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Objective: The study assessed the prevalence of suicidal ideation, suicide plans, and suicide attempts as well as patterns of mental health service use among adolescents.Methods: Data came from the National Comorbidity Survey–Adolescent Supplement, a nationally representative sample of 10,123 adolescents aged 13 to 18 years who participated in computer-assisted, face-to-face interviews between February 2001 and January 2004. Prevalences of suicidal thoughts and behaviors in the past year were determined. Past-year use of any mental health treatment and receipt of four or more visits from one provider among youths with suicidal ideation, plans, or attempts were also assessed. Associations were evaluated by using logistic regression.Results: During the course of 12 months, 3.6% of adolescents reported suicidal ideation without a plan or attempt, .6% reported a suicide plan without an attempt, and 1.9% made a suicide attempt. Overall, two-thirds of adolescents with suicidal ideation (67.3%) and half of those with a plan (54.4%) or attempt (56.9%) did not have any contact with a mental health specialist in the past year. Different predictors of use of care were identified for each group.Conclusions: Adolescent suicidality often is untreated in the United States. Increased outreach efforts to improve treatment access for youths with suicidal ideation and attempts are needed. [ABSTRACT FROM AUTHOR]

In recent years, an increasing number of studies have demonstrated that a myopathy is present, contributes, and, to a certain extent, determines the pathogenesis of peripheral arterial occlusive disease (PAD). These works provide evidence that a state of repetitive cycles of exercise-induced ischemia followed by reperfusion at rest operates in PAD patients and mediates a large number of structural and metabolic changes in the muscle, resulting in reduced strength and function. The key players in this process appear to be defective mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a progressive decline in muscle performance. In this 2-part review, we highlight the currently available evidence that characterizes the nature and mechanisms responsible for this myopathy. In part 1, the authors review the functional and histomorphological characteristics of the myopathy and focus on the biochemistry and bioenergetics of its mitochondriopathy. In part 2, they then review accumulating evidence that oxidative stress related to ischemia reperfusion is probably the major operating mechanism of PAD myopathy. Important new findings of a possible neuropathy and a shift in muscle fiber type are also reviewed. Learning more about these mechanisms will enhance our understanding of the degree to which they are preventable and treatable. [ABSTRACT FROM AUTHOR]

Objective: To present estimates of the lifetime prevalence of DSM-IV mental disorders with and without severe impairment, their comorbidity across broad classes of disorder, and their sociodemographic correlates.Method: The National Comorbidity Survey-Adolescent Supplement NCS-A is a nationally representative face-to-face survey of 10,123 adolescents aged 13 to 18 years in the continental United States. DSM-IV mental disorders were assessed using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview.Results: Anxiety disorders were the most common condition (31.9%), followed by behavior disorders (19.1%), mood disorders (14.3%), and substance use disorders (11.4%), with approximately 40% of participants with one class of disorder also meeting criteria for another class of lifetime disorder. The overall prevalence of disorders with severe impairment and/or distress was 22.2% (11.2% with mood disorders, 8.3% with anxiety disorders, and 9.6% behavior disorders). The median age of onset for disorder classes was earliest for anxiety (6 years), followed by 11 years for behavior, 13 years for mood, and 15 years for substance use disorders.Conclusions: These findings provide the first prevalence data on a broad range of mental disorders in a nationally representative sample of U.S. adolescents. Approximately one in every four to five youth in the U.S. meets criteria for a mental disorder with severe impairment across their lifetime. The likelihood that common mental disorders in adults first emerge in childhood and adolescence highlights the need for a transition from the common focus on treatment of U.S. youth to that of prevention and early intervention. [ABSTRACT FROM AUTHOR]

Background: The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain., Objective: To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia., Design: Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407)., Setting: 144 clinical sites in 6 countries., Participants: 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL., Intervention: Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events., Measurements: Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting., Results: The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death., Limitation: Unmeasured confounding may have persisted despite adjustment., Conclusion: The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds., Primary Funding Source: National Heart, Lung, and Blood Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0571.

Strong epidemiologic evidence from ecological and individual-level studies in the United States supports the claim that access to firearms substantially increases the risk of dying by suicide, homicide, and firearm accidents. Less certain is how well particular interventions work to prevent these deaths and other firearm-related harms. Given the limits of existing data to study firearm violence and the infeasibility of conducting randomized trials of firearm access, it is important to do the best we can with the data we already have. We argue that falsification strategies are a critical-yet underutilized-component of any such analytical approach. The falsification strategies we focus on are versions of "negative controls" analyses in which we expect that an analysis should yield a null causal effect, and thus where not obtaining a null effect estimate raises questions about the assumptions underlying causal interpretation of a study's findings. We illustrate the saliency of this issue today with examples drawn from studies published in leading peer-reviewed journals within the last 5 years. Collecting rich, high-quality data always takes time, urgent as the need may be. On the other hand, doing better with the data we already have can start right now., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Legislative firearm policies are often proposed as a way of preventing firearm-related harm. Confounding is a substantial threat to accurately estimating the causal effects of firearm policies. This scoping review characterizes selection of potential confounders in US firearm policy evaluations in the health sciences literature. We identified empirical research articles indexed in PubMed from 1/1/2000-9/1/2021 that examined any of 18 pre-specified firearm policies and extracted key study elements, including the exposure (firearm policy), outcomes, potential confounders adjusted for in analyses, and study approach (i.e., static, uncontrolled pre-post, and controlled pre-post). There was wide variation in potential confounders within study approach-policy-outcome combinations. The most common potential confounders included sociodemographic and economic variables, rurality/urbanicity, violent crime, law enforcement-related variables, alcohol use, and firearm access (mostly measured via proxies for firearm ownership). Firearm policies other than the policy being evaluated were included in the adjustment set in 23-44% of studies, depending on the study approach. Confounder selection was most often said to be based on prior research (n=49, 40%) or not explicitly stated (n=48, 39%). This scoping review provides a comprehensive resource for critically appraising the firearm policy literature and offers considerations to support more rigorous confounding control in future firearm policy research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Women and other people of childbearing potential living with HIV (WLHIV) have a higher risk of adverse birth outcomes than those without HIV (WWHIV). A higher risk of anemia in WLHIV could partially explain this disparity. Using a birth outcomes surveillance study in Botswana, we emulated target trials corresponding to currently available or feasible interventions on anemia. The first target trial evaluated two interventions: initiate multiple micronutrient supplementation (MMS), and MMS or iron and folic acid supplementation by 24 weeks gestation. The remaining target trials evaluated the interventions: eliminate anemia before pregnancy; and jointly eliminate anemia before pregnancy and initiate MMS. We estimated the observed disparity in adverse birth outcomes between WLHIV and WWHIV and compared the observed disparity measure (ODM) to the counterfactual disparity measure (CDM) under each intervention. Of 137,499 individuals (22% WLHIV), the observed risk of any adverse birth outcome was 26.0% in WWHIV and 34.5% in WLHIV (ODM, 8.5% [95% CI, 7.9-9.1%]). CDMs (95% CIs) ranged from 6.6% (4.8-8.4%) for the intervention to eliminate anemia and initiate MMS to 8.4% (7.7-9.1%) for the intervention to eliminate anemia only. Preventing anemia and expanding MMS may reduce HIV disparities in birth outcomes, but interventions with greater impact should be identified., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Evidence about which firearm policies work, to what extent, and for whom is hotly debated, perhaps partly because variation in research methodology has produced mixed and inconclusive effect estimates. We conducted a scoping review of firearm policy research in the health sciences in the United States, focusing on methodological considerations for causal inference., Methods: We identified original, empirical articles indexed in PubMed from 1 January 2000 to 1 September 2021 that examined any of 18 prespecified firearm policies. We extracted key study components, including policy type(s) examined, policy operationalization, outcomes, study setting and population, study approach and design, causal language, and whether and how authors acknowledged potential sources of bias., Results: We screened 7733 articles and included 124. A plurality of studies used a legislative score as their primary exposure (n = 39; 32%) and did not examine change in policies over time (n = 47; 38%). Most examined firearm homicide (n = 51; 41%) or firearm suicide (n = 40; 32%) as outcomes. One-third adjusted for other firearm policies (n = 41; 33%). Three studies (2%) explicitly mentioned that their goal was to estimate causal effects, but over half used language implying causality (n = 72; 58%). Most acknowledged causal identification assumptions of temporality (n = 91; 73%) and exchangeability (n = 111; 90%); other assumptions were less often acknowledged. One-third of studies included bias analyses (n = 42; 34%)., Conclusions: We identified a range of methodologic approaches in firearm policy research in the health sciences. Acknowledging the imitations of data availability and quality, we identify opportunities to improve causal inferences about and reporting on the effects of firearm policies on population health., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Mendelian randomization (MR) requires strong unverifiable assumptions to estimate causal effects. However, for categorical exposures, the MR assumptions can be falsified using a method known as the instrumental inequalities. To apply the instrumental inequalities to a continuous exposure, investigators must coarsen the exposure, a process which can itself violate the MR conditions. Violations of the instrumental inequalities for an MR model with a coarsened exposure might therefore reflect the effect of coarsening rather than other sources of bias. We aim to evaluate how exposure coarsening affects the ability of the instrumental inequalities to detect bias in MR models with multiple proposed instruments under various causal structures. To do so, we simulated data mirroring existing studies of the effect of alcohol consumption on cardiovascular disease under a variety of exposure-outcome effects in which the MR assumptions were met for a continuous exposure. We categorized the exposure based on subject matter knowledge or the observed data distribution and applied the instrumental inequalities to MR models for the effects of the coarsened exposure. In simulations of multiple binary instruments, the instrumental inequalities did not detect bias under any magnitude of exposure outcome effect when the exposure was coarsened into more than 2 categories. However, in simulations of both single and multiple proposed instruments, the instrumental inequalities were violated in some scenarios when the exposure was dichotomized. The results of these simulations suggest that the instrumental inequalities are largely insensitive to bias due to exposure coarsening with greater than 2 categories, and could be used with coarsened exposures to evaluate the required assumptions in applied MR studies, even when the underlying exposure is truly continuous., (© 2024. Springer Nature B.V.)

Background: Several observational studies have described an inverse association between cancer diagnosis and subsequent dementia risk. Multiple biologic mechanisms and potential biases have been proposed in attempts to explain this association. One proposed explanation is the opposite expression of Pin1 in cancer and dementia, and we use this explanation and potential drug target to illustrate the required assumptions and potential sources of bias for inferring an effect of Pin1 on dementia risk from analyses measuring cancer diagnosis as a proxy for Pin1 expression., Methods: We used data from the Rotterdam Study, a population-based cohort. We estimate the association between cancer diagnosis (as a proxy for Pin1) and subsequent dementia diagnosis using two different proxy methods and with confounding and censoring for death addressed with inverse probability weights. We estimate and compare the complements of a weighted Kaplan-Meier survival estimator at 20 years of follow-up., Results: Out of 3634 participants, 899 (25%) were diagnosed with cancer, of whom 53 (6%) had dementia, and 567 (63%) died. Among those without cancer, 15% (411) were diagnosed with dementia, and 667 (24%) died over follow-up. Depending on the confounding and selection bias control, and the way in which cancer was used as a time-varying proxy exposure, the risk ratio for dementia diagnosis ranged from 0.71 (95% confidence interval [CI] = 0.49, 0.95) to 1.1 (95% CI = 0.79, 1.3)., Conclusion: Being explicit about the underlying mechanism of interest is key to maximizing what we can learn from this cancer-dementia association given available or readily collected data, and to defining, detecting, and preventing potential biases., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Although many epidemiologic studies focus on point identification, it is also possible to partially identify causal effects under consistency and the data alone. However, the literature on the so-called "assumption-free" bounds has focused on settings with time-fixed exposures. We describe assumption-free bounds for the effects of both static and dynamic sustained interventions. To provide intuition for the width of the bounds, we also discuss a mathematical connection between assumption-free bounds and clone-censor-weight approaches to causal effect estimation. The bounds, which are often wide in practice, can provide important information about the degree to which causal analyses depend on unverifiable assumptions made by investigators., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The blue whale, Balaenoptera musculus, is the largest animal known to have ever existed, making it an important case study in longevity and resistance to cancer. To further this and other blue whale-related research, we report a reference-quality, long-read-based genome assembly of this fascinating species. We assembled the genome from PacBio long reads and utilized Illumina/10×, optical maps, and Hi-C data for scaffolding, polishing, and manual curation. We also provided long read RNA-seq data to facilitate the annotation of the assembly by NCBI and Ensembl. Additionally, we annotated both haplotypes using TOGA and measured the genome size by flow cytometry. We then compared the blue whale genome with other cetaceans and artiodactyls, including vaquita (Phocoena sinus), the world's smallest cetacean, to investigate blue whale's unique biological traits. We found a dramatic amplification of several genes in the blue whale genome resulting from a recent burst in segmental duplications, though the possible connection between this amplification and giant body size requires further study. We also discovered sites in the insulin-like growth factor-1 gene correlated with body size in cetaceans. Finally, using our assembly to examine the heterozygosity and historical demography of Pacific and Atlantic blue whale populations, we found that the genomes of both populations are highly heterozygous and that their genetic isolation dates to the last interglacial period. Taken together, these results indicate how a high-quality, annotated blue whale genome will serve as an important resource for biology, evolution, and conservation research., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Exposure to cleaning products has been associated with harm to the respiratory system, neurotoxicity, harm to the reproductive system, and elevated risk of cancer, with greatest adverse impacts for workers exposed in an occupational setting. Social and consumer interest in cleaning products that are safer for health created a market category of "green" products defined here as products advertised as healthier, non-toxic, or free from harmful chemicals as well as products with a third-party certification for safety or environmental features. In the present study we examined the air quality impacts of cleaning products and air fresheners, measuring the number, concentrations, and emission factors of volatile organic compounds (VOCs) in an air chamber following product application. Across seven common product categories, 30 products were tested overall including 14 conventional, 9 identified as "green" with fragrance, and 7 identified as "green" and fragrance-free. A total of 530 unique VOCs were quantified with 205 additional VOCs detected below the limits of quantification. Of the quantifiable VOCs, 193 were considered hazardous according to either the California's Department of Toxic Substances Control Candidate Chemicals List or the European Chemical Agency's Classification and Labeling Inventory. The total concentration of VOCs and total emission factors across all products with detections ranged from below limits of detection to 18,708 μg/m 3 , 38,035 μg/g product and 3803 μg/application. Greater total concentration, total emission factors, and numbers of VOCs were generally observed in conventional cleaning products compared to products identified as "green", particularly compared to fragrance-free products. A hazard index approach was utilized to assess relative risk from measured VOC emissions. The five products with the highest hazard indices were conventional products with emissions of 2-butoxyethanol, isopropanol, toluene and chloroform. Overall, this analysis suggests that the use of "green" cleaning products, especially fragrance-free products, may reduce exposure to VOC emissions., Competing Interests: Declaration of competing interest Environmental Working Group is a nonprofit organization and the current employer of S.L.G., A.M.T, S.A.S., O.V.N., D.Q.A. and previous employer of N.S.L. All authors declare no financial conflict of interest. Since June 2021, N.S.L. is employed at Amazon.com, Inc. as Sustainable Shopping principal program manager. This study was not funded by Amazon nor did it play any part in the design of the study, the collection, analyses, or interpretation of data, the writing of the manuscript, or the decision to publish the results. Environmental Working Group evaluates and publicly ranks cleaning products based on the evaluation of ingredient hazards and transparency. Environmental Working Group accepts cleaning product sample product donations for inclusion in annual fundraisers. Additionally, as a result of EWG's cleaning product licensing program, EWG VERIFIED™, EWG maintains financial relationships with producers of cleaning products; these relationships had no direct or indirect influence on the study described herein., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Observational studies are increasingly used to inform health decision-making when randomised trials are not feasible, ethical or timely. The target trial approach provides a framework to help minimise common biases in observational studies that aim to estimate the causal effect of interventions. Incomplete reporting of studies using the target trial framework limits the ability for clinicians, researchers, patients and other decision-makers to appraise, synthesise and interpret findings to inform clinical and public health practice and policy. This paper describes the methods that we will use to develop the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) reporting guideline., Methods/design: The TARGET reporting guideline will be developed in five stages following recommended guidance. The first stage will identify target trial reporting practices by systematically reviewing published studies that explicitly emulated a target trial. The second stage will identify and refine items to be considered for inclusion in the TARGET guideline by consulting content experts using sequential online surveys. The third stage will prioritise and consolidate key items to be included in the TARGET guideline at an in-person consensus meeting of TARGET investigators. The fourth stage will produce and pilot-test both the TARGET guideline and explanation and elaboration document with relevant stakeholders. The fifth stage will disseminate the TARGET guideline and resources via journals, conferences and courses., Ethics and Dissemination: Ethical approval for the survey has been attained (HC220536). The TARGET guideline will be disseminated widely in partnership with stakeholders to maximise adoption and improve reporting of these studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Importance: Observational (nonexperimental) studies that aim to emulate a randomized trial (ie, the target trial) are increasingly informing medical and policy decision-making, but it is unclear how these studies are reported in the literature. Consistent reporting is essential for quality appraisal, evidence synthesis, and translation of evidence to policy and practice., Objective: To assess the reporting of observational studies that explicitly aimed to emulate a target trial., Evidence Review: We searched Medline, Embase, PsycINFO, and Web of Science for observational studies published between March 2012 and October 2022 that explicitly aimed to emulate a target trial of a health or medical intervention. Two reviewers double-screened and -extracted data on study characteristics, key predefined components of the target trial protocol and its emulation (eligibility criteria, treatment strategies, treatment assignment, outcome[s], follow-up, causal contrast[s], and analysis plan), and other items related to the target trial emulation., Findings: A total of 200 studies that explicitly aimed to emulate a target trial were included. These studies included 26 subfields of medicine, and 168 (84%) were published from January 2020 to October 2022. The aim to emulate a target trial was explicit in 70 study titles (35%). Forty-three studies (22%) reported use of a published reporting guideline (eg, Strengthening the Reporting of Observational Studies in Epidemiology). Eighty-five studies (43%) did not describe all key items of how the target trial was emulated and 113 (57%) did not describe the protocol of the target trial and its emulation., Conclusion and Relevance: In this systematic review of 200 studies that explicitly aimed to emulate a target trial, reporting of how the target trial was emulated was inconsistent. A reporting guideline for studies explicitly aiming to emulate a target trial may improve the reporting of the target trial protocols and other aspects of these emulation attempts.

Competing Interests: The authors report no conflicts of interest.

Mendelian randomization (MR) is an increasingly popular approach to estimating causal effects. Although the assumptions underlying MR cannot be verified, they imply certain constraints, the instrumental inequalities, which can be used to falsify the MR conditions. However, the instrumental inequalities are rarely applied in MR. We aimed to explore whether the instrumental inequalities could detect violations of the MR conditions in case studies analyzing the effect of commonly studied exposures on coronary artery disease risk.Using 1077 single nucleotide polymorphisms (SNPs), we applied the instrumental inequalities to MR models for the effects of vitamin D concentration, alcohol consumption, C-reactive protein (CRP), triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol on coronary artery disease in the UK Biobank. For their relevant exposure, we applied the instrumental inequalities to MR models proposing each SNP as an instrument individually, and to MR models proposing unweighted allele scores as an instrument. We did not identify any violations of the MR assumptions when proposing each SNP as an instrument individually. When proposing allele scores as instruments, we detected violations of the MR assumptions for 5 of 6 exposures.Within our setting, this suggests the instrumental inequalities can be useful for identifying violations of the MR conditions when proposing multiple SNPs as instruments, but may be less useful in determining which SNPs are not instruments. This work demonstrates how incorporating the instrumental inequalities into MR analyses can help researchers to identify and mitigate potential bias., (© 2023. The Author(s).)

Studying causal exposure effects on dementia is challenging when death is a competing event. Researchers often interpret death as a potential source of bias, although bias cannot be defined or assessed if the causal question is not explicitly specified. Here we discuss 2 possible notions of a causal effect on dementia risk: the "controlled direct effect" and the "total effect." We provide definitions and discuss the "censoring" assumptions needed for identification in either case and their link to familiar statistical methods. We illustrate concepts in a hypothetical randomized trial on smoking cessation in late midlife, and emulate such a trial using observational data from the Rotterdam Study, the Netherlands, 1990-2015. We estimated a total effect of smoking cessation (compared with continued smoking) on 20-year dementia risk of 2.1 (95% confidence interval: -0.1, 4.2) percentage points and a controlled direct effect of smoking cessation on 20-year dementia risk had death been prevented of -2.7 (95% confidence interval: -6.1, 0.8) percentage points. Our study highlights how analyses corresponding to different causal questions can have different results, here with point estimates on opposite sides of the null. Having a clear causal question in view of the competing event and transparent and explicit assumptions are essential to interpreting results and potential bias., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Competing Interests: The authors report no conflicts of interest.

Background: As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR., Objectives: We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected., Methods: Using data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified., Results: The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied., Conclusions: Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Competing Interests: The authors report no conflicts of interest.

Background: Researchers often use random-effects or fixed-effects meta-analysis to combine findings from multiple study populations. However, the causal interpretation of these models is not always clear, and they do not easily translate to settings where bounds, rather than point estimates, are computed., Methods: If bounds on an average causal effect of interest in a well-defined population are computed in multiple study populations under specified identifiability assumptions, then under those assumptions the average causal effect would lie within all study-specific bounds and thus the intersection of the study-specific bounds. We demonstrate this by pooling bounds on the average causal effect of prenatal alcohol exposure on attention deficit-hyperactivity disorder symptoms, computed in two European cohorts and under multiple sets of assumptions in Mendelian randomization (MR) analyses., Results: For all assumption sets considered, pooled bounds were wide and did not identify the direction of effect. The narrowest pooled bound computed implied the risk difference was between -4 and 34 percentage points., Conclusions: All pooled bounds computed in our application covered the null, illustrating how strongly point estimates from prior MR studies of this effect rely on within-study homogeneity assumptions. We discuss how the interpretation of both pooled bounds and point estimation in MR is complicated by possible heterogeneity of effects across populations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Firearm ownership is strongly related to suicide risk, yet little is known about how much risk declines when ownership ends ("divestment")., Methods: Using data from 523,182 handgun owners, we estimated the effect of divesting and remaining divested versus never divesting on the risk of suicide and firearm-specific suicide. We used pooled logistic regression with inverse probability weighting, adjusting for demographic and area-level measures., Results: The 5-year risk of suicide death was 25.6 (95% confidence interval [CI] = 15.1, 37.2) per 10,000 persons with divestment and 15.2 (95% CI = 13.2, 17.3) per 10,000 persons with no divestment, corresponding to a risk difference of 10.4 (95% CI = 0.7, 21.1) per 10,000 persons. The 5-year risk of firearm-specific suicide death was 6.3 (95% CI = 1.4, 11.9) per 10,000 persons with divestment and 12.9 (95% CI = 11.0, 14.6) per 10,000 persons with no divestment, corresponding to a risk difference of -6.6 (95% CI = -11.4, -0.1) per 10,000 persons. Comparing divestment to no divestment, risks were elevated for deaths due to other causes proposed as negative control outcomes; we incorporated these estimates into a series of bias derivations to better understand the magnitude of unmeasured confounding., Conclusions: Collectively, these estimates suggest that divestment reduces firearm suicide risk by 50% or more and likely reduces overall suicide risk as well, although future data collection is needed to fully understand the extent of biases such as unmeasured confounding., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Binge eating, loss of control eating and overeating often develop during late childhood or early adolescence. Understanding the presentation of binge eating as early as symptoms manifest and its preceding and concurrent factors is essential to hamper the development of eating disorders. This study examined the prevalence, concurrent and preceding factors (e.g. compensatory behaviors, emotional and behavioral problems) of subclinical binge eating symptoms in early adolescence., Methods: Data from the population-based Generation R Study were used (n = 3595). At 10 years and 14 years, preceding and concurrent factors including eating behaviors, body dissatisfaction, emotional and behavioral problems and body composition were assessed. At 14 years, 3595 adolescents self-reported on binge eating symptoms in the past 3 months and were categorized into four groups: no symptoms (n = 3143, 87.4%), overeating only (n = 121, 3.4%), loss of control (LOC) eating only (n = 252, 7.0%) or binge eating (i.e. both, n = 79, 2.2%)., Results: In total, 452 (12.6%) young adolescents reported subclinical binge eating symptoms. Those who reported LOC eating and binge eating showed most compensatory behaviors (e.g. hide or throw away food, skipping meals). Concurrent emotional and behavioral problems, body dissatisfaction, more emotional-, restrained- and uncontrolled eating, and a higher BMI were associated with subclinical binge eating symptoms. Preceding self-reported emotional and behavioral problems, body dissatisfaction, more restrained eating and higher BMI (both fat mass and fat-free mass) at 10 years were associated with LOC eating and binge eating, but not with overeating., Discussion: Among young adolescents, subclinical binge eating symptoms were common. Considering the high prevalence of LOC eating, and the overlapping preceding and concurrent factors of LOC eating and binge eating compared to overeating, LOC eating seems to be a key symptom of binge eating in early adolescence., (© 2022. The Author(s).)

Background: The Nile rat (Avicanthis niloticus) is an important animal model because of its robust diurnal rhythm, a cone-rich retina, and a propensity to develop diet-induced diabetes without chemical or genetic modifications. A closer similarity to humans in these aspects, compared to the widely used Mus musculus and Rattus norvegicus models, holds the promise of better translation of research findings to the clinic., Results: We report a 2.5 Gb, chromosome-level reference genome assembly with fully resolved parental haplotypes, generated with the Vertebrate Genomes Project (VGP). The assembly is highly contiguous, with contig N50 of 11.1 Mb, scaffold N50 of 83 Mb, and 95.2% of the sequence assigned to chromosomes. We used a novel workflow to identify 3613 segmental duplications and quantify duplicated genes. Comparative analyses revealed unique genomic features of the Nile rat, including some that affect genes associated with type 2 diabetes and metabolic dysfunctions. We discuss 14 genes that are heterozygous in the Nile rat or highly diverged from the house mouse., Conclusions: Our findings reflect the exceptional level of genomic resolution present in this assembly, which will greatly expand the potential of the Nile rat as a model organism., (© 2022. The Author(s).)

Introduction: Chronic stress and burnout are highly prevalent among academically trained healthcare professionals, negatively affecting their well-being and capacity to engage in their work. Resilience to stress develops early in one's career path, hence offering resilience training to university students in these professions is one approach to fostering well-being and mental health. The aim of this study is to assess whether offering mindfulness-based resilience training to university students in healthcare professions reduces their perceived chronic stress., Methods and Analysis: The study has a hybrid design combining a longitudinal observational cohort with a nested randomized controlled trial (RCT) with sequential multiple assignment and multistage adaptive interventions while taking participants' preferences into account. All students in healthcare related programmes at the Erasmus University Rotterdam are invited to participate. Within the observational cohort, students with a score of 14 or higher on the Perceived Stress Scale (PSS) are invited to take part in the RCT (n = 706). Eligible participants are randomized to control or active intervention in a ratio of 1:6. Those randomized to the control group and non-randomized participants in the cohort receive passive web-based psychoeducation about chronic stress and burnout through referral to specific websites. Participants randomized to the intervention group receive one of 8 active mindfulness-based interventions. They select a rank order of 4 preferred interventions and are randomized across these with equal probability. Non-response to the intervention is followed by sequential randomized assignment to another intervention, for a total maximum of 3 sequential interventions. All participants receive questionnaires at baseline, before and after each 8-week intervention period, and at 1- and 2-year follow-up. The primary outcome is perceived chronic stress measured with the PSS. Secondary outcomes include mental well-being, burnout, quality of life, healthcare utilization, drug use, bodyweight, mental and physical stress-related symptoms, resilience, and study progress., Ethics and Registration: Approval from the Medical Ethics Review Committee was obtained under protocol number MEC-2018-1645. The trial is registered in the Netherlands National Trial Register by registration number NL7623, 22/03/2019, https://www.trialregister.nl/., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Apart from funding for this study as mentioned, Dr. Hunink receives (or received in the past 36 months) Royalties from Cambridge University Press for a textbook on Medical Decision Making, reimbursement of expenses from the European Society of Radiology (ESR) for work on the ESR guidelines for imaging referrals, reimbursement of expenses from the European Institute for Biomedical Imaging Research (EIBIR) for membership of the Scientific Advisory Board, and research funding from the American Diabetes Association, the Netherlands Organization for Health Research and Development, the German Innovation Fund, and the Gordon and Betty Moore Foundation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Dietary trans fatty acids (TFAs) are primarily industrially produced and remain abundant in processed food, particularly in low- and middle-income countries. Although TFAs are a cause of adverse cardiometabolic outcomes, little is known about exposure to TFAs in relation to brain development. We aimed to investigate the effect of maternal TFA concentration during pregnancy on offspring head growth in utero and during childhood. In a prospective population-based study in Rotterdam, the Netherlands, with 6900 mother-child dyads, maternal plasma TFA concentration was assessed using gas chromatography in mid-gestation. Offspring head circumference (HC) was measured in the second and third trimesters using ultrasonography; childhood brain morphology was assessed using magnetic resonance imaging at age 10 years. We performed regression analyses adjusting for sociodemographic and lifestyle confounders and instrumental variable (IV) analyses. Our IV analysis leveraged a national policy change that led to a substantial reduction in TFA and occurred mid-recruitment. After adjusting for covariates, maternal TFA concentration during pregnancy was inversely related to fetal HC in the third trimester (mean difference per 1% wt:wt increase: - 0.33, 95% CI - 0.51, - 0.15, cm) and to fetal HC growth from the second to the third trimester (- 0.04, 95% CI - 0.06, - 0.02, cm/week). Consistent findings were obtained with IV analyses, strengthening a causal interpretation. Association between prenatal TFA exposure and HC in the second trimester or global brain volume at age 10 years was inconclusive. Our findings are of important public health relevance as TFA levels in food remain high in many countries., (© 2022. The Author(s).)

All else being equal, if we had 1 causal effect we wished to estimate, we would conduct a randomized trial with a protocol that mapped onto that causal question, or we would attempt to emulate that target trial with observational data. However, studying the social determinants of health often means there are not just 1 but several causal contrasts of simultaneous interest and importance, and each of these related but distinct causal questions may have varying degrees of feasibility in conducting trials. With this in mind, we discuss challenges and opportunities that arise when conducting and emulating such trials. We describe designing trials with the simultaneous goals of estimating the intention-to-treat effect, the per-protocol effect, effects of alternative protocols or joint interventions, effects within subgroups, and effects under interference, and we describe ways to make the most of all feasible randomized trials and emulated trials using observational data. Our comments are grounded in the study results of Courtin et al. (Am J Epidemiol. 2022;191(8):1444-1452)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Antenatal multiple micronutrient supplementation (MMS) with iron, folic acid, and other micronutrients might improve birth outcomes, but it is not currently universally recommended by WHO., Methods: In this observational cohort study, we surveyed pregnancies for adverse birth outcomes at eight hospitals from July, 2014, to July, 2018, and 18 hospitals from August, 2018, to December, 2020, in Botswana to assess four routine supplementation strategies in women presenting before 24 weeks' gestation: folic acid only, iron only, iron and folic acid supplementation (IFAS), and MMS. Women with singleton pregnancies; a known HIV status, age, and delivery site; haemoglobin measured within 7 days of presenting to antenatal care; and weight measured within 31 days of presenting to care were included in our analysis. Data were abstracted from the maternity obstetric record (a record of antenatal care) at the time of birth from all women giving birth at selected hospitals throughout the country. We estimated risk differences overall and in key subgroups, adjusting for demographic and clinical factors., Findings: Between July 6, 2014, and Dec 8, 2020, 96 341 eligible women (21 659 [22·5%] of whom had HIV) were included in the study. 36 334 (37·7%) women initiated iron only supplementation, 1133 (11·8%) initiated folic acid only supplementation, 23 101 (24·0%) initiated IFAS, and 31 588 (32·8%) women initiated MMS. Women who initiated iron only and folic acid only supplementation had higher risks of stillbirth, preterm birth, very preterm birth, low and very low birthweight, and neonatal death compared with women who received IFAS (adjusted risk differences for iron only supplementation vs IFAS ranged from 0·22% [95% CI 0·04 to 0·40] for neonatal death to 2·39% [1·78 to 3·00] for preterm birth; and adjusted risk differences for folic acid only supplementation vs IFAS ranged from 0·77% [-0·80 to 2·34] for neonatal death to 5·75% [1·38 to 10·13] for preterm birth), with greater difference in women with HIV and those aged 35 years and older. Compared with IFAS, women who initiated MMS had lower risks of preterm and very preterm births, and low and very low birthweight (adjusted risk differences ranged from -0·50% [-0·77 to 0·23] for very preterm birth to -1·06% [-1·69 to -0·42] for preterm birth)., Interpretation: Nationwide data from Botswana support improved birth outcomes with MMS compared with IFAS., Funding: National Institutes of Health, National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests We declare no competing interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Little is known about the extent to which secondhand exposure to household firearms is associated with risk of suicide in adults who do not own guns, most of whom are women., Objective: To evaluate changes in risk of suicide among women living in gun-free households after one of their cohabitants became a handgun owner., Design, Setting, and Participants: This cohort study observed participants for up to 12 years and 2 months from October 18, 2004, to December 31, 2016. Data were analyzed from April to November 2021. The study population included 9.5 million adult women in California who did not own guns and who entered the study while living with 1 or more adults in a handgun-free home., Exposures: Secondhand exposure to household handguns., Main Outcomes and Measures: Suicide, firearm suicide, nonfirearm suicide., Results: Of 9.5 million women living in handgun-free homes, 331 968 women (3.5% of the study population; mean [SD] age, 41.6 [18.0] years) became exposed to household handguns during the study period. In the entire study population, 294 959 women died: 2197 (1%) of these were by suicide, 337 (15%) of which were suicides by firearm. Rates of suicide by any method during follow-up were higher among cohort members residing with handgun owners compared with those residing in handgun-free homes (hazard ratio, 1.43; 95% CI, 1.11-1.84). The excess suicide rate was accounted for by higher rates of suicide by firearm (hazard ratio, 4.32; 95% CI, 2.89-6.46). Women in households with and without handguns had similar rates of suicide by nonfirearm methods (hazard ratio, 0.90; 95% CI, 0.63-1.27)., Conclusions and Relevance: In this study, the rate of suicide among women was significantly higher after a cohabitant of theirs became a handgun owner compared with the rate observed while they lived in handgun-free homes.

Background: Little is known about voluntary divestment of firearms among US firearm owners. Here, we aim to estimate the proportion of handgun owners who divest their handguns in the years following their initial acquisition; examine the timing, duration, and dynamics of those divestments; and describe characteristics of those who divest., Methods: We use data from the Longitudinal Study of Handgun Ownership and Transfer, a cohort of registered voters in California with detailed information on 626,756 adults who became handgun owners during the 12-year study period, 2004-2016. For the current study, persons were followed from the time of their initial handgun acquisition until divestment, loss to follow-up, death, or the end of the study period. We describe the cumulative proportion who divest overall and by personal and area-level characteristics. We also estimate the proportion who reacquired handguns among persons who divested., Results: Overall, 4.5% (95% CI 4.5-4.6) of handgun owners divested within 5 years of their first acquisition, with divestment relatively more common among women and among younger adults. Among those who divested, 36.6% (95% CI 35.8-37.5) reacquired a handgun within 5 years., Conclusions: Handgun divestment is rare, with the vast majority of new handgun owners retaining them for years., (© 2022. The Author(s).)

Mendelian randomization (MR) is often used to estimate effects of time-varying exposures on health outcomes using observational data. However, MR studies typically use a single measurement of exposure and apply conventional instrumental variable (IV) methods designed to handle time-fixed exposures. As such, MR effect estimates for time-varying exposures are often biased, and interpretations are unclear. We describe the instrumental conditions required for IV estimation with a time-varying exposure, and the additional conditions required to causally interpret MR estimates as a point effect, a period effect or a lifetime effect depending on whether researchers have measurements at a single or multiple time points. We propose methods to incorporate time-varying exposures in MR analyses based on g-estimation of structural mean models, and demonstrate its application by estimating the period effect of alcohol intake, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol on intermediate coronary heart disease outcomes using data from the Framingham Heart Study. We use this data example to highlight the challenges of interpreting MR estimates as causal effects, and describe other extensions of structural mean models for more complex data scenarios., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In many applications of instrumental variable (IV) methods, the treatments of interest are intrinsically time-varying and outcomes of interest are failure time outcomes. A common example is Mendelian randomization (MR), which uses genetic variants as proposed IVs. In this article, we present a novel application of g-estimation of structural nested cumulative failure models (SNCFTMs), which can accommodate multiple measures of a time-varying treatment when modelling a failure time outcome in an IV analysis., Methods: A SNCFTM models the ratio of two conditional mean counterfactual outcomes at time k under two treatment strategies which differ only at an earlier time m. These models can be extended to accommodate inverse probability of censoring weights, and can be applied to case-control data. We also describe how the g-estimates of the SNCFTM parameters can be used to calculate marginal cumulative risks under nondynamic treatment strategies. We examine the performance of this method using simulated data, and present an application of these models by conducting an MR study of alcohol intake and endometrial cancer using longitudinal observational data from the Nurses' Health Study., Results: Our simulations found that estimates from SNCFTMs which used an IV approach were similar to those obtained from SNCFTMs which adjusted for confounders, and similar to those obtained from the g-formula approach when the outcome was rare. In our data application, the cumulative risk of endometrial cancer from age 45 to age 72 under the "never drink" strategy (4.0%) was similar to that under the "always ½ drink per day" strategy (4.3%)., Conclusions: SNCFTMs can be used to conduct MR and other IV analyses with time-varying treatments and failure time outcomes., (© 2021. The Author(s).)

Dimitris and Platt (Am J Epidemiol. 2021;190(11):2275-2279) take on the challenging topic of using "shocks" such as the severe acute respiratory system coronavirus 2 (SARS-CoV-2) pandemic as instrumental variables to study the effect of some exposure on some outcome. Evoking our recent lived experiences, they conclude that the assumptions necessary for an instrumental variable analysis will often be violated and therefore strongly caution against such analyses. Here, we build upon this warranted caution while acknowledging that such analyses will still be pursued and conducted. We discuss strategies for evaluating or reasoning about when such an analysis is clearly inappropriate for a given research question, as well as strategies for interpreting study findings with special attention to incorporating plausible sources of bias in any conclusions drawn from a given finding., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation., Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies., Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021., Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed., Conclusions and Relevance: STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the SNSF, NIHR Biomedical Research Centre at University Hospitals Bristol, Weston NHS Foundation Trust, and University of Bristol for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; EWL (head of research at The BMJ) played no part in the peer review or decision making of this paper at the editorial level, and contributed solely as an author; no other relationships or activities that could appear to have influenced the submitted work. Provenance and peer review: Not commissioned; externally peer reviewed

The organic food market's recent rapid global growth reflects the public's interest in buying certified organic foods, including packaged products. Our analysis shows that packaged foods containing fewer ingredients associated with negative public health outcomes are more likely to be labeled organic. Previous studies comparing organic and conventional foods focused primarily on nutrient composition. We expanded this research by additionally examining ingredient characteristics, including processing and functional use. Our dataset included nutrition and ingredient data for 8240 organic and 72,205 conventional food products sold in the U.S. from 2019 to 2020. Compared to conventional foods, organic foods in this dataset had lower total sugar, added sugar, saturated fat and sodium content. Using a mixed effects logistic regression, we found that likelihood of classification as organic increased as sodium content, added sugar content and the number of ultra-processed ingredients and cosmetic additives on the product label decreased. Products containing no trans-fat ingredients were more likely to be labeled organic. A product was more likely to be classified "organic" the more potassium it contained. These features of organic foods sold in the U.S. are significant because lower dietary ingestion of ultra-processed foods, added sugar, sodium and trans-fats is associated with improved public health outcomes.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10 -6 ; IFNAR2, P = 9.8 × 10 -11 and IL-10RB, P = 2.3 × 10 -14 ) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

We aimed to study the effects of hypothetical interventions on systolic blood pressure (SBP) and smoking on risk of stroke and dementia using data from 15 years of follow-up in the Rotterdam Study. We used data from 4930 individuals, aged 55-80 years, with no prior history of stroke, dementia or cognitive impairment, followed for 15 years within the Rotterdam Study, a population-based cohort. We defined the following sustained interventions on SBP: (1) maintaining SBP below 120 mmHg, (2) maintaining SBP below 140 mmHg, (3) reducing SBP by 10% if above 140 mmHg, (4) reducing SBP by 20% if above 140 mmHg, and a combined intervention of quitting smoking with each of these SBP-lowering strategies. We considered incident stroke and incident dementia diagnoses as outcomes. We applied the parametric g-formula to adjust for baseline and time-varying confounding. The observed 15-year risk for stroke was 10.7%. Compared to no specified intervention (i.e., the "natural course"), all interventions that involved reducing SBP were associated with a stroke risk reduction of about 10% (e.g., reducing SBP by 20% if above 140 mmHg risk ratio: 0.89; 95% CI 0.76, 1). Jointly intervening on SBP and smoking status further decreased the risk of stroke (e.g., risk ratio: 0.83; 95% CI 0.71, 0.94). None of the specified interventions were associated with a substantive change in dementia risk. Our study suggests that a joint intervention on SBP and smoking cessation during later life may reduce stroke risk, while the potential for reducing dementia risk were not observed.