Definition Of Exposure Research Articles

Sex differences in mortality associated with heatwaves: a systematic review and meta-analysis

Abstract Introduction The existence of sex and gender differences in the mortality associated with heatwaves remains unclear. Methods A systematic review and random-effects meta-analysis of population-based studies that investigated the mortality associated with heatwaves and reported results stratified by sex/gender was conducted (PROSPERO registration CRD42023430208). Bibliographic databases Medline and Embase were searched from inception to May 2024 with MESH terms for heatwaves/extreme heat and mortality. This was complemented with hand-searching of reference lists of relevant studies. The methodological quality of eligible studies was assessed using the Joanna Briggs Institute critical appraisal tool. Results In total, 931 studies were identified, of which 32 studies were included in the qualitative review and 11 in the meta-analysis. Most studies (20/32) reported a higher risk of heat-related death for women than men even after adjusting for or stratifying by age. Twelve studies showed statistically significant higher risks of death for women than men and 7 studies identified an increased risk of death for women, but the wide confidence intervals precluded making definite conclusions. Two studies reported a higher risk of death for men in comparison to women but only one was statistically significant. The remaining 10 studies found comparable risks for women and men. For the 11 studies included in the meta-analysis, women had an 8% increased risk of death in comparison to men (RR 1.08, 95% CI [1.02 to 1.14]). There was significant heterogeneity (I2=69%, p = 0.001) due to the variability in the definition of exposure, population, and setting. Most studies had a low to moderate risk of bias. Conclusions Women appeared to have an increased risk of death associated with heatwaves in comparison to men. Further research is warranted to understand the underlying factors and ensure the health protection response considers the gendered impact of heatwaves.

Long-term associations between time-varying exposure to ambient PM2.5 and mortality: an analysis of the UK Biobank.

Evidence for long-term mortality risks of PM2.5 comes mostly from large administrative studies with incomplete individual information and limited exposure definitions. Here we assess PM2.5-mortality associations in the UK Biobank cohort using detailed information on confounders and exposure. We reconstructed detailed exposure histories for 498,090 subjects by linking residential data with high-resolution PM2.5 concentrations from spatio-temporal machine learning models. We split the time-to-event data and assigned yearly exposures over a lag window of 8 years. We fitted Cox proportional hazard models with time-varying exposure controlling for contextual and individual-level factors, as well as trends. In secondary analyses, we inspected the lag structure using distributed lag models and compared results with alternative exposure sources and definitions. In fully adjusted models, an increase of 10 μg/m³ in PM2.5 was associated with hazard ratios (HRs) of 1.27 (95%CI: 1.06-1.53) for all-cause, 1.24 (1.03-1.50) for non-accidental, 2.07 (1.04-4.10) for respiratory, and 1.66 (0.86-3.19) for lung cancer mortality. We found no evidence of association with cardiovascular deaths (HR=0.88, 95%CI: 0.59-1.31). We identified strong confounding by both contextual- and individual-level lifestyle factors. The distributed lag analysis suggested differences in relevant exposure windows across mortality causes. Using more informative exposure summaries and sources resulted in higher risk estimates. We found associations of long-term PM2.5 exposure with all-cause, non-accidental, respiratory, and lung cancer mortality, but not with cardiovascular mortality. This study benefits from finely reconstructed time-varying exposures and extensive control for confounding, further supporting a plausible causal link between long-term PM2.5 and mortality.

Neurodevelopmental outcomes in children prenatally exposed to opioid maintenance treatment: A population-based study.

Opioid maintenance treatment (OMT), with methadone or buprenorphine, is a key approach for managing opioid use disorder (OUD) during pregnancy. Despite buprenorphine's superior short-term outcomes, its long-term effects remain understudied. This study aims to evaluate the effects of prenatal OMT exposure on the incidence of childhood neurodevelopmental disorders (NDDs) considering timing effect. A retrospective cohort study using Rhode Island Medicaid data linked to vital statistics from 2008 to 2018 was conducted. The study included pregnancies having live birth from 2008 to 2016 with continuous Medicaid insurance and OUD diagnosis within 3 months preceding conception until delivery. At least one buprenorphine dispensing or a claim of methadone was required for exposure definition. Exposure was evaluated during early (0-90 days) or late (>90 days) gestation, or at any pregnancy phase. NDDs, including autism, attention-deficit/hyperactivity disorder (ADHD), learning disabilities, speech/language disorders, developmental coordination disorder, intellectual disability, and behavioral disorders, were identified using validated algorithms. Applying Cox proportional-hazard models with propensity score overlap weighting, adjusted hazard ratios (aHR) were calculated, mitigating potential confounders. Children were followed up from birth until NDD diagnosis, disenrollment, or study end. Of 416 mother-child dyads with OUD, 40% used methadone and 20% had buprenorphine exposure during pregnancy. NDDs were observed in 36% of children with early methadone exposure compared to 17% in the early buprenorphine exposed group (aHR: 2.75; 95% confidence interval [CI]: 1.42-5.35). Further comparison to late buprenorphine exposure, late methadone exposure was associated with higher NDD risk (aHR: 2.05; 95% CI: 1.09-3.86). Compared to unexposed group, children exposed to methadone during early and late periods showed higher NDD incidences (aHR: 2.33; 95% CI: 1.51-3.60 and aHR: 2.42; 95% CI: 1.54-3.80, respectively). The study suggests that buprenorphine is a good treatment option for OUD during pregnancy due to minimal long-term neurodevelopmental impacts on children. However, further extensive research is necessary to rule-out potential confounding.

An Update on the Six Recommendations from the 2012 IADMS Standard Measures Initiative: Assessing and Reporting Dancer Capacities, Risk Factors, and Injuries.

In 2012, the Standard Measures Consensus Initiative (SMCI) of the International Association for Dance Medicine and Science (IADMS) presented 6 recommendations regarding dance injury surveillance, definitions of injury and exposure, dance-specific screening, risk reduction strategies, and collaborative data management. The aim was to standardize risk factor measurement and injury reporting by researchers in dance medicine and science. Since then, numerous reports on the recording and reporting of injury data in sport and performing arts have been published. IADMS commissioned SMCI to update the 2012 recommendations, a process that involved 3 stages: (1) current field experts were invited to join SMCI, (2) SMCI members reviewed recent and relevant sport and performing arts literature, then drafted, discussed, and revised section updates, (3) IADMS invited individuals representing diverse backgrounds in the IADMS community to critically review drafted updates. The final update serves as a bridge from the 6 recommendations in the 2012 report to the current state of evidence. We continue to encourage use of dance injury surveillance systems and support that surveillance protocols be fit-for-purpose, and that failure to use clear and consistent injury definitions perpetuates a lack of rigor in dance injury research. Based on new evidence, we recommend that some aspects of injury surveillance be self-reported, that the choice of dance exposure measures be dependent on the research question, contextual factors, and type of injury/health problem(s) of interest, and that studies using dance-specific screening articulate specific objectives, validity, and reliability of each protocol. Future studies should focus on the development, implementation, and evaluation of strategies to minimize injury risk to improve consistency and rigor in data collection and research reporting on the health and wellness of dancer populations, thus facilitating a future dance injury consensus statement similar to recent statements published for sports and circus arts.

ECO-MIND: enhancing pro-environmental behaviours and mental health through nature contact for urban youth – a research protocol for a multi-country study using geographic ecological momentary assessment and mental models

IntroductionUrban youth are experiencing increasing mental health problems due to diverse personal, social and environmental concerns. Youths’ detachment from natural environments, including green and blue spaces, may intensify such issues...

Canadian beach cohort study: protocol of a prospective study to assess the burden of recreational water illness

BackgroundRecreational water activities at beaches are popular among Canadians. However, these activities can increase the risk of recreational water illnesses (RWI) among beachgoers. Few studies have been conducted in Canada to determine the risk of these illnesses. This protocol describes the methodology for a study to determine the risk and burden of RWI due to exposure to fecal pollution at beaches in Canada.MethodsThis study will use a mixed-methods approach, consisting of a prospective cohort study of beachgoers with embedded qualitative research. The cohort study involves recruiting and enrolling participants at public beaches across Canada, ascertaining their water and sand contact exposure status, then following-up after seven days to determine the incidence of acute RWI outcomes. We will test beach water samples each recruitment day for culture-based E. coli, enterococci using rapid molecular methods, and microbial source tracking biomarkers. The study started in 2023 and will continue to 2025 at beaches in British Columbia, Manitoba, Ontario, and Nova Scotia. The target enrollment is 5000 beachgoers. Multilevel logistic regression models will be fitted to examine the relationships between water and sand contact and RWI among beachgoers. We will also examine differences in risks by beachgoer age, gender, and beach location and the influence of fecal indicator bacteria and other water quality parameters on these relationships. Sensitivity analyses will be conducted to examine the impact of various alternative exposure and outcome definitions on these associations. The qualitative research phase will include focus groups with beachgoers and key informant interviews to provide additional contextual insights into the study findings. The study will use an integrated knowledge translation approach.DiscussionInitial implementation of the study at two Toronto, Ontario, beaches in 2023 confirmed that recruitment is feasible and that a high completion rate (80%) can be achieved for the follow-up survey. While recall bias could be a concern for the self-reported RWI outcomes, we will examine the impact of this bias in a negative control analysis. Study findings will inform future recreational water quality guidelines, policies, and risk communication strategies in Canada.

Glyburide use is associated with a greater likelihood of mortality or rehospitalization after acute coronary syndrome compared to gliclazide use in adults with type 2 diabetes: A cohort study.

To examine the likelihood of mortality or rehospitalization following acute coronary syndrome with glyburide versus gliclazide use in adults with type 2 diabetes undergoing cardiac catheterization. This retrospective cohort study used clinical data linked with administrative health data from Alberta, Canada between April 2008 and March 2021. Three methods were used to define exposure to glyburide and gliclazide in the year before catheterization. Multivariable logistic regression was used to compare the likelihood of a composite outcome of 1-year mortality or rehospitalization with use of glyburide versus use of gliclazide. A total of 11 140 individuals with type 2 diabetes had a cardiac catheterization for acute coronary syndrome. Their mean age was 66 years and 31% were female. In the year before catheterization, 5% used glyburide and 19% used gliclazide. Any glyburide or gliclazide exposure in the year before catheterization was associated with a similar likelihood of all-cause mortality or rehospitalization (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 0.93-1.41; p = 0.20). However, current glyburide exposure (aOR 1.37, 95% CI 1.06-1.79; p = 0.018) and long exposure to glyburide (aOR 1.37, 95% CI 1.03-1.83; p = 0.030) were associated with a higher likelihood of the composite outcome compared to current and long exposure to gliclazide, respectively. Current and long exposure to glyburide was associated with a greater likelihood of mortality or rehospitalization following cardiac catheterization for acute coronary syndrome, when compared to similar gliclazide exposure definitions. This study adds further evidence of the need to avoid using glyburide if a sulphonylurea is required for type 2 diabetes management.

Trends in Asbestos Exposure and Malignant Mesothelioma Incidence in Emilia-Romagna Italy: A Retrospective Study 1996-2023.

Malignant mesothelioma (MM) is a rare but lethal cancer strongly associated with asbestos exposure. This retrospective study examines trends in asbestos exposure in Emilia-Romagna, Northern Italy. Between 1996 and 2023, 3,513 cases of MM were recorded, predominantly in males (72%) and in older than 65 years (79%). Occupational exposure accounted for 82% of cases, with a significant increase observed over time from 71% to 88% in the most recent period. A greater definition of professional exposure indicates that certain exposure has gone from 49% in the first period to 62% and 58% in the last two periods; probable exposure showed a decrease from 21% to 16% while possible exposure decreased from 16% to 13%. Familiar exposure remained relatively constant at around 8%, environmental exposure showed a slight decrease from 4% to 2%, while non-occupational exposure remained stable at 2%. Among patients with exclusively occupational exposure (1,826 cases), 87% were male and aged between 65 and 75 years (36%) and 75+ (41%). The exposure rates for the province of residence see the province of Reggio Emilia with the highest occupational exposure rate (2.5 x 100,000 residents), followed by Ravenna (2.3 x 100,000 residents) and Parma and Piacenza which have similar exposure rates with 2.2 x 100,000 residents. Professional sectors such as construction, railway maintenance and metalworking are identified as high-risk industries. Despite efforts to mitigate exposure, non-occupational and environmental exposures persist. The study highlights the importance of continuous surveillance and exposure monitoring to guide effective interventions and legal recognition of MM.

The association between long working hours, shift work, and suicidal ideation: A systematic review and meta-analyses.

The association between occupational psychosocial factors and mental health has been studied in several systematic reviews. However, few systematic reviews exist that specifically address suicidal ideation. Therefore, this systematic review and meta-analysis aimed to examine the associations between long working hours, shift work, and suicidal ideation. We systematically screened and collected studies published between January 1970 and September 2022 from three electronic databases and Google Scholar. We conducted a meta-analysis using a random-effects model and assessed the risk of bias using a navigation guide. Additionally, the grading of recommendations assessment, development and evaluation (GRADE) approach was used to consider five items, including the risk of bias and publication bias. Twenty-eight articles were included in this meta-analysis. After adjusting for covariates, the overall odds ratio (OR) for long working hours and shift work were 1.44 [95% confidence interval (CI) 1.26-1.63] and 1.34 (95% CI 1.22-1.47), respectively. Compared with those who worked <40 hours per week, those who worked >55 hours per week had a 1.65 (95% CI 1.37-1.98) higher risk of suicidal ideation, and fixed night shift workers had 1.37 (95% CI 1.03-1.83) higher risk than non-shift workers. Evidence has shown associations between long working hours, shift work, and suicidal ideation. Implementing evidence-based interventions to address these risk factors may help prevent the progression of suicidal ideation. However, further studies are critically needed, especially those using standardized exposure definitions and longitudinal data.

Hydroxychloroquine and Pre-eclampsia in a Diverse Cohort of Women With Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) are at risk for pregnancy complications such as pre-eclampsia and eclampsia. These clinically important complications are associated with maternal morbidity, mortality, and postpartum cardiovascular disease. Some studies suggest that hydroxychloroquine (HCQ) may reduce pre-eclampsia risk in lupus pregnancy. Using a cohort of pregnant patients with prevalent SLE at Kaiser Permanente Northern California (KPNC), we investigated whether HCQ treatment in early pregnancy reduced the risk of pre-eclampsia or eclampsia. Among pregnant patients with SLE from 2011 to 2020, we assessed HCQ treatment from three months before pregnancy through the first trimester. HCQ exposure was defined multiple ways to account for adherence and duration of treatment. Propensity scores accounted for multiple confounders and modified Poisson models estimated risk ratios (RRs) and 95% confidence intervals of the association between HCQ treatment and pre-eclampsia or eclampsia. Effect modification by pregestational hypertension, history of nephritis, and antiphospholipid antibody (aPL) status was investigated through stratified analysis. There were 399 pregnancies among 324 patients with SLE at KPNC between 2011 and 2020. Considering multiple exposure definitions, we consistently found a null association between HCQ and pre-eclampsia or eclampsia. The RRs were consistently lower among nullipara patients, and RRs were consistently protective but not statistically significant among the high-risk subgroup of patients with a history of nephritis, aPL positivity, or pregestational hypertension (for both nullipara and multipara patients). Although this study found no reduced risk of HCQ on pre-eclampsia or eclampsia, residual confounding may be attenuating the effect despite an integrated health care delivery system setting with detailed clinical data.

Prevalence of exposure to domestic and family violence among Aboriginal and non-Aboriginal children in the Northern Territory of Australia

IntroductionAlthough there is substantial evidence regarding the detrimental effect exposure to domestic and family violence (DFV) has on healthy child development, there is a paucity of information on the prevalence of childhood DFV exposure. This study aimed to estimate the prevalence of DFV exposure among Aboriginal and non-Aboriginal children in the Northern Territory (NT) of Australia. MethodsThis was a retrospective observational cohort study using linked individual-level records. The cohort consisted of all children aged 0-17 residing in the NT and exposed to DFV as recorded in Child Protection Services and police data in 2018. ‘Exposure to DFV’ was defined broadly as being a child in a household in which DFV occurred, including children who were not physically present at the time of the incident. In our main analyses, exposure to DFV was defined as having either any DFV-related notification or any DFV-related substantiated notification with Child Protection Services, or any DFV-related record in police datasets. ResultsIn 2018, 13.3% of NT children had a record of exposure to DFV with the prevalence for Aboriginal children around six times greater than non-Aboriginal children (24.4% compared to 4.2%). Using a single data source, the estimates of exposure to DFV, for Aboriginal and non-Aboriginal children, varied from: 3.3% and 0.3% respectively, for substantiated child protection notifications; 7.1% and 1.1% for investigated notifications, 15.9% and 2.6% for all notifications; and, 17.2% and 2.9% for police data. Prevalence of exposure varied with age and was highest for Aboriginal children aged from 0-4 years (31.4%) and for non-Aboriginal children aged 14-17 years (4.9%). ConclusionsMany NT children are exposed to DFV, with much greater exposure among Aboriginal children. The prevalence estimates varied between sources of data and with the definition of childhood exposure to DFV. Our findings highlight the value of linking records from multiple sources to provide a more comprehensive estimate of the magnitude of exposure of children to DFV, an essential base on which to plan a public health response to DFV prevention.

A Simplified Procedure for the Out-of-Plane Seismic Assessment of Free-Standing URM Elements: Application to the Abandoned Ancient Village of Bussana (Sanremo, Imperia - Italy)

ABSTRACT This paper addresses the safety of connections within urban areas, where free-standing elements that menacingly overlook them are susceptible to potential overturning mechanisms. Such a condition recurs in post-earthquake scenarios and in historical centers abandoned after disasters in seismic-prone areas, which aimed to be restored to create safe pathways for tourists. The paper presents a simplified procedure for the out-of-plane seismic risk assessment of free-standing unreinforced masonry (URM) elements in historical centers. The procedure can be applied to several URM free-standing elements, such as artistic pieces or nonstructural components, but also rocking panels resulting from the collapse of structures in post-event damage scenarios. The procedure is based on the definition of hazard, exposure, and vulnerability, which are combined to assign a risk class to each element and define a priority of intervention. The procedure relies on the kinematic approach but requires a limited number of parameters to be feasible when applied to many elements. Some of them can also be acquired through innovative survey techniques, like unmanned aerial vehicle photogrammetry. To demonstrate its utility, the procedure is applied to the abandoned village of Bussana (Sanremo, Imperia — Italy), severely hit by the 1887 earthquake and partially reoccupied in the 1960s.

Impact of the pre-biologic treatment journey on biologic drug survival in psoriasis: A nationwide cohort study.

It is unknown whether the pre-biologic treatment journey affects subsequent biologic drug survival. To examine the potential impact of a complex treatment journey on subsequent biologic drug survival in patients with psoriasis. The study utilized longitudinal data from Danish national registries and included all patients who, for the first time, initiated a biological treatment for psoriasis. Maximum follow-up was 5 years and patients were included from 1 January 2010 to 30 June 2021. The study used three definitions of exposure to a complex treatment journey and the following conventional systemic treatments: acitretin, cyclosporine, dimethyl fumarate and methotrexate. The first definition was the cumulative number of treatment series. The second definition comprised the number of unique treatments. The third definition was time from the first conventional systemic treatment to biological therapy. Drug survival for the three definitions were illustrated using Kaplan-Meier curves and compared using log-rank test. The sensitivity analysis largely confirmed these findings by grouping patients according to pharmacotherapy. A total of 2496 patients were included in the study, with 1380 (55.3%) receiving adalimumab, 608 (24.4%) receiving ustekinumab, 271 (10.9%) receiving secukinumab, 166 (6.7%) receiving etanercept and 71 (2.8%) receiving infliximab. The mean age at initiation of biologics was 43.6 years (standard deviation (SD) 15.2 years), and most patients were male (62.9%). During the follow-up of 5477 patient years, 1953 patients (78.2%) reached the main endpoint of discontinuation. Using a log-rank test, the probability of remaining on treatment was unaffected by the three definitions of complexity of the treatment journey. None of the three exposures used to assess the complexity of the pre-biologic treatment journey appeared to impact drug survival. As long as patients experience adequate disease control, these results suggest that conventional systemic treatment do not negatively impact the drug survival of subsequent biologics.

The Retrospective Implementation of Standardized In Utero HIV Exposure Definitions Using Routinely Collected Public Sector Data Across the Western Cape Province, South Africa.

Using the Data Evaluation and Preparation for HIV-Exposed Uninfected Child Cohorts project's standardized child HIV exposure definitions, 64%, 64% and 90% of children exposed to HIV in utero could be classified as HIV-uninfected with moderate or high certainty at the ages of 1 and 3 years and at the time of first infectious disease hospitalization, respectively. These definitions can be applied retrospectively to routine datasets with linked mother-child data.

Extreme Temperatures and Stroke Mortality: Evidence From a Multi-Country Analysis.

Extreme temperatures contribute significantly to global mortality. While previous studies on temperature and stroke-specific outcomes presented conflicting results, these studies were predominantly limited to single-city or single-country analyses. Their findings are difficult to synthesize due to variations in methodologies and exposure definitions. Within the Multi-Country Multi-City Network, we built a new mortality database for ischemic and hemorrhagic stroke. Applying a unified analysis protocol, we conducted a multinational case-crossover study on the relationship between extreme temperatures and stroke. In the first stage, we fitted a conditional quasi-Poisson regression for daily mortality counts with distributed lag nonlinear models for temperature exposure separately for each city. In the second stage, the cumulative risk from each city was pooled using mixed-effect meta-analyses, accounting for clustering of cities with similar features. We compared temperature-stroke associations across country-level gross domestic product per capita. We computed excess deaths in each city that are attributable to the 2.5% hottest and coldest of days based on each city's temperature distribution. We collected data for a total of 3 443 969 ischemic strokes and 2 454 267 hemorrhagic stroke deaths from 522 cities in 25 countries. For every 1000 ischemic stroke deaths, we found that extreme cold and hot days contributed 9.1 (95% empirical CI, 8.6-9.4) and 2.2 (95% empirical CI, 1.9-2.4) excess deaths, respectively. For every 1000 hemorrhagic stroke deaths, extreme cold and hot days contributed 11.2 (95% empirical CI, 10.9-11.4) and 0.7 (95% empirical CI, 0.5-0.8) excess deaths, respectively. We found that countries with low gross domestic product per capita were at higher risk of heat-related hemorrhagic stroke mortality than countries with high gross domestic product per capita (P=0.02). Both extreme cold and hot temperatures are associated with an increased risk of dying from ischemic and hemorrhagic strokes. As climate change continues to exacerbate these extreme temperatures, interventional strategies are needed to mitigate impacts on stroke mortality, particularly in low-income countries.

The interplay between systemic inflammatory factors and endometriosis: A bidirectional mendelian randomization study

ObjectiveTo utilize vast genetic data to reveal the interplay between 41 systemic inflammatory factors and endometriosis. DesignBidirectional Mendelian randomization study. Mains outcome measuresThis study obtained believable genetic instrumental variables for systemic inflammatory factors. The effect of systemic inflammatory factors on different endometriosis phenotypes, and the effect of endometriosis on the concentrations of systemic inflammatory factors were investigated. ResultsIn this mendelian randomization study, we found 20 causal relationships involving 18 systemic inflammatory factors and it was shown that Monocyte chemotactic protein-1, Macrophage inflammatory protein-1a, Granulocyte colony-stimulating factor, Macrophage migration inhibitory factor, Interleukin-4, Interleukin-5, Interleukin-8, Interleukin-9, Interleukin-12p70, Interleukin-16, and Interleukin-17 may be the upstream causes of endometriosis (P<0.05). Additionally, if the definition of exposure in the mendelian randomization was endometriosis, it could suggestively cause an increase in Eotaxin, cutaneous T-cell attracting chemokine, and Interferon gamma-induced protein 10 levels, and a decrease in growth-regulated oncogene-alpha, Interleukin-2 receptor, alpha subunit, platelet-derived growth factor BB, and Interleukin-18 (P<0.05). Reverse causality was not observed between a single systemic inflammatory factor and endometriosis. ConclusionsOur findings indicate that several systemic inflammatory factors may act as the initiator at the onset of endometriosis. Additionally, several other inflammatory factors are far more probable to involved downstream during disease development.

Update to: Assessing the efficacy of male Wolbachia-infected mosquito deployments to reduce dengue incidence in Singapore

BackgroundThis trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial.MethodsThe key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics.DiscussionThe findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter.Trial registrationClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.

A new framework for exploratory network mediator analysis in omics data.

Omics methods are widely used in basic biology and translational medicine research. More and more omics data are collected to explain the impact of certain risk factors on clinical outcomes. To explain the mechanism of the risk factors, a core question is how to find the genes/proteins/metabolites that mediate their effects on the clinical outcome. Mediation analysis is a modeling framework to study the relationship between risk factors and pathological outcomes, via mediator variables. However, high-dimensional omics data are far more challenging than traditional data: (1) From tens of thousands of genes, can we overcome the curse of dimensionality to reliably select a set of mediators? (2) How do we ensure that the selected mediators are functionally consistent? (3) Many biological mechanisms contain nonlinear effects. How do we include nonlinear effects in the high-dimensional mediation analysis? (4) How do we consider multiple risk factors at the same time? To meet these challenges, we propose a new exploratory mediation analysis framework, medNet, which focuses on finding mediators through predictive modeling. We propose new definitions for predictive exposure, predictive mediator, and predictive network mediator, using a statistical hypothesis testing framework to identify predictive exposures and mediators. Additionally, two heuristic search algorithms are proposed to identify network mediators, essentially subnetworks in the genome-scale biological network that mediate the effects of single or multiple exposures. We applied medNet on a breast cancer data set and a metabolomics data set combined with food intake questionnaire data. It identified functionally consistent network mediators for the exposures' impact on the outcome, facilitating data interpretation.

Fluoroquinolones and the risk of severe hypoglycaemia among sulphonylurea users: Population-based cohort study.

Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible.

Considerations for the assessment of blast exposure in service members and veterans.

Blast exposure is an increasingly present occupational hazard for military service members, particularly in modern warfare scenarios. The study of blast exposure in humans is limited by the lack of a consensus definition for blast exposure and considerable variability in measurement. Research has clearly demonstrated a robust and reliable effect of blast exposure on brain structure and function in the absence of other injury mechanisms. However, the exact mechanisms underlying these outcomes remain unclear. Despite clear contributions from preclinical studies, this knowledge has been slow to translate to clinical applications. The present manuscript empirically demonstrates the consequences of variability in measurement and definition across studies through a re-analysis of previously published data from the Chronic Effects of Neurotrauma Study 34. Definitions of blast exposure used in prior work were examined including Blast TBI, Primary Blast TBI, Pressure Severity, Distance, and Frequency of Exposure. Outcomes included both symptom report and cognitive testing. Results demonstrate significant differences in outcomes based on the definition of blast exposure used. In some cases the same definition was strongly related to one type of outcome, but unrelated to another. The implications of these results for the study of blast exposure are discussed and potential actions to address the major limitations in the field are recommended. These include the development of a consensus definition of blast exposure, further refinement of the assessment of blast exposure, continued work to identify relevant mechanisms leading to long-term negative outcomes in humans, and improved education efforts.