. PROSPERO REGISTRATION NUMBER: CRD42023429145
Barriers to uptake and implementation of malaria chemoprevention in school-aged children: a stakeholder engagement meeting report
Get PDFMalaria is a leading cause of death in school-aged children in sub-Saharan Africa, and non-fatal chronic malaria infections are associated with anaemia, school absence and decreased learning, preventing children from reaching their full potential. Malaria chemoprevention has led to substantial reductions in malaria in younger children in sub-Saharan Africa. In 2022, the WHO updated its recommendations for chemoprevention to older, school-aged children where epidemiologically indicated. To date, there has been limited uptake of these policies which include both extending the age of seasonal malaria chemoprevention in seasonal transmission settings and providing intermittent preventive treatment to school-aged children in perennial transmission settings. In April 2024, a stakeholder meeting was convened in Kigali, Rwanda, to analyse barriers to implementation of malaria chemoprevention targeting school-aged children. Key evidence gaps were identified and needs for coordination and advocacy were highlighted
An epigenome-wide analysis of DNA methylation, racialized and economic inequities, and air pollution.
Get PDFBACKGROUND: DNA methylation (DNAm) provides a plausible mechanism by which adverse exposures become embodied and contribute to health inequities, due to its role in genome regulation and responsiveness to social and biophysical exposures tied to societal context. However, scant epigenome-wide association studies (EWAS) have included structural and lifecourse measures of exposure, especially in relation to structural discrimination. Our study tested the hypothesis that DNAm is a mechanism by which racial discrimination, economic adversity, and air pollution become biologically embodied, via a series of cross-sectional EWAS, conducted in two population-based samples of US-born Black non-Hispanic (Black NH), white non-Hispanic (white NH), and Hispanic individuals (My Body My Story:: n = 224 Black NH and 69 white NH;; and the Multi-Ethnic Study of Atherosclerosis:: n = 229 Black NH, n = 555 white NH and n = 191 Hispanic). Genome-wide changes in DNAm were measured using the Illumina EPIC BeadChip (MBMS; using frozen blood spots) and Illumina 450 k BeadChip (MESA; using purified monocytes).
RESULTS: We observed the strongest associations with traffic-related air pollution (between 0 and 22 DNAm sites associated at p < 2.4e-07, measured via black carbon and nitrogen oxides exposure), with evidence from both studies suggesting that air pollution exposure may induce epigenetic changes related to inflammatory processes. However, we did not replicate previous air pollution EWAS findings. We also found suggestive associations of DNAm variation with measures of structural racial discrimination (e.g. for Black NH participants, in MBMS born in a Jim Crow state associates with a DNAm site in ZNF286B at p = 8.43E-08; and in MESA adult exposure to racialized economic residential segregation associates with a DNAm site in FUT6 at p = 4.05E-08) situated in genes with plausible links to effects on health.
CONCLUSIONS: Overall, this work suggests that DNAm is a biological mechanism through which structural racism and air pollution (of which distribution of exposure is inequitable) become embodied and may lead to health inequities. Due to the extensive range of exposures we tested, further replication in additional studies and other tissues is warranted
Effect of a safe and dignified burial intervention on Ebola virus transmission in the eastern Democratic Republic of the Congo, 2018-19: a propensity score analysis.
Get PDFBACKGROUND: Safe and dignified burial (SDB) is a pillar of the response to epidemics of Ebola virus disease and other diseases caused by pathogens transmissible through contact with corpses. A large epidemic of Ebola virus disease affected eastern DR Congo during 2018-20, throughout which the DR Congo Red Cross and local authorities, with support from the International Federation of Red Cross and Red Crescent Societies, provided SDB services. We aimed to estimate the effect of SDB performance on the transmission of Ebola virus during this epidemic. METHODS: For this quasi-experimental propensity score analysis, we retrospectively approximated intervention randomisation conditions by grouping geographical-time observations on the basis of their similarity in terms of potential confounder variables representing epidemiological surveillance, vaccination coverage, insecurity, and infrastructure. We computed two transmission outcomes by health zone and week: the change in Ebola virus disease incidence over adjacent 2-week time windows and the effective reproduction number. We modelled the association between the proportions of timely (same-day) and successful (involving a secured body, environmental disinfection, and safe burial) SDBs (as exposures) and either transmission outcome while adjusting for potential confounding by combining variables identified through a directed acyclic graph into propensity scores that help to group observations, in order to approach randomised trial conditions. FINDINGS: SDB timeliness and successfulness were associated with respective reductions of 7% (95% CI -6 to 18) and 40% (22 to 54) in incidence across adjacent time windows, and with decreases in the log reproduction number (linear coefficient -0·39 [95% CI -0·81 to 0·03] and -0·45 [-0·74 to -0·16]). A dose-response relationship with SDB successfulness was apparent for both transmission outcomes. Transmission decreased below the epidemic extinction thresholds when more than around 40% of SDBs were successful. INTERPRETATION: The SDB service was associated with a substantial and plausibly causal reduction in the transmission of Ebola virus during the 2018-19 epidemic in eastern DR Congo. This intervention should be considered whenever exposure to corpses contributes to epidemic propagation. FUNDING: Elrha's Research for Health in Humanitarian Crises Programme. TRANSLATION: For the French translation of the abstract see Supplementary Materials section
Gaps in the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials: a citation analysis reveals a need for updated ethics guidelines.
Get PDFBACKGROUND: Although commonly used to evaluate health interventions, cluster randomized trials raise difficult ethical issues. Recognizing this, the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues across seven domains. But due to several developments in the design and implementation of cluster randomized trials, there are new issues requiring guidance. To inform the forthcoming update of the Ottawa Statement, we aimed to identify any gaps in the Ottawa Statement discussed within the literature.
METHODS: We searched Google Scholar, Scopus, and Web of Science using the 'cited by' function on 11 November 2022.We included all types of publications, including articles, book chapters, commentaries, editorials, ethics guidelines, theses and trial-related publications (i.e., primary reports, protocols, and secondary analyses), that cited and engaged with the Ottawa Statement, the Ottawa Statement précis, or one or more of its four background papers. Data were extracted by four reviewers working in rotating pairs. Reviewers captured relevant text verbatim and recorded whether it reflected a gap relating to one or more of the Ottawa Statement domains. Using a thematic analysis approach, semantic coding was used to summarize the content of the data into distinct gaps within the Ottawa Statement domains, which was subsequently expanded in an inductive manner through discussion.
RESULTS: The qualitative analysis of the text from 53 articles resulted in the identification of 24 distinct gaps in the Ottawa Statement: 4 gaps about justifying the cluster randomized design; 2 gaps about research ethics committee review; 3 gaps about identifying research participants; 4 gaps about obtaining informed consent; 3 gaps about gatekepeers; 6 gaps about assessing benefits and harms; 1 gap about protecting vulnerable participants; and 1 gap about equity-related issues in cluster randomized trials.
CONCLUSION: Identifying 24 gaps reveals a need to update the Ottawa Statement. Alongside additional gaps identified in ongoing empirical work and through engagement with our patient and public partners, the gaps identified through this citation analysis should be considered in the forthcoming Ottawa Statement update