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Enhanced virulence and stress tolerance are signatures of epidemiologically successful Shigella sonnei.
Get PDFShigellosis is a leading cause of diarrhoeal deaths, with Shigella sonnei increasingly implicated as a dominant agent. S. sonnei is divided into five monophyletic lineages, yet most infections are caused by a few clonal sub-lineages within Lineage 3 that are quite distinct from the widely used Lineage 2 laboratory strain 53G. Factors underlying the success of these globally dominant lineages remain unclear in part due to a lack of complete genome sequences and animal models. Here, we utilise a novel reference collection of representative Lineage 1, 2 and 3 isolates and find that epidemiologically successful S. sonnei harbour fewer genes encoding putative immunogenic components whilst key virulence-associated regions (including the type three secretion system and O-antigen) remain highly conserved. Using a zebrafish infection model, Lineage 3 isolates proved most virulent, driven by increased dissemination and a greater neutrophil response. These isolates also show increased resistance to complement-mediated killing alongside upregulated expression of group four capsule synthesis genes. Consistently, primary human neutrophil infections revealed an increased tolerance to phagosomal killing. Together, our findings link the epidemiological success of S. sonnei to heightened virulence and stress tolerance, and highlight zebrafish as a valuable platform to illuminate factors underlying establishment of epidemiological success
Global disparities in the introduction, scale-up, and effectiveness evaluation of COVID-19 vaccines.
Get PDFThe global response to COVID-19 saw the most rapid and extensive vaccination rollout in history. Yet there were large disparities in the introduction, scale-up, and evaluation of programmes. To systematically quantify these disparities, we generate linkages across public datasets containing country- and territory-level income data, COVID-19 vaccination rates, and COVID-19 vaccine effectiveness (VE). Our results show that, compared with high-income countries, lower-income countries introduced vaccines later, were less likely to achieve key coverage milestones, and were slower to do so where these milestones were achieved. The literature on primary series COVID-19 VE has been dominated by studies of mRNA vaccines from high-income countries, with data for other vaccines and lower-income countries appearing later and in substantially lower quantities. For vaccines with available VE data across multiple income settings (BNT162b2, mRNA-1273, and ChAdOx1-S), our meta-regression highlights robust protection against severe COVID-19, with no significant differences in primary series VE according to country-level income status during the Delta and Omicron periods. Our findings demonstrate the strong protection conferred by COVID-19 vaccines across diverse populations. Nonetheless, our results quantify the stark disparities that pervaded each stage of COVID-19 vaccine implementation, and highlight evidence gaps related to products and platforms being used across much of the globe
Agent-Based Modeling as an Evaluation Tool to Understand the Mechanisms of a Financial Incentives Scheme for Maternal and Child Health in Tanzania
Get PDFAgent-based models (ABMs) offer a robust mechanism for modeling dynamic health systems and their responses to reforms, capturing vital feedback loops between agents, and incorporating agent heterogeneities. We constructed an ABM to investigate the effects of a supply-side payment-for-performance (P4P) scheme for childbirth care in Tanzania, specifically focusing on its impact on demand-side behaviours. Three classes of agents were included in the model: women of reproductive age, healthcare providers (facilities), and a district manager. For women, we incorporated a key decision-behavior with respect to the location of the birth: opting for the nearest facility or home. On the providers’ end, responses to bonus incentives were modeled, considering aspects such as staff kindness and the levying of out-of-pocket informal charges. The model demonstrated that supply-side improvements could occur due to (i) changes in provider behavior driven by financial incentives, (ii) alterations in facility characteristics resulting from received incentive payments, and (iii) district manager facilitation of resource and strategy sharing. In particular, the model captured the potential limits of improvement on the supply side as demand increases, representing the added demand pressure on the system. The agent’s decision about delivery site is influenced by (i) her previous experience with home and facility delivery, (ii) experiences shared by peers, and (iii) advice from traditional birth attendants. Agent characteristics were derived from impact evaluation data, a multilevel mixed-effect logistic backward stepwise regression analysis, and unmeasured influences captured through literature and stakeholder input, all contributing to the model’s authenticity. The model, developed in AnyLogic, estimates that the current implementation of P4P, including bonus payment delays, led to a 21.5% increase (+15.4 percentage points) in facility-based deliveries compared to a counterfactual without P4P. Furthermore, avoiding payment delays observed during implementation could result in a further increase of 4.7% (+4.1 percentage points) in facility-based deliveries. The model explored variations in facility responses to P4P, finding that initial facility performance indicators, along with the size of the population of the catchment and the capacity ratios of the facility, are key factors that enabled facilities with lower initial performance and smaller catchment areas to perform better. Programmatic steps to avoid payment delays (and the associated increases in ’out-of-pocket’ informal charges during delays) should be prioritized. Through the model, we have demonstrated how program evaluation data can inform the development of an ABM, which can elucidate the pathways to impact and program bottlenecks by virtually reconstructing agents and observing emergent system-level behaviours. Our framework has generalizable methodological steps for others seeking to use ABM to better understand how health system strengthening programs such as P4P affect the behavior of providers and patients
Global Gender Disparities in Access to Refractive Error Services: A Systematic Review and Meta-Analysis.
Get PDFTOPIC: Summarize existing evidence on global gender disparities in access to refractive error (RE) correction, among adults and children. CLINICAL RELEVANCE: Uncorrected RE remains the leading cause of vision impairment worldwide. Women and girls experience disproportionate levels of vision impairment, but gender disparities in access to RE correction are not well understood. Lower coverage among women may lead to prolonged vision impairment and functional limitations, impacting education, employment, and quality of life. METHODS: We searched MEDLINE (Ovid), Embase (Ovid), Global Health, and gray literature sources from inception to 15 February 2024 for population-based observational studies reporting effective or overall RE coverage (REC), stratified by sex. There were no restrictions on language, publication date, or location. Titles and abstracts were independently reviewed. Quality appraisal was performed in duplicate using the Joanna Briggs Institute tool. Random-effects models were made of the age-adjusted female:male odds ratio (OR) of REC, stratified by age (0-17, ≥18 years), geographic setting, and super region. The protocol was registered on the International Prospective Register of Systematic Reviews (identifier, CRD42021271297). RESULTS: Across 43 studies in 18 countries, 33 534 (36.7%) of 91 487 adults and 23 008 (2.91%) of 790 145 children had refractive needs. The certainty of evidence for gender disparities in REC was rated as low for adults and very low for children using the Grading of Recommendations Assessment, Development and Evaluation approach. Women had lower REC than men (OR: 0.86; 95% confidence interval [CI]: 0.78-0.96; P = 0.01). Urban, but not rural, women were significantly less likely than men to access RE correction (OR: 0.70; 95% CI: 0.60-0.83; P < 0.01). Gender disparities were most evident in Southeast Asia, East Asia, and Oceania, where women were significantly less likely than men to access RE correction (OR: 0.75; 95% CI: 0.62-0.91; P < 0.01). Globally, adult women were less likely to access RE correction than men (OR: 0.85; 95% CI: 0.75-0.96; P = 0.01), but no significant sex differences were observed among children (OR: 0.86; 95% CI: 0.68-1.10; P = 0.24). CONCLUSIONS: Targeted interventions are needed to address barriers to refractive services among women and girls, with a particular focus on urban settings, adult women, and low-income regions. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article
Efficacy of Vector Guard®, a mosaic alpha-cypermethrin and piperonyl butoxide-treated net, for the control of pyrethroid-resistant malaria vectors: a non-inferiority experimental hut evaluation in Benin.
Get PDFBACKGROUND: Insecticide-treated nets (ITNs) incorporating pyrethroids with piperonyl butoxide (PBO) have demonstrated enhanced effectiveness against malaria transmitted by pyrethroid-resistant vectors compared with standard pyrethroid-only ITNs. To sustain progress in malaria prevention, a broader portfolio of effective pyrethroid-PBO nets is required to promote market diversity and strengthen supply resilience. In this study, we evaluated the entomological efficacy and wash durability of Vector Guard®, a novel mosaic alpha-cypermethrin-PBO ITN, against pyrethroid-resistant Anopheles gambiae sensu lato (An. gambiae s.l.) in southern Benin.
METHODS: An experimental hut trial was conducted in Covè, Benin, against wild, free-flying An. gambiae s.l. The effectiveness of the Vector Guard® ITN was tested unwashed and after 20 standardized washes, and also compared to two WHO-prequalified ITNs: Olyset® Plus (a permethrin-PBO net) and Royal Sentry® 2.0 (an alpha-cypermethrin-only net). Primary outcomes were mosquito mortality and blood-feeding protection. Susceptibility bioassays were conducted to assess local vector resistance to insecticides. Laboratory cone and tunnel tests were also performed to help explain the finding in the experimental huts. Chemical content analyses were performed to investigate active ingredient wash retention. Vector Guard® was assessed for its non-inferiority to Olyset® Plus following WHO guidance.
RESULTS: The wild An. gambiae s.l. population at Covè exhibited high frequencies of pyrethroid resistance, with PBO pre-exposure restoring partial susceptibility to alpha-cypermethrin (34% vs 4% mortality) but not to permethrin (2.0% vs 2.1% mortality). A total of 6799 females were collected in the experimental huts. Vector Guard® outperformed both Royal Sentry® 2.0 and Olyset® Plus across all entomological endpoints. Mortality with Vector Guard® was significantly higher than with Olyset® Plus both when unwashed (36.4% vs 17.5%, p 94% for alpha-cypermethrin) compared to Olyset® Plus (40.2% for PBO and 69.6% for permethrin).
CONCLUSIONS: Vector Guard® demonstrated superior entomological efficacy and wash durability compared to Royal Sentry® 2.0 and Olyset® Plus, and fulfilled WHO non-inferiority criteria for mosquito mortality and blood-feeding inhibition. These findings support its addition to the WHO list of prequalified pyrethroid-PBO ITNs and its potential to provide improved malaria control when deployed on a large scale in areas with high levels of pyrethroid resistance
The association between PM2.5, greenness (NDVI) and road noise exposures and the academic performance of state school pupils in England: a National Pupil Database study.
Get PDFResearch suggests that exposure to air pollution, greenspace and noise may affect children's academic performance, however further large-scale, longitudinal evidence is needed. This study quantifies the relationship between PM2.5 and children's academic performance while considering the effects of greenness and road noise using the National Pupil Database. 1,048,167 children starting state school in England at ages 4-5 years in 2005 and 2006 were followed for 12 years. Annual average environmental exposures at home and school were measured since the start of formal education up until each academic assessment. The associations of PM2.5 with cohort-standardised Z-scores of academic performance at ages 4-5, 6-7, 10-11 and 15-16 years were investigated using multilevel mixed effects linear regression models controlling for greenness, road noise and other individual, school and areal characteristics. PM2.5 was related to -0.055 (95 % CI: 0.064, -0.045) lower Z-scores per inter-quartile range (IQR, 2.08 μg/m3) exposure increase at ages 15-16 years, but not at other ages. Greenness was associated with 0.016 (95 % CI: 0.009, 0.022), 0.016 (95 % CI: 0.009, 0.024) and 0.035 (95 % CI: 0.029, 0.04) higher Z-scores at ages 6-7, 10-11 and 15-16 years, respectively, per IQR (0.1 NDVI) exposure increase. Road noise was related to -0.014 (95 % CI: 0.018, -0.01), -0.006 (95 % CI: 0.01, -0.003), -0.009 (95 % CI: 0.014, -0.005) and -0.008 (95 % CI: 0.012, -0.004) lower Z-scores at ages 4-5, 6-7, 10-11 and 15-16 years, respectively, per IQR (ages 4-5, 7.06 dB; 6-7, 6.81; 10-11, 6.56; 15-16, 6.32) exposure increase. This nation-wide study suggests that greater exposure to PM2.5 and road noise are harmful to academic performance later in school and throughout school, respectively, while greenness exposure has beneficial impacts across most school age groups in this sample. Reducing PM2.5 and road noise and increasing greenness around children's homes and schools may improve academic performance
Impact of vaccination timing and coverage on measles near elimination dynamics: a mathematical modelling analysis.
Get PDFThe Joint Committee for Vaccination and Immunisation recommended to implement an earlier second dose for the Measles-Mumps-Rubella (MMR) vaccine starting in 2026 in the United Kingdom. We investigated the impact of these changes on measles transmission in England. Using an age- and region-stratified mathematical model, we simulated outbreaks with different vaccination schedules and coverage, using electronic health records and outbreak data from 2010 to 2019. Delivering the second MMR dose at 24 months reduced cases by 11.86% (IQR: -3.3; 23.81%) compared to the current schedule (3 years and 4 months) and showed a 22.39% (IQR: 10.05; 32.79%) reduction of cases if achieving the same coverage as the first MMR dose. The effect of delivering an earlier second MMR was lower when waning of vaccine-induced immunity was included (5.28% (-10.92; 19.63%)). Increasing first-dose coverage by 0.5% annually yielded slightly better outcomes than an earlier second dose (14.68% reduction, IQR:1.19; 27.49.9%). While improving first-dose uptake had the greatest impact, it may be difficult to achieve. Thus, an earlier second MMR dose can be a feasible alternative to reduce the measles burden in England where measles transmission follows typical near-elimination dynamics
We have the evidence but governments must now build the systems to deliver on hand hygiene.
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Topography and environmental deficiencies are associated with chikungunya virus exposure in urban informal settlements in Salvador, Brazil.
Get PDFBACKGROUND: Chikungunya virus (CHIKV) is an arbovirus with a significant global public health burden. Delineating the specific contributions of individual behaviour, household, natural and built environment to CHIKV transmission is important for reducing risk in urban informal settlements but challenging due to their heterogeneous environments. The aim of this study was to quantify variation in CHIKV seroprevalence between and within four urban communities in a large Brazilian city, and identify the respective contributions of individual, household, and environmental factors for seropositivity.
METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional serological survey was conducted in four low-income communities in Salvador, Brazil in 2018 to collect individual, household and CHIKV IgG serology data for 1318 participants. Fine-scale community mapping of high-risk environmental features and remotely sensed environmental data were used to improve characterisation of the microenvironment close to the household. We categorised risk factors into three domains - individual, household, and environmental and used binomial mixed-effect models to identify associations with CHIKV seropositivity. CHIKV seroprevalence was 4.8%, 6.1% and 4.3% in three communities and 22.6% in one community which had a distinct topographical profile. The only individual domain variable associated with seropositivity was male sex (OR 1.67, 95% CI 1.11 - 2.36), but several environmental variables, including living in a house on a steep hillside, at medium to high elevations, and with surface water nearby, were associated with higher seropositivity.
CONCLUSIONS/SIGNIFICANCE: Our findings indicate that CHIKV exposure risk can vary significantly between nearby communities and at fine spatial scales within communities and is likely to be driven more strongly by the availability of mosquito breeding sites rather than individual exposure patterns. They suggest that environmental deficiencies and topography, a proxy for several environmental processes including the degree of urbanisation and flooding risk, may play an important role in driving risk at both of these scales
Effectiveness of tuberculosis preventive treatment on disease incidence among people living with HIV/AIDS: A systematic review and meta-analysis.
Get PDFBACKGROUND: Clinical trials have shown the protective efficacy of tuberculosis preventive treatment (TPT) for averting disease and death from tuberculosis among people living with HIV/AIDS (PLHIV). TPT has been recommended for PLHIV since the 1980s. However, tuberculosis is still the first cause of death in PLHIV.
OBJECTIVE: We aimed to summarize the evidence related to the real-world effectiveness of TPT on tuberculosis incidence among PLHIV.
METHOD: This is a systematic review and meta-analysis of observational cohort studies. The search was carried out in PubMed (via MEDLINE), Embase, LILACS, Scopus and Web of Science databases. Free and controlled vocabulary was used for the searches, with no restrictions on language or publication period. Studies reporting hazard ratios (HR) for tuberculosis incidence among PLHIV who received TPT were pooled using random-effects meta-analysis models. Meta-regression was performed to assess whether study-level characteristics accounted for heterogeneity, as evaluated by Cochran's I² statistic. Study quality was appraised using the Newcastle-Ottawa Scale. This study was registered with PROSPERO (CRD42024586273).
RESULTS: Among 8,330 screened studies, 34 were included, with nine contributing to the meta-analysis. TPT was associated with a 63% reduction in tuberculosis incidence risk (HR = 0.37, 95% CI: 0.28-0.48; I² = 43%). Children exhibited consistent stronger protection (82% risk reduction, HR = 0.18, 0.09-0.37; I² = 0%) than adults (56% reduction, HR = 0.44, 0.37-0.53; I² = 21%).
CONCLUSION: In real world conditions, TPT significantly and substantially reduces tuberculosis incidence in PLHIV, with consistent evidence of stronger protective effects in children. Despite some heterogeneity among adult studies, the pooled evidence confirms the protective effectiveness previously observed in clinical trials. These findings reinforce the global recommendation for broad implementation of TPT among PLHIV