Mixed-effects Meta-regression Research Articles

Global incidence and risk factors for glaucoma: A systematic review and meta-analysis of prospective studies.

This study aims to estimate global incidence and assess risk factors for glaucoma subtypes. The literature search was performed in three English (PubMed, Embase, MEDLINE) and three Chinese (China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database) databases to identify prospective studies on glaucoma incidence between 1 January 1990 and 29 November 2022. We used a multilevel mixed-effects meta-regression to estimate the age- and sex-specific incidence rate of primary open-angle glaucoma (POAG). The global and regional incidence rate of POAG in 2022 were respectively estimated. The annual cumulative incidence (ACI) of POAG and primary angle-closure glaucoma (PACG), and risk factors for POAG were pooled using a random-effects meta-analysis, respectively. The heterogeneity of the included articles was tested using the Q statistic and measured by I2 index. Publication bias was detected by funnel plots, Egger's regression test, and Begg's rank correlation test. A total of 9050 articles were identified in literature search, and 50 articles provided incidence data of glaucoma subtypes. In 2022, the global incidence rate of POAG was 23.46 (95% confidence interval (CI) = 15.68-32.91) per 10 000 person-years among 40-79 years. An increase from 5.51 (95% CI = 1.63-11.12) per 10 000 person-years in 40-44 years to 64.36 (95% CI = 49.82-80.70) per 10 000 person-years in 75-79 years was noted between the year 1990 and 2019. Across sociodemographic index (SDI) and World Health Organization (WHO) regions, the incidence rate was the highest in low SDI region and Africa, respectively. The pooled ACI of POAG was 0.21% (95% CI = 0.13%-0.30%). Six risk factors for POAG were identified, including intraocular pressure (IOP) treatment (meta-odds ratio (OR) = 3.69; 95% CI = 2.64-5.15), a family history of glaucoma (meta-OR = 2.49; 95% CI = 1.92-3.24), myopia (meta-OR = 2.08; 95% CI = 1.59-2.70), elevated IOP (meta-OR = 1.13; 95% CI = 1.11-1.15), advanced age (meta-OR = 1.07; 95% CI = 1.05-1.08), male (female: meta-OR = 0.76; 95% CI = 0.66-0.88). The pooled ACI of PACG was 0.05% (95% CI = 0.00%-0.16%). Significant disparities existed in incidence rates for glaucoma across geographic regions and age groups. Further research is needed to understand which risk factors drive glaucoma incidence in different socioeconomic strata for tailored health policy on preventing glaucoma. This study is registered with PROSPERO (number CRD42023434203).

Temporal change in minimum mortality temperature under changing climate: A multicountry multicommunity observational study spanning 1986-2015.

The minimum mortality temperature (MMT) or MMT percentile (MMTP) is an indicator of population susceptibility to nonoptimum temperatures. MMT and MMTP change over time; however, the changing directions show region-wide heterogeneity. We examined the heterogeneity of temporal changes in MMT and MMTP across multiple communities and in multiple countries. Daily time-series data for mortality and ambient mean temperature for 699 communities in 34 countries spanning 1986-2015 were analyzed using a two-stage meta-analysis. First, a quasi-Poisson regression was employed to estimate MMT and MMTP for each community during the designated subperiods. Second, we pooled the community-specific temporally varying estimates using mixed-effects meta-regressions to examine temporal changes in MMT and MMTP in the entire study population, as well as by climate zone, geographical region, and country. Temporal increases in MMT and MMTP from 19.5 °C (17.9, 21.1) to 20.3 °C (18.5, 22.0) and from the 74.5 (68.3, 80.6) to 75.0 (71.0, 78.9) percentiles in the entire population were found, respectively. Temporal change was significantly heterogeneous across geographical regions (P < 0.001). Temporal increases in MMT were observed in East Asia (linear slope [LS] = 0.91, P = 0.02) and South-East Asia (LS = 0.62, P = 0.05), whereas a temporal decrease in MMT was observed in South Europe (LS = -0.46, P = 0.05). MMTP decreased temporally in North Europe (LS = -3.45, P = 0.02) and South Europe (LS = -2.86, P = 0.05). The temporal change in MMT or MMTP was largely heterogeneous. Population susceptibility in terms of optimum temperature may have changed under a warming climate, albeit with large region-dependent variations.

Effect modification of air pollution on the association between heat and mortality in five European countries

BackgroundEvidence suggests that air pollution modifies the association between heat and mortality. However, most studies have been conducted in cities without rural data. This time-series study examined potential effect modification of particulate matter (PM) and ozone (O3) on heat-related mortality using small-area data from five European countries, and explored the influence of area characteristics. MethodsWe obtained daily non-accidental death counts from both urban and rural areas in Norway, England and Wales, Germany, Italy, and the Attica region of Greece during the warm season (2000–2018). Daily mean temperatures and air pollutant concentrations were estimated by spatial-temporal models. Heat effect modification by air pollution was assessed in each small area by over-dispersed Poisson regression models with a tensor smoother between temperature and air pollution. We extracted temperature-mortality relationships at the 5th (low), 50th (medium), and 95th (high) percentiles of pollutant distributions. At each air pollution level, we estimated heat-related mortality for a temperature increase from the 75th to the 99th percentile. We applied random-effects meta-analysis to derive the country-specific and overall associations, and mixed-effects meta-regression to examine the influence of urban-rural and coastal typologies and greenness on the heat effect modification by air pollution. ResultsHeat-related mortality risks increased with higher PM levels, rising by 6.4% (95% CI: −2.0%–15.7%), 10.7% (2.6%–19.5%), and 14.1% (4.4%–24.6%) at low, medium, and high PM levels, respectively. This effect modification was consistent in urban and rural regions but more pronounced in non-coastal regions. In addition, heat-mortality associations were slightly stronger at high O3 levels, particularly in regions with low greenness. ConclusionOur analyses of both urban and rural data indicate that air pollution may intensify heat-related mortality, particularly in non-coastal and less green regions. The synergistic effect of heat and air pollution implies a potential pathway of reducing heat-related health impacts by improving air quality.

Effectiveness and implementation of decentralized, community- and primary care-based strategies in promoting hepatitis B testing uptake: a systematic review and meta-analysis

Expanding chronic hepatitis B (CHB) testing through effective implementation strategies in primary- and community-care setting is crucial for elimination. Our study aimed to determine the effectiveness of all available strategies in the literature and evaluate their specifications and implementation outcomes, thereby informing future programming and policymaking. We conducted a systematic review and meta-analysis (PROSPERO CRD42023455781), searching Scopus, Embase, PubMed, and CINAHL databases up to June 05, 2024, for randomized controlled trials investigating primary- and community-care-based implementation strategies to promote CHB testing. Studies were screened against a priori eligibility criteria, and their data were extracted using a standardized protocol if included. ROB-2 was used to assess the risk of bias. Implementation strategies' components were characterized using the Behavior Change Wheel (BCW) framework. Random-effect models were applied to pool the effectiveness estimate by strategy. Mixed-effect meta-regression was employed to investigate if effectiveness varied by the number of strategy's BCW components. 7146 unique records were identified. 25 studies were eligible for the review, contributing 130,598 participants. 19 studies were included in the meta-analysis. No studies were conducted in low-and-middle-income countries. Implementation outcomes were reported in only ten studies (40%). Community-based strategies included lay health workers-led education (Pooled Risk Difference=27.9% [95% Confidence Interval=3.4-52.4], I2=99.3%) or crowdsourced education on social media (3.1% [-2.2 to 8.4], 0.0%). Primary care-based strategies consisted of electronic alert system (8.4% [3.7-13.1], 95.0%) and healthcare providers-led education (HCPs, 62.5% [53.1-71.9], 27.5%). The number of BCW-framework-driven strategy components showed a significant dose-response relationship with effectiveness. HCPs-led education stands out, and more enriched multicomponent strategies had better effectiveness. Future implementation strategies should consider critical contextual factors and policies to achieve a sustainable impact towards hepatitis B elimination targets. Tran Dolch Post-Doctoral Fellowship in Hepatology, Johns Hopkins University School of Medicine, Baltimore MD, USA.

Temporal change and spatial heterogeneity of the association between ambient temperature and transport accident mortality in Japan from 1972 to 2019: a nationwide time-stratified case-crossover study

Abstract Studies have demonstrated that ambient temperature was associated with transport accidents; however, little is known about the temporal change and spatial heterogeneity of this association. This study investigated the temporal change and spatial variation in the association between temperature and transport accident mortality in Japan using daily time-series data from 1972 to 2019. First, we used time-stratified case-crossover analyses with a distributed lag nonlinear model to estimate the risks of transport accident mortality with temperature in 47 prefectures in Japan. We then pooled the estimates to obtain the risk at the country level through multivariate meta-analysis. In addition, we divided the whole time period into five sub-periods to explore temporal changes in the association and fitted the mixed-effects meta-regression to identify climatic, demographic, and socioeconomic factors that may explain the spatial heterogeneity. We found that temperature was positively associated with transport accident mortality, with a percent change (PC) of 1.47% (95% confidence interval [CI]: 1.10%, 1.85%) increase in transport accident mortality per 1 °C increase in daily mean temperature. The risk of transport accident mortality associated with temperature has decreased from 1972 [PC = 2.14% (95% CI: 1.51%, 2.77%)] to 2000 [PC = 0.89% (95% CI: 0.21%, 1.57%)] but increased slightly from 2001 [PC = 1.13% (95% CI: 0.47%, 1.48%)] to 2019 [PC = 1.60% (95% CI: 0.73%, 2.48%)]. The association between temperature and transport accident mortality was larger in relatively less developed prefectures, as explained by demographic and socioeconomic factors (e.g., total population, proportion of older people and females, and number of general hospitals). Our findings may help to better understand the association between high temperature and transport accident mortality and underlying potential mechanisms, which can provide implications for public health policies to reduce the mortality burden from transport accidents in the future.

Effectiveness of internet-delivered psychological treatments for children and adolescents with anxiety and/or depressive disorders: Systematic review and network meta-analysis

BackgroundAnxiety and depression symptomatology has increased in the child and adolescent population. Internet-delivered psychological treatments (IDPT) can help to reduce this symptomatology, attending to the largest possible population. AimTo conduct a systematic review and network meta-analysis of IDPT to reduce anxiety and depression symptoms in children and adolescents. MethodsThe search for studies was conducted in SCOPUS, PsycINFO, PSICODOC, PsycARTICLES and Medline, between 2000 and 2022, in December 2022. Studies were selected if they were conducted with a sample of children and/or adolescents with previous symptoms of anxiety and depression, had applied IDPT, and included at least two comparative groups with pretest-posttest measures. Network meta-analyses were separately performed for anxiety and depression outcomes. Publication bias was analyzed using Egger's test and funnel plots, and mixed-effects meta-regression models were applied to account for heterogeneity. Results37 studies were included in the meta-analysis, providing a total of 74 comparative groups. IDPT exhibited low-to-moderate, statistically significant average effect sizes when compared to both inactive and active controls. No statistical significance was found when IDPT was compared with other types of interventions. DiscussionIDPT is recommended to reduce anxiety and depression symptomatology in children and adolescents, but more studies are needed which compare treatments with other types of interventions, such as face-to-face therapy.

Validation of PD-L1 as a predictive biomarker of response in operable gastroesophageal adenocarcinoma: A meta-analysis and meta-regression of neoadjuvant chemoimmunotherapy trials.

4065 Background: Perioperative chemotherapy (ChT) is a standard for operable gastroesophageal adenocarcinoma (GEA). The addition of immune checkpoint inhibitors (ICIs) has improved pathological complete response (pCR) with unclear survival advantages in an unselected population. In the advanced setting, PD-L1 is a validated biomarker of response to ICIs. We aimed to assess its predictive role in the early stages wherein remains unexplored. Methods: We conducted a systematic review of randomised clinical trials (RCTs) of neoadjuvant or peri-operative ChT +/- ICIs in non-metastatic GEA, published between 2006-2024. Biomarker-unselected phase 2/3 or phase 3 RCTs with an active comparator were selected. Odds ratios (ORs) for pathological response (defined as pCR, ypT0, or ypT≤1), the primary outcome of this meta-analysis, were extracted and analysed using a random-effect meta-analysis. Subgroup analysis (ICI-ChT versus ChT) was performed to estimate the pooled effect of peri-operative ICIs on pathological response. Sensitivity analyses were performed to account for between-study heterogeneity. We then extracted pCR data by PD-L1 (cutoffs 1, 5, 10) from phase 2 trials of neoadjuvant ICIs+ChT or chemoradiotherapy (CRT) published between 2006-2024. Weighted Pearson trial-level correlation and a meta-regression model were used to assess the relationship of PD-L1 with pCR. Results: Nine RCTs were eligible for the analysis, one of which had two experimental arms contributing to two comparisons. Of 5359 included patients, 1302 received ICI-ChT and 4057 systemic ChT. ICI-ChT showed a significant improvement in pathological response (pooled OR 2.90, 95% CI 1.81-4.63, p&lt;0.001) with a larger effect compared to ChT-only trials (pooled OR 1.40, 95% CI 1.10-1.79, p=0.007). Results were consistent in sensitivity analyses of pCR-only, non-Asian, and since-FLOT studies. Fourteen studies were included in the phase 2 trials dataset (n=10 ICI+ChT and n=4 ICI+CRT) accounting for 708 patients receiving ICIs. PD-L1 showed a moderate positive correlation with pCR, stronger for higher cut-offs (weighted R for cut-offs 1, 5, and 10: 0.33, 0.51, and 0.65, respectively) and after exclusion of CRT trials (weighted R for cut-offs 5 and 10: 0.67 and 0.99, respectively). In a mixed-effect meta-regression model, PD-L1 ≥5 was a significant predictor of response (effect size [ES]: 0.71, 95% CI, 0.29-1.13, p=0.001), even after accounting for the backbone treatment (ChT versus CRT) (ES: 0.60, 95% CI, 0.20-1.00, p=0.003). Conclusions: Neoadjuvant ICI-ChT consistently improves pathological response in operable GEA, particularly in PD-L1-positive tumours. PD-L1 ≥5 appears a significant biomarker of pCR in non-metastatic GEA, supporting stratification by PD-L1 and biomarker-selected trials for evaluation at the individual patient level.

Aetiology of vaginal discharge, urethral discharge, and genital ulcer in sub-Saharan Africa: A systematic review and meta-regression.

Syndromic management is widely used to treat symptomatic sexually transmitted infections in settings without aetiologic diagnostics. However, underlying aetiologies and consequent treatment suitability are uncertain without regular assessment. This systematic review estimated the distribution, trends, and determinants of aetiologies for vaginal discharge, urethral discharge, and genital ulcer in sub-Saharan Africa (SSA). We searched Embase, MEDLINE, Global Health, Web of Science, and grey literature from inception until December 20, 2023, for observational studies reporting aetiologic diagnoses among symptomatic populations in SSA. We adjusted observations for diagnostic test performance, used generalised linear mixed-effects meta-regressions to generate estimates, and critically appraised studies using an adapted Joanna Briggs Institute checklist. Of 4,418 identified records, 206 reports were included from 190 studies in 32 countries conducted between 1969 and 2022. In 2015, estimated primary aetiologies for vaginal discharge were candidiasis (69.4% [95% confidence interval (CI): 44.3% to 86.6%], n = 50), bacterial vaginosis (50.0% [95% CI: 32.3% to 67.8%], n = 39), chlamydia (16.2% [95% CI: 8.6% to 28.5%], n = 50), and trichomoniasis (12.9% [95% CI: 7.7% to 20.7%], n = 80); for urethral discharge were gonorrhoea (77.1% [95% CI: 68.1% to 84.1%], n = 68) and chlamydia (21.9% [95% CI: 15.4% to 30.3%], n = 48); and for genital ulcer were herpes simplex virus type 2 (HSV-2) (48.3% [95% CI: 32.9% to 64.1%], n = 47) and syphilis (9.3% [95% CI: 6.4% to 13.4%], n = 117). Temporal variation was substantial, particularly for genital ulcer where HSV-2 replaced chancroid as the primary cause. Aetiologic distributions for each symptom were largely the same across regions and population strata, despite HIV status and age being significantly associated with several infection diagnoses. Limitations of the review include the absence of studies in 16 of 48 SSA countries, substantial heterogeneity in study observations, and impeded assessment of this variability due to incomplete or inconsistent reporting across studies. In our study, syndrome aetiologies in SSA aligned with World Health Organization guidelines without strong evidence of geographic or demographic variation, supporting broad guideline applicability. Temporal changes underscore the importance of regular aetiologic re-assessment for effective syndromic management. CRD42022348045.

Influence of climate and land use on watershed anthropogenic phosphorus inputs and riverine phosphorus export dynamics: A global analysis

Many studies have found predictive relationships between riverine phosphorus (P) export and net anthropogenic P inputs (NAPI) at the watershed scale, but the global or regional extent of these relationships has not been empirically quantified. Herein, we present a data-driven global assessment of the response of riverine total P (TP) fluxes to NAPI based on 358 watersheds. NAPI exhibited high spatial heterogeneity (2–12,085 kg P km−2 yr−1) and was well correlated with riverine TP fluxes. Riverine TP export fractions of NAPI were primarily regulated by NAPI components, hydroclimate factors, and land-use as determined through a random-forest meta-analysis. In watersheds dominated by disturbed land-use (e.g., agricultural and developed lands), runoff emerged as pivotal climate-related factors influencing riverine export fractions of NAPI. In watersheds dominated by natural land-use, runoff, precipitation and temperature were identified as the most critical factors. We developed a mixed-effects meta-regression model (R2 = 0.63–0.70, RMSE = 19–78 %, n = 87–202) to examine the quantitative relationship between riverine TP fluxes and NAPI, which avoids subjectivity in selecting influencing factors and regression forms. The model estimated that legacy P contributed 14–17 % of annual riverine TP fluxes in Chinese watersheds, 25 % in North American watersheds and 11–27 % in European watersheds. Annual NAPI contributions to annual riverine TP flux were 83–86 % in China, 75 % in North America and 73–89 % in Europe. The model forecasted 52–67 %, 69–71 % and 74–77 % reductions in riverine TP fluxes across Chinese, North American, and European watersheds by 2050 under five shared socio-economic pathway scenarios compared to 2010 baseline conditions, respectively. This study provides a straightforward and reliable method for quantifying anthropogenic P input and riverine P export dynamics within an acceptable error range. It provides guidance for developing phosphorus pollution control strategies to counter potential increases in phosphorus inputs due to expected changes in climate and land use.

Evaluation of the correlation between cerebral hemodynamics and blood pressure by comparative analysis of variation in cerebral blood flow in hypertensive versus normotensive individuals: A systematic review and meta-analysis.

Current understanding of the cerebral vascular response to variations in blood pressure (BP) among individuals with hypertension is limited. The aim of this meta-analysis was to determine the correlation between hypertension, risk of stroke, and cerebral blood flow (CBF). We reviewed studies published between 2000 and 2023 from PubMed, Google Scholar, and Science Direct that compared mean CBF in normotensive (NTN) and hypertensive (HTN) patients. A random effects model was used to construct the risk ratio (RR), 95% confidence interval (CI), forest plot, and inverse variance weighting. Additionally, a mixed-effects meta-regression was employed to examine the impact of study-specific patient variables. This meta-analysis included eight prospective cross-sectional studies published from 2002 to 2023. It revealed a significant average difference in the standard mean CBF of -0.45 (95% CI -0.60 to -0.30, I2 = 69%, P < 0.00001), distinguishing NTN from HTN subjects. A RR of 0.90 (95% CI 0.63 to 1.30, I2 = 89%, P = 0.04) indicated a significant decrease in CBF among individuals with hypertension. We found a statistically significant relationship between changes in diastolic and systolic BPs and the mean CBF (R -0.81, P = 0.001 and R = -0.90, P = 0.005, respectively). Our research demonstrates a strong relationship between elevated BP and reduced CBF, with hypertension reducing CBF compared to NTN individuals, by increasing cerebrovascular resistance.

Rising trend and regional disparities of the global burden of disease attributable to ambient low temperature, 1990-2019: An analysis of data from the Global Burden of Disease 2019 study.

Previous studies on the effect of global warming on the global burden of disease have mainly focussed on the impact of high temperatures, thereby providing limited evidence of the effect of lower temperatures. We adopted a three-stage analysis approach using data from the Global Burden of Disease 2019 study. First, we explored the global burden of disease attributable to low temperatures, examining variations by gender, age, cause, region, and country. Second, we analysed temporal trends in low-temperature-related disease burdens from 1990 to 2019 by meta-regression. Finally, we fitted a mixed-effects meta-regression model to explore the effect modification of country-level characteristics. In 2019, low temperatures were responsible for 2.92% of global deaths and 1.03% of disability-adjusted life years (DALYs), corresponding to a death rate of 21.36 (95% uncertainty interval (UI) = 18.26, 24.73) and a DALY rate of 335 (95% UI = 280, 399) per 100 000 population. Most of the deaths (85.12%) and DALYs (94.38%) attributable to low temperatures were associated with ischaemic heart disease, stroke, and chronic obstructive pulmonary disease. In the last three decades, we observed an upward trend for the annual number of attributable deaths (P < 0.001) and a downward trend for the rates of death (P < 0.001) and DALYs (P < 0.001). The disease burden associated with low temperatures varied considerably among regions and countries, with higher burdens observed in regions with middle or high-middle socio-demographic indices, as well as countries with higher gross domestic product per capita and a larger proportion of ageing population. Our findings emphasise the significance of raising public awareness and prioritising policies to protect global population health from the adverse effects of low temperatures, even in the face of global warming. Particular efforts should be targeted towards individuals with underlying diseases (e.g. cardiovascular diseases) and vulnerable countries or regions (e.g. Central Asia and central Europe).

The effect of differences in trial design on estimates of efficacy of olanzapine in randomized studies

BackgroundDifferences in trial design may affect estimates of efficacy of psychotropic drugs. The purpose of this meta-analysis is to evaluate whether the use of Olanzapine (OLZ) as either investigational or control drug affects the observed efficacy of OLZ. MethodsWe performed a search for Randomized-Controlled Trials (RCTs) in which the efficacy of OLZ is assessed in patients with schizophrenia or schizoaffective disorder. We assessed overall efficacy of OLZ and performed subgroup analyses of studies with OLZ as intervention or comparator. Mixed-effect meta-regression analyses were performed. ResultsOf the 25 RCTs included, OLZ was considered as investigational drug or active control in 13 and 12 studies, respectively. The reduction of PANSS score was greater in trials in which OLZ was used as investigational drug. Multivariate meta-regression models showed that a higher PANSS score at baseline and trial duration were the main predictors of greater PANSS score reduction. ConclusionsTrials with OLZ used as investigational drug differ from those of trials with OLZ as comparator for baseline PANSS scores and study duration; these differences may produce differences in estimates of efficacy. As a consequence, the severity of illness at enrollment and trial duration should be carefully considered to ensure the reliability of indirect comparisons among antipsychotics.

Exposure to Concurrent Heatwaves and Ozone Pollution and Associations with Mortality Risk: A Nationwide Study in China.

Concurrent extreme events are projected to occur more frequently under a changing climate. Understanding the mortality risk and burden of the concurrent heatwaves and ozone () pollution may support the formulation of adaptation strategies and early warning systems for concurrent events in the context of climate change. We aimed to estimate the mortality risk and excess deaths of concurrent heatwaves and pollution across 250 counties in China. We collected daily mortality, meteorological, and air pollution data for the summer (1 June to 30 September) during 2013-2018. We defined heatwaves and high pollution days, then we divided the identified days into three categories: a) days with only heatwaves (heatwave-only event), b) days with only high pollution (high pollution-only event), and c) days with concurrent heatwaves and high pollution (concurrent event). A generalized linear model with a quasi-Poisson regression was used to estimate the risk of mortality associated with extreme events for each county. Then we conducted a random-effects meta-analysis to pool the county-specific estimates to derive the overall effect estimates. We used mixed-effects meta-regression to identify the drivers of the heterogeneity. Finally, we estimated the excess death attributable to extreme events (heatwave-only, high pollution-only, and concurrent events) from 2013 to 2020. A higher all-cause mortality risk was associated with exposure to the concurrent heatwaves and high pollution than exposure to a heatwave-only or a high pollution-only event. The effects of a concurrent event on circulatory and respiratory mortality were higher than all-cause and nonaccidental mortality. Sex and age significantly impacted the association of concurrent events and heatwave-only events with all-cause mortality. We estimated that annual average excess deaths attributed to the concurrent events were 6,249 in China from 2017 to 2020, 5.7 times higher than the annual average excess deaths attributed to the concurrent events from 2013 to 2016. The annual average proportion of excess deaths attributed to the concurrent events in the total excess deaths caused by three types of events (heatwave-only events, high pollution-only events, and concurrent events) increased significantly in 2017-2020 (31.50%; 95% CI: 26.73%, 35.53%) compared with 2013-2016 (9.65%; 95% CI: 5.67%, 10.81%). Relative excess risk due to interaction revealed positive additive interaction considering the concurrent effect of heatwaves and high pollution. Our findings may provide scientific basis for establishing a concurrent event early warning system to reduce the adverse health impact of the concurrent heatwaves and high pollution. https://doi.org/10.1289/EHP13790.

Magnetic Resonance Imaging, Clinical, and Biopsy Findings in Suspected Prostate Cancer

Multiple strategies integrating magnetic resonance imaging (MRI) and clinical data have been proposed to determine the need for a prostate biopsy in men with suspected clinically significant prostate cancer (csPCa) (Gleason score ≥3 + 4). However, inconsistencies across different strategies create challenges for drawing a definitive conclusion. To determine the optimal prostate biopsy decision-making strategy for avoiding unnecessary biopsies and minimizing the risk of missing csPCa by combining MRI Prostate Imaging Reporting & Data System (PI-RADS) and clinical data. PubMed, Ovid MEDLINE, Embase, Web of Science, and Cochrane Library from inception to July 1, 2022. English-language studies that evaluated men with suspected but not confirmed csPCa who underwent MRI PI-RADS followed by prostate biopsy were included. Each study had proposed a biopsy plan by combining PI-RADS and clinical data. Studies were independently assessed for eligibility for inclusion. Quality of studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies 2 tool and the Newcastle-Ottawa Scale. Mixed-effects meta-analyses and meta-regression models with multimodel inference were performed. Reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Independent risk factors of csPCa were determined by performing meta-regression between the rate of csPCa and PI-RADS and clinical parameters. Yields of different biopsy strategies were assessed by performing diagnostic meta-analysis. The analyses included 72 studies comprising 36 366 patients. Univariable meta-regression showed that PI-RADS 4 (β-coefficient [SE], 7.82 [3.85]; P = .045) and PI-RADS 5 (β-coefficient [SE], 23.18 [4.46]; P < .001) lesions, but not PI-RADS 3 lesions (β-coefficient [SE], -4.08 [3.06]; P = .19), were significantly associated with a higher risk of csPCa. When considered jointly in a multivariable model, prostate-specific antigen density (PSAD) was the only clinical variable significantly associated with csPCa (β-coefficient [SE], 15.50 [5.14]; P < .001) besides PI-RADS 5 (β-coefficient [SE], 9.19 [3.33]; P < .001). Avoiding biopsy in patients with lesions with PI-RADS category of 3 or less and PSAD less than 0.10 (vs <0.15) ng/mL2 resulted in reducing 30% (vs 48%) of unnecessary biopsies (compared with performing biopsy in all suspected patients), with an estimated sensitivity of 97% (vs 95%) and number needed to harm of 17 (vs 15). These findings suggest that in patients with suspected csPCa, patient-tailored prostate biopsy decisions based on PI-RADS and PSAD could prevent unnecessary procedures while maintaining high sensitivity.

Elimination of transmission of onchocerciasis (river blindness) with long-term ivermectin mass drug administration with or without vector control in sub-Saharan Africa: a systematic review and meta-analysis

WHO has proposed elimination of transmission of onchocerciasis (river blindness) by 2030. More than 99% of cases of onchocerciasis are in sub-Saharan Africa. Vector control and mass drug administration of ivermectin have been the main interventions for many years, with varying success. We aimed to identify factors associated with elimination of onchocerciasis transmission in sub-Saharan Africa. For this systematic review and meta-analysis we searched for published articles reporting epidemiological or entomological assessments of onchocerciasis transmission status in sub-Saharan Africa, with or without vector control. We searched MEDLINE, PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, African Index Medicus, and Google Scholar databases for all articles published from database inception to Aug 19, 2023, without language restrictions. The search terms used were "onchocerciasis" AND "ivermectin" AND "mass drug administration". The three inclusion criteria were (1) focus or foci located in Africa, (2) reporting of elimination of transmission or at least 10 years of ivermectin mass drug administration in the focus or foci, and (3) inclusion of at least one of the following assessments: microfilarial prevalence, nodule prevalence, Ov16 antibody seroprevalence, and blackfly infectivity prevalence. Epidemiological modelling studies and reviews were excluded. Four reviewers (NM, AJ, AM, and TNK) extracted data in duplicate from the full-text articles using a data extraction tool developed in Excel with columns recording the data of interest to be extracted, and a column where important comments for each study could be highlighted. We did not request any individual-level data from authors. Foci were classified as achieving elimination of transmission, being close to elimination of transmission, or with ongoing transmission. We used mixed-effects meta-regression models to identify factors associated with transmission status. This study is registered in PROSPERO, CRD42022338986. Of 1525 articles screened after the removal of duplicates, 75 provided 282 records from 238 distinct foci in 19 (70%) of the 27 onchocerciasis-endemic countries in sub-Saharan Africa. Elimination of transmission was reported in 24 (9%) records, being close to elimination of transmission in 86 (30%) records, and ongoing transmission in 172 (61%) records. I2 was 83·3% (95% CI 79·7 to 86·3). Records reporting 10 or more years of continuous mass drug administration with 80% or more therapeutic coverage of the eligible population yielded significantly higher odds of achieving elimination of transmission (log-odds 8·5 [95% CI 3·5 to 13·5]) or elimination and being close to elimination of transmission (42·4 [18·7 to 66·1]) than those with no years achieving 80% coverage or more. Reporting 15-19 years of ivermectin mass drug administration (22·7 [17·2 to 28·2]) and biannual treatment (43·3 [27·2 to 59·3]) were positively associated with elimination and being close to elimination of transmission compared with less than 15 years and no biannual mass drug administration, respectively. Having had vector control without vector elimination (-42·8 [-59·1 to -26·5]) and baseline holoendemicity (-41·97 [-60·6 to -23·2]) were associated with increased risk of ongoing transmission compared with no vector control and hypoendemicity, respectively. Blackfly disappearance due to vector control or environmental change contributed to elimination of transmission. Mass drug administration duration, frequency, and coverage; baseline endemicity; and vector elimination or disappearance are important determinants of elimination of onchocerciasis transmission in sub-Saharan Africa. Our findings underscore the importance of improving and sustaining high therapeutic coverage and increasing treatment frequency if countries are to achieve elimination of onchocerciasis transmission. The Bill & Melinda Gates Foundation and Neglected Tropical Diseases Modelling Consortium, UK Medical Research Council, and Global Health EDCTP3 Joint Undertaking. For the Swahili, French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Effect of pharmacological selectivity of SGLT2 inhibitors on cardiovascular outcomes in patients with type 2 diabetes: a meta-analysis

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetic (T2DM) patients. Pharmacological selectivity of these agents to SGLT2 over SGLT1 is highly variant, with unknown clinical relevance. Genetically reduced SGLT1—but not SGLT2—activity correlates with lower risk of heart failure and mortality, therefore additional non-selective SGLT1 inhibition might be beneficial. In this prespecified meta-analysis, we included 6 randomized, placebo-controlled cardiovascular outcome trials of SGLT2 inhibitors assessing MACE in 57,553 patients with T2DM. Mixed-effects meta-regression revealed that pharmacological selectivity of SGLT2 inhibitors (either as continuous or dichotomized variable) had no significant impact on most outcomes. However, lower SGLT2 selectivity correlated with significantly lower risk of stroke (pseudo-R2 = 78%; p = 0.011). Indeed, dual SGLT1/2 inhibitors significantly reduced the risk of stroke (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64–0.94), unlike selective agents (p for interaction = 0.018). The risk of diabetic ketoacidosis and genital infections was higher in both pharmacological groups versus placebo. However, hypotension occurred more often with non-selective SGLT2 inhibitors (odds ratio [OR], 1.87; 95% CI, 1.20–2.92) compared with selective agents (p for interaction = 0.044). In conclusion, dual SGLT1/2 inhibition reduces stroke in high-risk T2DM patients but has limited additional effect on other clinical outcomes.

Surrogate endpoints for overall survival in advanced hepatocellular carcinoma: A meta-analysis.

563 Background: Recent advances in systemic therapies have resulted in improved overall survivals (OS) for patients with advanced hepatocellular carcinoma (aHCC). The most commonly utilized primary endpoint for phase III trials in aHCC is OS. A robust surrogate endpoint (SEP) can reduce time and financial costs of future trials and accelerate regulatory approvals of new therapies. We conducted a literature-based meta-analysis to evaluate SEPs for OS in aHCC. Methods: Randomized controlled trials evaluating systemic therapies in aHCC published 2007 - 2023 were identified through a systemic literature search of Cochrane and Medline databases as well as of abstracts presented at ASCO and ESMO meetings. Hazard ratios (HR) for OS and progression-free survival (PFS) and time to progression (TTP) were extracted. ΔORR was calculated as the difference in overall response rates (ORR) between control and experimental arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Surrogate threshold effect (STE) was determined for each comparison when possible. A p &lt; 0.05 was considered to be statistically significant. Results: 26 trials were identified in the first-line setting with 14,827 patients and 11 trials in the subsequent-line setting with 5,316 patients. In first-line trials, immunotherapy (IO) is associated with higher ORR than other agents (p=0.003). There are statistically significant correlations between HRs of PFS/TTP/ΔORR and OS (Table). The relationship between HR-PFS and HR-OS persists in trials with or without IO, but only in trials enrolling &lt; 30% patients of non-viral aetiologies. In subsequent-line trials, there are statistically significant correlations between HRs of PFS/TTP and OS (Table). STE for HR PFS is 0.68 and 0.87 respectively for 1st and subsequent line trials. Conclusions: There are moderate to strong correlations between PFS and OS in aHCC in first-line and subsequent line trials. STE for HR-PFS of 0.68 in first-line and 0.87 in subsequent-line settings can guide sample size calculation in future clinical trials. [Table: see text]

Intravascular Imaging-Guided Versus Angiography-Guided Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Trials.

Despite the initial evidence supporting the utility of intravascular imaging to guide percutaneous coronary intervention (PCI), adoption remains low. Recent new trial data have become available. An updated study-level meta-analysis comparing intravascular imaging to angiography to guide PCI was performed. This study aimed to evaluate the clinical outcomes of intravascular imaging-guided PCI compared with angiography-guided PCI. A random-effects meta-analysis was performed on the basis of the intention-to-treat principle. The primary outcomes were major adverse cardiac events, cardiac death, and all-cause death. Mixed-effects meta-regression was performed to investigate the impact of complex PCI on the primary outcomes. A total of 16 trials with 7814 patients were included. The weighted mean follow-up duration was 28.8 months. Intravascular imaging led to a lower risk of major adverse cardiac events (relative risk [RR], 0.67 [95% CI, 0.55-0.82]; P<0.001), cardiac death (RR, 0.49 [95% CI, 0.34-0.71]; P<0.001), stent thrombosis (RR, 0.63 [95% CI, 0.40-0.99]; P=0.046), target-lesion revascularization (RR, 0.67 [95% CI, 0.49-0.91]; P=0.01), and target-vessel revascularization (RR, 0.60 [95% CI, 0.45-0.80]; P<0.001). In complex lesion subsets, the point estimate for imaging-guided PCI compared with angiography-guided PCI for all-cause death was a RR of 0.75 (95% CI, 0.55-1.02; P=0.07). In patients undergoing PCI, intravascular imaging is associated with reductions in major adverse cardiac events, cardiac death, stent thrombosis, target-lesion revascularization, and target-vessel revascularization. The magnitude of benefit is large and consistent across all included studies. There may also be benefits in all-cause death, particularly in complex lesion subsets. These results support the use of intravascular imaging as standard of care and updates of clinical guidelines.

Screen Time and Autism Spectrum Disorder

Contemporary studies raise concerns regarding the implications of excessive screen time on the development of autism spectrum disorder (ASD). However, the existing literature consists of mixed and unquantified findings. To conduct a systematic review and meta-analyis of the association between screen time and ASD. A search was conducted in the PubMed, PsycNET, and ProQuest Dissertation & Theses Global databases for studies published up to May 1, 2023. The search was conducted independently by 2 authors. Included studies comprised empirical, peer-reviewed articles or dissertations published in English with statistics from which relevant effect sizes could be calculated. Discrepancies were resolved by consensus. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Two authors independently coded all titles and abstracts, reviewed full-text articles against the inclusion and exclusion criteria, and resolved all discrepancies by consensus. Effect sizes were transformed into log odds ratios (ORs) and analyzed using a random-effects meta-analysis and mixed-effects meta-regression. Study quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Publication bias was tested via the Egger z test for funnel plot asymmetry. Data analysis was performed in June 2023. The 2 main variables of interest in this study were screen time and ASD. Screen time was defined as hours of screen use per day or per week, and ASD was defined as an ASD clinical diagnosis (yes or no) or ASD symptoms. The meta-regression considered screen type (ie, general use of screens, television, video games, computers, smartphones, and social media), age group (children vs adults or heterogenous age groups), and type of ASD measure (clinical diagnosis vs ASD symptoms). Of the 4682 records identified, 46 studies with a total of 562 131 participants met the inclusion criteria. The studies were observational (5 were longitudinal and 41 were cross-sectional) and included 66 relevant effect sizes. The meta-analysis resulted in a positive summary effect size (log OR, 0.54 [95% CI, 0.34 to 0.74]). A trim-and-fill correction for a significant publication bias (Egger z = 2.15; P = .03) resulted in a substantially decreased and nonsignificant effect size (log OR, 0.22 [95% CI, -0.004 to 0.44]). The meta-regression results suggested that the positive summary effect size was only significant in studies targeting general screen use (β [SE] = 0.73 [0.34]; t58 = 2.10; P = .03). This effect size was most dominant in studies of children (log OR, 0.98 [95% CI, 0.66 to 1.29]). Interestingly, a negative summary effect size was observed in studies investigating associations between social media and ASD (log OR, -1.24 [95% CI, -1.51 to -0.96]). The findings of this systematic review and meta-analysis suggest that the proclaimed association between screen use and ASD is not sufficiently supported in the existing literature. Although excessive screen use may pose developmental risks, the mixed findings, the small effect sizes (especially when considering the observed publication bias), and the correlational nature of the available research require further scientific investigation. These findings also do not rule out the complementary hypothesis that children with ASD may prioritize screen activities to avoid social challenges.

Acceptance and Commitment Therapy Among Informal Caregivers of People With Chronic Health Conditions

Although there is substantial evidence to suggest the health benefits of acceptance and commitment therapy (ACT) among informal caregivers of people with chronic health conditions, the great variation in intervention designs among published studies limits its application. To identify intervention characteristics of ACT that are associated with improved psychological health and to assess the acceptability of ACT among informal caregivers. Seven English- and 3 Chinese-language databases without limits on publication dates, the reference lists of previous reviews, and gray literature were searched up to February 2023. Randomized clinical trials comparing the effect of ACT vs control groups on improving psychological health among informal caregivers. Two reviewers independently screened searched records and extracted data from eligible studies. Random-effects meta-analysis and mixed-effects metaregression were performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed. Psychological health outcomes (eg, depressive symptoms) measured by valid measurements and the acceptability of ACT based on identified parameters. A total of 29 studies with 2010 participants, published between 2015 and 2023, were identified. ACT showed moderate to large effect sizes for improving psychological health at postintervention assessments (Hedges g range, -0.55 [95% CI, -0.98 to -0.12] to -1.14 [95% CI, -1.83 to -0.45]) and at 1-to-3-month and 4-to-6-month follow-ups (Hedges g range, -0.47 [95% CI, -0.69 to -0.25] to -1.29 [95% CI, -2.33 to -0.24]). Multivariable metaregression analysis regarding intervention characteristics found that ACT delivered in a mixed individual- and group-based format, face-to-face, or through more intervention sessions was associated with greater improvements for experiential avoidance (face-to-face: β = -1.170 [95% CI, -2.020 to -0.319]; number of sessions: β = -0.242 [95% CI, -0.353 to -0.130]), depressive symptoms (mixed delivery format: β = -2.583 [95% CI, -4.845 to -0.321]; face-to-face: β = -1.555 [95% CI, -3.002 to -0.108]), or anxiety symptoms (face-to-face: β = -1.241 [95% CI, -2.337 to -0.146]). In general, ACT had low attrition rates (11%), and participants' adherence (51%-80%) and satisfactory ratings (72%-95%) lend support to its acceptability. This systematic review and meta-analysis found that ACT was consistently associated with improvements in psychological health, supporting its application to improve informal care for chronic disease management. This review provides specific details on the design parameters of ACT for achieving greater efficacy.