Using Parametric g-Computation for Time-to-Event Data and Distributed Lag Models to Identify Critical Exposure Windows for Preterm Birth: An Illustrative Example Using PM2.5 in a Retrospective Birth Cohort Based in Eastern Massachusetts (2011-2016).

BACKGROUND: Parametric g-computation is an attractive analytic framework to study the health effects of air pollution. Yet, the ability to explore biologically relevant exposure windows within this framework is underdeveloped. OBJECTIVES: We outline a novel framework for how to incorporate complex lag-responses using distributed lag models (DLMs) into parametric g-computation analyses for survival data. We call this approach "g-survival-DLM" and illustrate its use examining the association between PM2.5 during pregnancy and the risk of preterm birth (PTB). METHODS: We applied the g-survival-DLM approach to estimate the hypothetical static intervention of reducing average PM2.5 in each gestational week by 20% on the risk of PTB among 9,403 deliveries from Beth Israel Deaconess Medical Center, Boston, Massachusetts, 2011-2016. Daily PM2.5 was taken from a 1-km grid model and assigned to address at birth. Models were adjusted for sociodemographics, time trends, nitrogen dioxide, and temperature. To facilitate implementation, we provide a detailed description of the procedure and accompanying R syntax. RESULTS: There were 762 (8.1%) PTBs in this cohort. The gestational week-specific median PM2.5 concentration was relatively stable across pregnancy at ∼7µg/m3. We found that our hypothetical intervention strategy changed the cumulative risk of PTB at week 36 (i.e., the end of the preterm period) by -0.009 (95% confidence interval: -0.034, 0.007) in comparison with the scenario had we not intervened, which translates to about 86 fewer PTBs in this cohort. We also observed that the critical exposure window appeared to be weeks 5-20. DISCUSSION: We demonstrate that our g-survival-DLM approach produces easier-to-interpret, policy-relevant estimates (due to the g-computation); prevents immortal time bias (due to treating PTB as a time-to-event outcome); and allows for the exploration of critical exposure windows (due to the DLMs). In our illustrative example, we found that reducing fine particulate matter [particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5)] during gestational weeks 5-20 could potentially lower the risk of PTB. https://doi.org/10.1289/EHP13891.

Temporal trends in temperature-related mortality and evidence for maladaptation to heat and cold in the Eastern Mediterranean region.

The eastern Mediterranean region is characterized by rising temperature trends exceeding the corresponding global averages and is considered a climate change hot-spot. Although previous studies have thoroughly investigated the impact of extreme heat and cold on human mortality and morbidity, both for the current and future climate change scenarios, the temporal trends in temperature-related mortality or the potential historical adaptation to heat and cold extremes has never been studied in this region. This study focuses on cardiovascular mortality and assesses the temporal evolution of the Minimum Mortality Temperature (MMT), as well as the disease-specific cold- and heat-attributable fraction of mortality in three typical eastern Mediterranean environments (Athens, Thessaloniki and Cyprus). Data on daily cardiovascular mortality (ICD-10 code: I00-I99) and meteorological parameters were available between 1999 and 2019 for Athens, 1999 to 2018 for Thessaloniki and 2004 to 2019 for Cyprus. Estimation of cardiovascular MMT and mortality fractions relied on time-series Poisson regressions with distributed lag nonlinear models (DLNM) controlling for seasonal and long-term trends, performed over a series of rolling sub-periods at each site. The results indicated that in Athens, the MMT decreased from 23 °C (67.5th percentile) in 1999-2007 to 21.8 °C (62nd percentile) in 2011-2019, while in Cyprus the MMT decreased from 26.3 °C (79th percentile) in 2004-2012 to 23.9 °C (66.5th percentile) in 2011-2019. In Thessaloniki, the decrease in MMT was rather negligible. In all regions under study, the fractions of mortality attributed to both cold and heat followed an upward trend throughout the years. In conclusion, the demonstrated increase in cold attributable fraction and the decreasing temporal trend of MMT across the examined sites are suggestive of maladaptation to extreme temperatures in regions with warm climate and highlight the need for relevant public health policies and interventions.

Protocol for the development of a reporting guideline for umbrella reviews on epidemiological associations using cross-sectional, case-control and cohort studies: the Preferred Reporting Items for Umbrella Reviews of Cross-sectional, Case-control and Cohort studies (PRIUR-CCC).

INTRODUCTION: Observational studies are fraught with several biases including reverse causation and residual confounding. Overview of reviews of observational studies (ie, umbrella reviews) synthesise systematic reviews with or without meta-analyses of cross-sectional, case-control and cohort studies, and may also aid in the grading of the credibility of reported associations. The number of published umbrella reviews has been increasing. Recently, a reporting guideline for overviews of reviews of healthcare interventions (Preferred Reporting Items for Overviews of Reviews (PRIOR)) was published, but the field lacks reporting guidelines for umbrella reviews of observational studies. Our aim is to develop a reporting guideline for umbrella reviews on cross-sectional, case-control and cohort studies assessing epidemiological associations. METHODS AND ANALYSIS: We will adhere to established guidance and prepare a PRIOR extension for systematic reviews of cross-sectional, case-control and cohort studies testing epidemiological associations between an exposure and an outcome, namely Preferred Reporting Items for Umbrella Reviews of Cross-sectional, Case-control and Cohort studies (PRIUR-CCC). Step 1 will be the project launch to identify stakeholders. Step 2 will be a literature review of available guidance to conduct umbrella reviews. Step 3 will be an online Delphi study sampling 100 participants among authors and editors of umbrella reviews. Step 4 will encompass the finalisation of PRIUR-CCC statement, including a checklist, a flow diagram, explanation and elaboration document. Deliverables will be (i) identifying stakeholders to involve according to relevant expertise and end-user groups, with an equity, diversity and inclusion lens; (ii) completing a narrative review of methodological guidance on how to conduct umbrella reviews, a narrative review of methodology and reporting in published umbrella reviews and preparing an initial PRIUR-CCC checklist for Delphi study round 1; (iii) preparing a PRIUR-CCC checklist with guidance after Delphi study; (iv) publishing and disseminating PRIUR-CCC statement. ETHICS AND DISSEMINATION: PRIUR-CCC has been approved by The Ottawa Health Science Network Research Ethics Board and has obtained consent (20220639-01H). Participants to step 3 will give informed consent. PRIUR-CCC steps will be published in a peer-reviewed journal and will guide reporting of umbrella reviews on epidemiological associations.

Panel stacking is a threat to consensus statement validity.

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated toward COVID-19 elimination (Zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases toward advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Relative humidity, temperature, and hypertensive disorders of pregnancy: Findings from the Project Viva cohort.

BACKGROUND: Preeclampsia is a multi-system hypertensive disorder of pregnancy that is a leading cause of maternal and fetal morbidity and mortality. Prior studies disagree on the cause and even the presence of seasonal patterns in its incidence. Using unsuitable time windows for seasonal exposures can bias model results, potentially explaining these inconsistencies. OBJECTIVES: We aimed to investigate humidity and temperature as possible causes for seasonal trends in preeclampsia in Project Viva, a prebirth cohort in Boston, Massachusetts, considering only exposure windows that precede disease onset. METHODS: Using the Parameter-elevation Relationships on Independent Slopes Model (PRISM) Climate Dataset, we estimated daily residential temperature and relative humidity (RH) exposures during pregnancy. Our primary multinomial regression adjusted for person-level covariates and season. Secondary analyses included distributed lag models (DLMs) and adjusted for ambient air pollutants including fine particulates (PM2.5). We used Generalized Additive Mixed Models (GAMMs) for systolic blood pressure (SBP) trajectories across hypertensive disorder statuses to confirm exposure timing. RESULTS: While preeclampsia is typically diagnosed late in pregnancy, GAMM-fitted SBP trajectories for preeclamptic and non-preeclamptic women began to diverge at around 20 weeks' gestation, confirming the need to only consider early exposures. In the primary analysis with 1776 women, RH in the early second trimester, weeks 14-20, was associated with significantly higher odds of preeclampsia (OR per IQR increase: 1.81, 95% CI: 1.10, 2.97). The DLM corroborated this window, finding a positive association from weeks 12-20. There were no other significant associations between RH or temperature and preeclampsia or gestational hypertension in any other time period. DISCUSSION: The association between preeclampsia and RH in the early second trimester was robust to model choice, suggesting that RH may contribute to seasonal trends in preeclampsia incidence. Differences between these results and those of prior studies could be attributable to exposure timing differences.

Association between density of food retailers and fitness centers and gestational diabetes mellitus in Eastern Massachusetts, USA: population-based study.

Background: Few studies have investigated the relationship between the food and physical activity environment and odds of gestational diabetes mellitus (GDM). This study quantifies the association between densities of several types of food establishments and fitness centers with the odds of having GDM. Methods: The density of supermarkets, fast-food restaurants, full-service restaurants, convenience stores and fitness centers at 500, 1000 and 1500 m (m) buffers was counted at residential addresses of 68,779 pregnant individuals from Eastern Massachusetts during 2000-2016. The 'healthy food index' assessed the relative availability of healthy (supermarkets) vs unhealthy (fast-food restaurants, convenience stores) food retailers. Multivariable logistic regression quantified the cross-sectional association between exposure variables and the odds of having GDM, adjusting for individual and area-level characteristics. Effect modification by area-level socioeconomic status (SES) was assessed. Findings: In fully adjusted models, pregnant individuals living in the highest density tertile of fast-food restaurants had higher GDM odds compared to those living in the lowest density tertile (500 m: odds ratio (OR):1.17 95% CI: [1.04, 1.31]; 1000 m: 1.33 95% CI: [1.15, 1.53]); 1500 m: 1.18 95% CI: [1.01, 1.38]). Greater residential density of supermarkets was associated with lower odds of GDM (1000 m: 0.86 95% CI: [0.74, 0.99]; 1500 m: 0.86 95% CI: [0.72, 1.01]). Similarly, living in the highest fitness center density tertile was associated with decreased GDM odds (500 m:0.87 95% CI: [0.76, 0.99]; 1500 m: 0.89 95% CI: [0.79, 1.01]). There was no evidence of effect modification by SES and no association found between the healthy food index and GDM odds. Interpretation: In Eastern Massachusetts, living near a greater density of fast-food establishments was associated with higher GDM odds. Greater residential access to supermarkets and fitness centers was associated with lower the odds of having GDM. Funding: NIH.

Evaluating the temperature-mortality relationship over 16 years in Cyprus.

In many regions of the world, the relationship between ambient temperature and mortality is well-documented, but little is known about Cyprus, a Mediterranean island country where climate change is progressing faster than the global average. We Examined the association between daily ambient temperature and all-cause mortality risk in Cyprus. We conducted a time-series analysis with quasipoisson distribution and distributed lag non-linear models to investigate the association between temperature and all-cause mortality from 1 January 2004 to 31 December 2019 in five districts in Cyprus. We then performed a meta-analysis to estimate the overall temperature-mortality dose-response relationship in Cyprus. Excess mortality was computed to determine the public health burden caused by extreme temperatures. We did not find evidence of heterogeneity between the five districts (p = 0.47). The pooled results show that for cold effects, comparing the 1st, 2.5th, and 5th percentiles to the optimal temperature (temperature associated with least mortality, 25 ℃), the overall relative risks of mortality were 1.55 (95% CI: 1.32, 1.82), 1.41 (95% CI: 1.21, 1.64), and 1.32 (95% CI: 1.15, 1.52), respectively. For heat effects, the overall relative risks of mortality at the 95th, 97.5th and 99th percentiles were 1.10 (95% CI: 1.04, 1.16), 1.17 (95% CI: 1.07, 1.29), and 1.29 (95% CI: 1.11, 1.5), respectively. The excess mortality attributable to cold days accounted for 8.0 deaths (95% empirical CI: 4.5-10.8) for every 100 deaths, while the excess mortality attributable to heat days accounted for 1.3 deaths (95% empirical CI: 0.7-1.7) for every 100 deaths. The results prompt additional research into environmental risk prevention in this under-studied hot and dry region that could experience disproportionate climate change related exposures.Implications: The quantification of excess mortality attributable to temperature extremes shows an urgent need for targeted public health interventions and climate adaptation strategies in Cyprus and similar regions facing rapid climate change. Future steps should look into subpopulation sensitivity, coping strategies, and adaptive interventions to reduce potential future risks.

The association of short-term increases in ambient PM2.5 and temperature exposures with stillbirth: racial/ethnic disparities among Medicaid recipients.

Racial/ethnic disparities in the association between short-term (e.g. days, weeks) ambient fine particulate matter (PM2.5) and temperature exposures and stillbirth in the US have been understudied. A time-stratified, case-crossover design using a distributed lag non-linear model (0 to 6-day lag) estimated stillbirth odds due to short-term increases in average daily PM2.5 and temperature exposures among 118,632 Medicaid recipients from 2000-2014. Disparities by maternal race/ethnicity (Black, White, Hispanic, Asian, American Indian) and zip-code level socioeconomic status (SES) were assessed. In the temperature-adjusted model, a 10 µg/m3 increase in PM2.5 concentration was marginally associated with increased stillbirth odds at lag 1 (0.68% 95%CI:[-0.04,1.40]) and lag 2 (0.52% 95%CI:[-0.03,1.06]), but not lag 0-6 (2.80% 95%CI:[-0.81,6.45]). An association between daily PM2.5 concentrations and stillbirth odds was found among Black individuals at the cumulative lag (0-6 days: 9.26% 95%CI:[3.12,15.77]), but not among other races/ethnicities. A stronger association between PM2.5 concentrations and stillbirth odds existed among Black individuals living in zip codes with the lowest median household income (lag0-6:14.13% 95%CI:[4.64,25.79]). Short-term temperature increases were not associated with stillbirth risk among any race/ethnicity. Black Medicaid enrollees, and especially those living in lower SES areas, may be more vulnerable to stillbirth due to short-term increases in PM2.5 exposure.

The association between maternal prenatal hair cortisol concentration and preterm birth: A systematic review and meta-analysis.

BACKGROUND: The risk of preterm birth (PTB) increases when experiencing stress during pregnancy. Chronic stress has been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis, for which hair cortisol concentration (HCC) is a promising biomarker. However, previous studies on the association between HCC and PTB yielded inconsistent results. This systematic review and meta-analysis synthesized previous studies on the association between maternal HCC before and during pregnancy and spontaneous PTB. METHODS: Data was extracted from N = 11 studies with k = 19 effect sizes retrieved from PubMed, Embase, Web of Science, CINAHL and citation searching by hand in June 2023 and updated in October 2023. Standardized mean differences were calculated, and a random-effects three-level meta-analysis was conducted. Effect heterogeneity was assessed using Q and I2. RESULTS: HCC during pregnancy was higher among PTB than term groups, but effects were not statistically significant (z = 0.11, 95% CI: - 0.28, 0.51, p = .54) and total heterogeneity was high (Q16 = 60.01, p < .001, I2Total = 92.30%). After leaving out two possible outlier studies in sensitivity analyses, HCC was lower among preterm compared to term delivering groups, although not statistically significant (z = - 0.06, 95% CI: - 0.20, 0.08, p = .39) but with a substantially reduced total heterogeneity (Q12 = 16.45, p = .17, I2Total = 42.15%). No moderators affected the estimates significantly, but an effect of trimester and gestational age at delivery is likely. CONCLUSION: There is currently no evidence of prenatal HCC differences between PTB and term groups as effects were small, imprecise, and not significant. Low statistical power and methodological weaknesses of the small-scale studies challenge possible biological inferences from the small effects, but further research on HCC during pregnancy is highly encouraged.

Magnitude and determinants of excess total, age-specific and sex-specific all-cause mortality in 24 countries worldwide during 2020 and 2021: results on the impact of the COVID-19 pandemic from the C-MOR project.

INTRODUCTION: To examine the impact of the COVID-19 pandemic on mortality, we estimated excess all-cause mortality in 24 countries for 2020 and 2021, overall and stratified by sex and age. METHODS: Total, age-specific and sex-specific weekly all-cause mortality was collected for 2015-2021 and excess mortality for 2020 and 2021 was calculated by comparing weekly 2020 and 2021 age-standardised mortality rates against expected mortality, estimated based on historical data (2015-2019), accounting for seasonality, and long-term and short-term trends. Age-specific weekly excess mortality was similarly calculated using crude mortality rates. The association of country and pandemic-related variables with excess mortality was investigated using simple and multilevel regression models. RESULTS: Excess cumulative mortality for both 2020 and 2021 was found in Austria, Brazil, Belgium, Cyprus, England and Wales, Estonia, France, Georgia, Greece, Israel, Italy, Kazakhstan, Mauritius, Northern Ireland, Norway, Peru, Poland, Slovenia, Spain, Sweden, Ukraine, and the USA. Australia and Denmark experienced excess mortality only in 2021. Mauritius demonstrated a statistically significant decrease in all-cause mortality during both years. Weekly incidence of COVID-19 was significantly positively associated with excess mortality for both years, but the positive association was attenuated in 2021 as percentage of the population fully vaccinated increased. Stringency index of control measures was positively and negatively associated with excess mortality in 2020 and 2021, respectively. CONCLUSION: This study provides evidence of substantial excess mortality in most countries investigated during the first 2 years of the pandemic and suggests that COVID-19 incidence, stringency of control measures and vaccination rates interacted in determining the magnitude of excess mortality.

Improved childhood asthma control after exposure reduction interventions for desert dust and anthropogenic air pollution: the MEDEA randomised controlled trial.

INTRODUCTION: Elevated particulate matter (PM) concentrations of anthropogenic and/or desert dust origin are associated with increased morbidity among children with asthma. OBJECTIVE: The Mitigating the Health Effects of Desert Dust Storms Using Exposure-Reduction Approaches randomised controlled trial assessed the impact of exposure reduction recommendations, including indoor air filtration, on childhood asthma control during high desert dust storms (DDS) season in Cyprus and Greece. DESIGN, PARTICIPANTS, INTERVENTIONS AND SETTING: Primary school children with asthma were randomised into three parallel groups: (a) no intervention (controls); (b) outdoor intervention (early alerts notifications, recommendations to stay indoors and limit outdoor physical activity during DDS) and (c) combined intervention (same as (b) combined with indoor air purification with high efficiency particulate air filters in children's homes and school classrooms. Asthma symptom control was assessed using the childhood Asthma Control Test (c-ACT), spirometry (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC)) and fractional exhaled nitric oxide (FeNO). RESULTS: In total, 182 children with asthma (age; mean=9.5, SD=1.63) were evaluated during 2019 and 2021. After three follow-up months, the combined intervention group demonstrated a significant improvement in c-ACT in comparison to controls (ß=2.63, 95% CI 0.72 to 4.54, p=0.007), which was more profound among atopic children (ß=3.56, 95% CI 0.04 to 7.07, p=0.047). Similarly, FEV1% predicted (ß=4.26, 95% CI 0.54 to 7.99, p=0.025), the need for any asthma medication and unscheduled clinician visits, but not FVC% and FeNO, were significantly improved in the combined intervention compared with controls. CONCLUSION: Recommendations to reduce exposure and use of indoor air filtration in areas with high PM pollution may improve symptom control and lung function in children with asthma. TRIAL REGISTRATION NUMBER: NCT03503812.

Short-Term Increases in NO2 and O3 Concentrations during Pregnancy and Stillbirth Risk in the U.S.: A Time-Stratified Case-Crossover Study.

Associations between gaseous pollutant exposure and stillbirth have focused on exposures averaged over trimesters or gestation. We investigated the association between short-term increases in nitrogen dioxide (NO2) and ozone (O3) concentrations and stillbirth risk among a national sample of 116 788 Medicaid enrollees from 2000 to 2014. A time-stratified case-crossover design was used to estimate distributed (lag 0-lag 6) and cumulative lag effects, which were adjusted for PM2.5 concentration and temperature. Effect modification by race/ethnicity and proximity to hydraulic fracturing (fracking) wells was assessed. Short-term increases in the NO2 and O3 concentrations were not associated with stillbirth in the overall sample. Among American Indian individuals (n = 1694), a 10 ppb increase in NO2 concentrations was associated with increased stillbirth odds at lag 0 (5.66%, 95%CI: [0.57%, 11.01%], p = 0.03) and lag 1 (4.08%, 95%CI: [0.22%, 8.09%], p = 0.04) but not lag 0-6 (7.12%, 95%CI: [-9.83%, 27.27%], p = 0.43). Among participants living in zip codes within 15 km of active fracking wells (n = 9486), a 10 ppb increase in NO2 concentration was associated with increased stillbirth odds in single-day lags (2.42%, 95%CI: [0.37%, 4.52%], p = 0.02 for lag 0 and 1.83%, 95%CI: [0.25%, 3.43%], p = 0.03 for lag 1) but not the cumulative lag (lag 0-6) (4.62%, 95%CI: [-2.75%, 12.55%], p = 0.22). Odds ratios were close to the null in zip codes distant from fracking wells. Future studies should investigate the role of air pollutants emitted from fracking and potential racial disparities in the relationship between short-term increases in NO2 concentrations and stillbirth.

Association between gestational exposure to solar activity and pregnancy loss using live births from a Massachusetts-based medical center.

BACKGROUND: Solar activity has been linked to biological mechanisms important to pregnancy, including folate and melatonin levels and inflammatory markers. Thus, we aimed to investigate the association between gestational solar activity and pregnancy loss. METHODS: Our study included 71,963 singleton births conceived in 2002-2016 and delivered at an academic medical center in Eastern Massachusetts. We studied several solar activity metrics, including sunspot number, Kp index, and ultraviolet radiation, with data from the NASA Goddard Space Flight Center and European Centre for Medium-Range Weather Forecasts. We used a novel time series analytic approach to investigate associations between each metric from conception through 24 weeks of gestation and the number of live birth-identified conceptions (LBICs) -the total number of conceptions in each week that result in a live birth. This approach fits distributed lag models to data on LBICs, adjusted for time trends, and allows us to infer associations between pregnancy exposure and pregnancy loss. RESULTS: Overall, the association between solar activity during pregnancy and pregnancy loss varied by exposure metric. For sunspot number, we found that an interquartile range increase in sunspot number (78·7 sunspots) in all of the first 24 weeks of pregnancy was associated with 14·0 (95% CI: 6·5, 21·3) more pregnancy losses out of the average 92 LBICs in a week, and exposure in weeks ten through thirteen was identified as a critical window. Although not statistically significant, higher exposure to Kp index and to UV radiation across all 24 weeks of pregnancy was associated with more and less pregnancy losses, respectively. CONCLUSION: While exposure to certain metrics of solar activity (i.e., sunspot number) throughout the first 24 weeks of pregnancy may be associated with pregnancy losses, exposure to other metrics were not. Solar activity is a complex phenomenon, and more studies are needed to clarify underlying pathways.

Does prehabilitation before esophagectomy improve postoperative outcomes? A systematic review and meta-analysis.

Esophagectomy for esophageal cancer is associated with high morbidity. It remains unclear whether prehabilitation, a strategy aimed at optimizing patients' physical and mental functioning prior to surgery, improves postoperative outcomes. A systematic review and meta-analysis was conducted to evaluate the effect of prehabilitation on post-operative outcomes after esophagectomy. Data sources included Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and PEDro, with information from 1 January 2000 to 5 August 2023. The analysis included randomized controlled trials and observational studies that compared prehabilitation interventions to standard care prior to esophagectomy. A random effects model was used to generate a pooled estimate for pairwise meta-analysis, meta-analysis of proportions, and meta-analysis of means. A total of 1803 patients were included with 584 in randomized controlled trials (RCTs) and 1219 in observational studies. In the randomized evidence, there were no significant differences between prehabilitation and control in the odds of postoperative pneumonia (15.0 vs. 18.9%, odds ratio (OR) 1.06 [95% confidence interval (CI): 0.66;1.72]) or pulmonary complications (14 vs. 25.6%, OR 0.68 [95% CI: 0.32;1.45]). In the observational data, there was a reduction in both postoperative pneumonia (22.5 vs. 32.9%, OR 0.48 [95% CI: 0.28;0.83]) and pulmonary complications (26.1 vs. 52.3%, OR 0.35 [95% CI: 0.17;0.75]) with prehabilitation. Hospital and intensive care unit length of stay (days), operative mortality, and severe complications (Clavien-Dindo ≥ 3) did not differ between groups in both the randomized data and observational data. Prehabilitation demonstrated reductions in postoperative pneumonia and pulmonary complications in observational studies, but not RCTs. The overall certainty of these findings is limited by the low quality of the available evidence.

Risk factors for preterm birth: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Preterm birth defined as delivery before 37 gestational weeks is a leading cause of neonatal and infant morbidity and mortality. The aim of this study is to summarize the evidence from meta-analyses of observational studies on risk factors associated with PTB, evaluate whether there are indications of biases in this literature, and identify which of the previously reported associations are supported by robust evidence. METHODS: We searched PubMed and Scopus until February 2021, in order to identify meta-analyses examining associations between risk factors and PTB. For each meta-analysis, we estimated the summary effect size, the 95% confidence interval, the 95% prediction interval, the between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. Evidence was graded as robust, highly suggestive, suggestive, and weak. RESULTS: Eighty-five eligible meta-analyses were identified, which included 1480 primary studies providing data on 166 associations, covering a wide range of comorbid diseases, obstetric and medical history, drugs, exposure to environmental agents, infections, and vaccines. Ninety-nine (59.3%) associations were significant at P < 0.05, while 41 (24.7%) were significant at P < 10-6. Ninety-one (54.8%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 37 (22.3%) and 12 (7.2%) associations, respectively. We evaluated all associations according to prespecified criteria. Seven risk factors provided robust evidence: amphetamine exposure, isolated single umbilical artery, maternal personality disorder, sleep-disordered breathing (SDB), prior induced termination of pregnancy with vacuum aspiration (I-TOP with VA), low gestational weight gain (GWG), and interpregnancy interval (IPI) following miscarriage < 6 months. CONCLUSIONS: The results from the synthesis of observational studies suggest that seven risk factors for PTB are supported by robust evidence. Routine screening for sleep quality and mental health is currently lacking from prenatal visits and should be introduced. This assessment can promote the development and training of prediction models using robust risk factors that could improve risk stratification and guide cost-effective preventive strategies. TRIAL REGISTRATION: PROSPERO 2021 CRD42021227296.

A Primer on Systematic Review and Meta-analysis in Diabetes Research.

A systematic review is a rigorous process that involves identifying, selecting, and synthesizing available evidence pertaining to an a priori-defined research question. The resulting evidence base may be summarized qualitatively or through a quantitative analytic approach known as meta-analysis. Systematic review and meta-analysis (SRMAs) have risen in popularity across the scientific realm including diabetes research. Although well-conducted SRMAs are an indispensable tool in informing evidence-based medicine, the proliferation of SRMAs has led to many reviews of questionable quality and misleading conclusions. The objective of this article is to provide up-to-date knowledge and a comprehensive understanding of strengths and limitations of SRMAs. We first provide an overview of the SRMA process and offer ways to identify common pitfalls at key steps. We then describe best practices as well as evolving approaches to mitigate biases, improve transparency, and enhance rigor. We discuss several recent developments in SRMAs including individual-level meta-analyses, network meta-analyses, umbrella reviews, and prospective meta-analyses. Additionally, we outline several strategies that can be used to enhance quality of SRMAs and present key questions that authors, editors, and readers should consider in preparing or critically reviewing SRMAs.

Ambient climatic factors and term birthweight: A study of critical windows of exposure in the Republic of Cyprus.

BACKGROUND: Reduced birthweight is associated with adverse perinatal and long-term outcomes. A few studies examined the association between climatic factors and birthweight with inconsistent results probably due to differences in exposure assessment, statistical models, climatic parameters, and study populations. METHODS: We obtained data from the Republic of Cyprus birth registry from 2007 to 2020, and matched climatic exposures (i.e., temperature, relative humidity, temperature variability, humidity variability) by the hospital district at birth. We used distributed lag models to examine the association between term birthweight, temperature, humidity, and their variability to identify critical windows. Our models were adjusted for coarse particulate matter level (≤10 µm [PM10), and individual-level covariates. Subgroup analysis was conducted to examine effect modification by maternal age and education. RESULTS: We identified two critical windows of exposure to ambient temperature at early and late pregnancy. The cumulative change of birthweight per 5 °C increases in mean weekly temperature was -57.27 (2%) (95% Confidence Interval [CI]: 99.62 (3.1%), -14.92 (0.5%)) and -79.2 (2.5%) (95%CI: 117.03 (3.5%), -41.52 (1.3%)) grams during weeks 1-8 and weeks 28-37, respectively. There was no significant effect of humidity, temperature variability, or humidity variability on birthweight. Based on subgroup analysis, mothers with post-secondary education were more sensitive to temperature, but the marginal significance of differences in effect estimates may be linked with differences in sample size. CONCLUSION: Our study suggests that higher ambient temperature exposure during early and late pregnancy is associated with lower birthweight in main and subgroup analysis. The findings demonstrate in a country highly impacted by climate change like Cyprus that rising temperatures may be associated with perinatal outcomes in susceptible populations during sensitive windows of exposure.