Causal Pathways Research Articles

Community First Responders' role in the current and future rural health and care workforce: a mixed-methods study.

Community First Responders are trained volunteers dispatched by ambulance services to potentially life-threatening emergencies such as cardiac arrest in the first vital minutes to provide care until highly skilled ambulance staff arrive. Community First Responder schemes were first introduced to support ambulance services in rural communities, where access to prehospital emergency care is more likely to be delayed. Evidence is lacking on their contribution to rural healthcare provision, how care is provided and how this might be improved. We aimed to describe Community First Responder activities, organisation, costs of provision and outcomes of care together with perceptions and views of patients, public, Community First Responders, ambulance service staff and commissioners of their current and future role including innovations in the rural health and care workforce. We used a mixed-methods design, using a lens of pragmatism and the 'actor', 'behaviour change' and 'causal pathway' framework to integrate quantitative routine and qualitative (policy, guideline and protocol documents with stakeholder interview) data from 6 of 10 English ambulance services. We identified potential innovations in Community First Responder provision and prioritised these using a modified nominal group technique. Patients and public were involved throughout the study. In 4.5 million incidents from six English regional ambulance services during 2019, pre COVID-19 pandemic, Community First Responders attended first a higher proportion of calls in rural areas (almost 4% of calls) than in urban areas (around 1.5%). They were significantly more likely to be called out to rural (vs. urban) areas and to attend older (vs. younger), white (vs. minority ethnic) people in more affluent (vs. deprived) areas with cardiorespiratory and neurological (vs. other emergency) conditions for higher-priority emergency or urgent (category 1 and 2 compared with category 3, 4 or 5) calls but did also attend lower-category calls for conditions such as falls. We examined 10 documents from seven ambulance services. Ambulance policies and protocols integrated Community First Responders into ambulance service structures to achieve the safe and effective operation of volunteers. Costs, mainly for training, equipment and support, varied widely but were not always clearly delineated. Community First Responders enabled a faster prehospital response time. There was no clear benefit in out-of-hospital cardiac arrest outcomes. A specific Community First Responder falls response reduced ambulance attendances and was potentially cost saving. We conducted semistructured interviews with 47 different stakeholders engaged in Community First Responder functions. This showed the trajectory of becoming a Community First Responder, the Community First Responder role, governance and practice, and the positive views of Community First Responders from stakeholders despite public lack of understanding of their role. Community First Responders' scope of practice varied between ambulance services and had developed into new areas. Innovations prioritised at the consensus workshop were changes in processes and structures and an expanded scope of practice supported by training, which included counselling, peer support, better communication with the control room, navigation and communication technology, and specific mandatory and standardised training for Community First Responders. Missing data and small numbers of interviews in some stakeholder groups (patients, commissioners) are sources of bias. Future research should include a robust evaluation of innovations involving Community First Responders. This trial is registered as ClinicalTrials.gov, NCT04279262. This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR127920) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 18. See the NIHR Funding and Awards website for further award information.

Association between the AHA life's essential 8 and prediabetes/diabetes: a cross-sectional NHANES study.

The American Heart Association (AHA) recently introduced the Life's Essential 8 (LE8) to improve cardiovascular health (CVH). However, the association between LE8 and the risk of prediabetes or diabetes is not yet fully understood. Consequently, this study aims to assess the association between CVH, as evaluated by LE8, and the risk of prediabetes and diabetes. This cross-sectional study encompassed 7,739 participants aged ≥20 years from the 2007-2018 National Health and Nutrition Examination Surveys (NHANES). The CVH of participants was evaluated using the LE8, combining four health behaviors and three health factors. Glucose metabolic status categories included normal glucose metabolism, prediabetes including isolated impaired fasting glucose, isolated impaired glucose tolerance, both IFG and IGT, and diabetes. The associations between CVH and prediabetes and diabetes were analyzed using logistic regression, linear regression, restricted cubic splines, and subgroup analyses. Among 7,739 participants, 1,949 had iIFG, 1,165 were diagnosed with iIGT, 799 were IFG+IGT, and 537 were diagnosed with diabetes. After multivariable adjustments, CVH scores were inversely associated with prediabetes and diabetes, with the most robust inverse association observed between IFG+IGT and CVH across all prediabetes subgroups. Of all CVH components not directly in the causal pathway, body mass index (BMI) had the most robust associations with prediabetes and diabetes. Subgroup analyses indicated that the negative correlation between CVH and prediabetes was stronger among those with university or higher education. CVH, as defined by LE8, showed a significant negative association with prediabetes and diabetes.

Additive effects of depression and obesity on neural correlates of inhibitory control

BackgroundDepression and obesity are associated with impaired inhibitory control. Behavioral evidence indicates an exacerbating additive effect when both conditions co-occur. However, the underlying neural mechanisms remain unclear. Moreover, systemic inflammation affects neurocognitive performance in both individuals with depression and obesity. Here, we investigate additive effects of depression and obesity on neural correlates of inhibitory control, and examine inflammation as a connecting pathway. MethodsWe assessed inhibitory control processing in 64 individuals with obesity and varying degrees of depressed mood by probing neural activation and connectivity during an fMRI Stroop task. Additionally, we explored associations of altered neural responses with individual differences in systemic inflammation. Data were collected as part of the BARICO (Bariatric surgery Rijnstate and Radboudumc neuroimaging and Cognition in Obesity) study. ResultsConcurrent depression and obesity were linked to increased functional connectivity between the supplementary motor area and precuneus and between the inferior occipital and inferior parietal gyrus. Exploratory analysis revealed that circulating inflammation markers, including plasma leptin, IL-6, IL-8, and CCL-3 correlated with the additive effect of depression and obesity on altered functional connectivity. LimitationsThe observational design limits causal inferences. Future research employing longitudinal or intervention designs is required to validate these findings and elucidate causal pathways. ConclusionThese findings suggest increased neural crosstalk underlying impaired inhibitory control in individuals with concurrent obesity and depressed mood. Our results support a model of an additive detrimental effect of concurrent depression and obesity on neurocognitive functioning, with a possible role of inflammation.

Retrospective Observational Study of the Frequency and Interrelationships Among Neonatal Near Miss Criteria

ObjectiveTo evaluate the frequency and interrelationships among neonatal near miss (NNM) criteria and the anticipated workload for audits in high-income countries. DesignObservational retrospective descriptive study. SettingTertiary maternal and neonatal units at Mater Mothers’ Hospital, Brisbane, Queensland, Australia. ParticipantsCases of stillbirths (n = 483), neonatal deaths (n = 203), and live births (n = 66,353) from January 2016 to July 2022 (N = 67,039). MethodsWe identified eight prespecified NNM criteria nominated by perinatal experts. Primary outcomes were NNM frequency, their interrelationships, and related workload. We used descriptive statistics and analysis of variance and considered p < .05 significant. ResultsWe found 2,243 unique NNM cases (33.7/1,000 live births). The NNM ratio per 1,000 live births according to each of the eight criteria were: unplanned resuscitation at birth (25.09/1,000 live births), birth asphyxia needing surveillance for hypoxic ischemic encephalopathy (8.46/1,000 live births), metabolic acidosis at birth (8.04/1,000 live births), advanced resuscitation at birth (3.68/1,000 live births), seizures and/or stroke (0.96/1,000 live births), severe intraventricular hemorrhage and/or cerebellar hemorrhage (0.95/1,000 live births), moderate to severe hypoxic ischemic encephalopathy (0.9/1,000 live births), and severe birth trauma (0.44/1,000 live births). Almost one third of NNM cases met more than one criterion. Anticipated workload for monthly NNM audits varied from 0.04 to 2.8 cases per 1,000 live births. ConclusionDifferent sets of NNM criteria considerably alter the frequency of NNMs and the anticipated workload for NNM audits. Their interrelationships are likely attributable to the fact that some of the criteria are risk factors for or are part of the causal pathway for other NNM criteria. These findings can assist with the determination of a pragmatic NNM definition considering the feasibility of NNM audits in high-income countries.

The causal relationship between immune cells mediating FIT3L, CCL4, OSM, and skin-derived deteriorated tumors.

Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of action have not been clarified in the exacerbation of cutaneous-origin tumors. Therefore, this study aims to investigate whether the causal relationship between circulating inflammatory factors and basal cell carcinoma (BCC), cutaneous malignant melanoma (SKCM), and cutaneous squamous cell carcinoma (cSCC) is regulated by immune cells. This study employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the causal relationships between 91 circulating inflammatory factors and three prevalent types of skin cancer from a genetic perspective. Bayesian Weighted Mendelian Randomization (BWMR) was also used to validate correlation and reverse MR to assess inverse relationships. Subsequent sensitivity analyses were conducted to limit the impact of heterogeneity and pleiotropy. Finally, the two-step Mendelian Randomization (two-step MR) method was utilized to ascertain the mediating effects of specific immune cell traits in the causal pathways linking circulating inflammatory factors with BCC, SKCM, and cSCC. The Inverse Variance Weighted (IVW) method and the Bayesian Weighted Algorithm collectively identified nine inflammatory factors causally associated with BCC, SKCM, and cSCC. The results from Cochran's Q test, mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger intercept were not statistically significant (p<0.05). Additionally, the proportions mediated by CD4+ CD8dim T cell %leukocyte, CD4-CD8-Natural Killer T %T cell, and CD20 on IgD-CD38-B cell for FIt3L, CCL4, and OSM were 9.26%, 8.96%, and 10.16%, respectively. Immune cell levels potentially play a role in the modulation process between circulating inflammatory proteins and cutaneous-origin exacerbated tumors. This finding offers a new perspective for the in-depth exploration of cutaneous malignancies.

AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice.

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use. To understand the scope of its benefits in damage reduction and potential limitations, this study evaluated the effects of AB-free kava on a panel of health indicators in mice exposed to 2 - 4 weeks of daily tobacco smoke exposure. Our comprehensive assessments included global transcriptional profiling of the lung and liver tissues, analysis of lung inflammation, evaluation of lung function, exploration of tobacco nicotine withdrawal, and characterization of the causal PKA signaling pathway. As expected, Tobacco smoke exposure perturbed a wide range of biological processes and compromised multiple functions in mice. Remarkably, AB-free kava demonstrated the ability to globally mitigate tobacco smoke-induced deficits at the molecular and functional levels with promising safety profiles, offering a unique promise to mitigate tobacco smoke-related health damages. Further pre-clinical evaluation and clinical translation are warranted to fully harness the potential of AB-free kava in combating tobacco smoke-related harms.

Type 2 diabetes, glycaemic traits, structural brain capacity and cognitive function: A Mendelian randomization analysis.

To estimate the causal associations of type 2 diabetes and glycaemic traits with cognitive function, and to determine the potential mediating role of various brain imaging-derived phenotypes (IDPs) using Mendelian randomization (MR) analysis. Using publicly available summary data, we performed a series of univariable and multivariable MR analysis to infer causality. Two-step MR analysis was then conducted in turn to evaluate the potential mediating role of each brain IDP. There was no evidence of causal associations between type 2 diabetes and cognitive function outcomes. Each 1-SD unit higher genetically predicted fasting proinsulin was associated with worse cognitive performance, as evidenced by both univariable (beta: -0.022; 95% confidence interval [CI] -0.038, -0.007) and multivariable MR analysis (beta: -0.027; 95% CI -0.048, -0.005). In addition, the univariable MR analysis identified several causal associations between fasting proinsulin and brain IDPs, and between brain IDPs and cognitive performance. The inverse association of genetically predicted fasting proinsulin with cognitive performance did not attenuate after adjusting for each of the brain IDPs in multivariable MR analysis. The present MR study provided credible evidence for the causal association between genetically predicted fasting proinsulin and cognitive function, informing a potential diagnosis and intervention target for patients with cognitive impairment. No significant brain IDP included in this study was identified as lying on the causal pathway from fasting proinsulin to cognitive performance. Future research involving more specific and granular brain IDP or other brain process is warranted to explore the potential biological mechanism underlying the association.

Mediation Analysis with the Mediator and Outcome Missing Not at Random

Mediation analysis is widely used for investigating direct and indirect causal pathways through which an effect arises. However, many mediation analysis studies are challenged by missingness in the mediator and outcome. In general, when the mediator and outcome are missing not at random, the direct and indirect effects are not identifiable without further assumptions. We study the identifiability of the direct and indirect effects under some interpretable mechanisms that allow for missing not at random in the mediator and outcome. We evaluate the performance of statistical inference under those mechanisms through simulation studies and illustrate the proposed methods via the National Job Corps Study. Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work.

Maladaptive health factors as potential mediators for the association between posttraumatic stress disorder and cardiovascular disease: A sex-stratified analysis in the U.S. adult population

ObjectivesThis study examined sex differences for health risk factors as potential mediators in the association between posttraumatic stress disorder (PTSD) and cardiovascular disease (CVD). MethodsSecondary data from the 2012–2013 National Epidemiological Survey on Alcohol and Related Conditions Wave 3 was used. This cross-sectional survey contains a nationally representative sample of 36,309 U.S. adults (nfemales = 20,447, Mage = 47.16, 95% CI = [46.74, 47,57]; nmales = 15,682, Mage = 45.88, 95% CI = [45.42, 46.34]). Natural effect models and logistic regression analyses were conducted to evaluate health risk factors (smoking, substance use, low physical activity, high body mass index [BMI], binge eating, and multiple health risk factors) as potential mediators for the PTSD-CVD relationship in females and males. ResultsHigh BMI (indirect AOR = 1.05, 95% CI = [1.02, 1.07]) and substance use (indirect AOR = 0.93, 95% CI = [0.88, 0.98], p = 0.005) were potential mediators in females and males respectively. Binge eating, smoking, and low physical activity were not mediators in either sex. The number of health risk factors was also a potential mediator in females (indirect AOR = 1.12, 95% CI = [1.07, 1.19], p = <0.001) though not males (indirect AOR = 1.09, 95% CI = [1.00, 1.19], p = .059). ConclusionsThe results inform prevention strategies, such as screening for health risk factors to mitigate the adverse effect of PTSD on CVD risk. Findings also inform important directions for future longitudinal research to establish causal pathways.

The Impact of Surgical Bowel Preparation on the Microbiome in Colon and Rectal Surgery.

Preoperative bowel preparation, through iterations over time, has evolved with the goal of optimizing surgical outcomes after colon and rectal surgery. Although bowel preparation is commonplace in current practice, its precise mechanism of action, particularly its effect on the human gut microbiome, has yet to be fully elucidated. Absent intervention, the gut microbiota is largely stable, yet reacts to dietary influences, tissue injury, and microbiota-specific byproducts of metabolism. The routine use of oral antibiotics and mechanical bowel preparation prior to intestinal surgical procedures may have detrimental effects previously thought to be negligible. Recent evidence highlights the sensitivity of gut microbiota to antibiotics, bowel preparation, and surgery; however, there is a lack of knowledge regarding specific causal pathways that could lead to therapeutic interventions. As our understanding of the complex interactions between the human host and gut microbiota grows, we can explore the role of bowel preparation in specific microbiome alterations to refine perioperative care and improve outcomes. In this review, we outline the current fund of information regarding the impact of surgical bowel preparation and its components on the adult gut microbiome. We also emphasize key questions pertinent to future microbiome research and their implications for patients undergoing colorectal surgery.

Understanding woody plant encroachment: A plant functional trait approach

AbstractThe increasing density of woody plants threatens the integrity of grassy ecosystems. It remains unclear if such encroachment can be explained mostly by direct effects of resources on woody plant growth or by indirect effects of disturbances imposing tree recruitment limitation. Here, we investigate whether woody plant functional traits provide a mechanistic understanding of the complex relationships between these resource and disturbance effects. We first assess the role of rainfall, soil fertility, texture, and geomorphology to explain variation in woody plant encroachment (WPE) following livestock grazing and consequent fire suppression across the Serengeti ecosystem. Second, we explore trait‐environment relationships and how these mediate vegetation response to fire suppression. We find that WPE is strongest in areas with high soil fertility, high rainfall, and intermediate catena positions. These conditions also promote woody plant communities characterized by small stature and seed sizes smaller relative to a comparative baseline within the Serengeti ecosystem, alongside high recruit densities (linked to a recruitment‐stature trade‐off). The positioning of species along this “recruitment‐stature axis” predicted woody stem density increase in livestock sites. Structural equation modeling suggested a causal pathway where environmental factors shape the community trait composition, subsequently influencing woody recruit numbers. These numbers, in turn, predicted an area's vulnerability to WPE. Our study underscores the importance of trait‐environment relationships in predicting the impact of human alterations on local vegetation change. Understanding how environmental factors directly (resources) and indirectly (legacy effects and plant traits) determine WPE supports the development of process‐based ecosystem structure and function models.

Unboxing the blackbox of human-centric and inclusive smart city initiatives: a theory based evaluation framework

ABSTRACT The concept of smart cities has evolved from a technology and data-driven approach to a more human-centred and inclusive model. This paper explores the shift in smart city development towards a focus on human-centric and inclusive solutions while suggesting a novel evaluation framework for these smart city initiatives. Through a comprehensive literature review, the study identifies key challenges in evaluating smart city initiatives including the lack of standardized evaluation frameworks, limited focus on social and environmental outcomes, and the need for citizen participation. To address these challenges, the paper proposes a theoretical framework grounded in a realist evaluation approach. This framework incorporates a Theory of Change (ToC) that outlines the causal pathways and contextual factors underlying smart city initiatives. The proposed framework is designed to guide the evaluation of smart city initiatives by providing specific evaluation criteria and sub-criteria that are aligned with the objectives of inclusive and sustainable urban development. By highlighting the importance of human-centric and inclusive approaches and providing a practical evaluation framework, the paper aims to contribute to the ongoing discourse on smart cities and their evaluation.

Prospective cohort study on non-specific symptoms, cognitive, behavioral, sleep and mental health in relation to electronic media use and transportation noise among adolescents (HERMES): study protocol

Electronic media (eMedia) devices along with exposure to transportation noise are integral to the daily routines of adolescents. The concerns associated with excessive eMedia usage extend beyond sleep deprivation to include the heightened exposure to radiofrequency electromagnetic fields (RF-EMF) emitted by these wireless devices. The aim of HERMES (Health Effects Related to Mobile PhonE Use in AdolescentS) study is to better understand biophysical and psychological pathways in relation to eMedia, RF-EMF exposure use and transportation noise that may effect on cognitive, behavioral, sleep and mental health, as well as non-specific symptoms. Following two previous HERMES cohorts conducted between 2012 and 2015 we have initiated the third wave of HERMES study as a prospective cohort with intermediate (every four months) and one year follows-up. Eligible participants are adolescents attending 7th or 8th school grades in Northwest and Central Switzerland. Baseline examinations are a questionnaire on eMedia usage and selected health outcomes, as well as computerized cognitive tests. In addition, parents/guardians are asked to fill in a questionnaire about their child’s health and potential eMedia use determinants. Far-field RF-EMF exposure and transportation noise at the place of residence and school are predicted based on a propagation model. Cumulative RF-EMF brain dose is calculated based on self-reported eMedia use, mobile phone operator data, and RF-EMF modelling. A follow-up visit is conducted one year later, and two interim questionnaires are sent to adolescents to be completed at home. Between baseline and 1-year follow-up, a subsample of 150 study participants is invited to collect personal RF-EMF measurements as well as sleep and physical activity data using accelerometers. This new recruitment wave of HERMES study provides a greater understanding of causal pathways between eMedia, RF EMF, and transportation noise exposure and their effects on health outcomes, with relevant implications for both governmental health policy and lay people alike.

The effect of heavy smoking on retirement risk: A mendelian randomisation analysis

Background and aimsThe extent to which heavy smoking and retirement risk are causally related remains to be determined. To overcome the endogeneity of heavy smoking behaviour, we employed a novel approach by exploiting the genetic predisposition to heavy smoking, as measured with a polygenic risk score (PGS), in a Mendelian Randomisation approach. Methods8164 participants (mean age 68.86 years) from the English Longitudinal Study of Ageing had complete data on smoking behaviour, employment and a heavy smoking PGS. Heavy smoking was indexed as smoking at least 20 cigarettes a day. A time-to-event Mendelian Randomization (MR) analysis, using a complementary log–log (cloglog) link function, was employed to model the retirement risk. ResultsOur results show that being a heavy smoker significantly increases the risk of retirement (β = 1.324, standard error = 0.622, p < 0.05). Results were robust to a battery of checks and a placebo analysis considering the never-smokers. ConclusionsOverall, our findings support a causal pathway from heavy smoking to earlier retirement.

Practical quality improvement changes for a low-resourced pediatric unit.

This work describes a sustainable and replicable initiative to optimize multi-disciplinary care and uptake of clinical best practices for patients in a pediatric intensive care unit in Low/Middle Income Countries and to understand the various factors that may play a role in the reduction in child mortality seen after implementation of the Quality Improvement Initiative. This was a longitudinal assessment of a quality improvement program with the primary outcome of intubated pediatric patient mortality. The program was assessed 36 months following implementation of the quality improvement intervention using a t-test with linear regression to control for co-variates. An Impact Pathway model was developed to describe potential pathways for improvement, and context was added with an exploratory analysis of adoption of the intervention and locally initiated interventions. 147 patients were included in the sustainability cohort. Comparing the initial post-implementation cohort to the sustainability cohort, the overall PICU unexpected extubations per 100 days mechanical ventilation decreased significantly from baseline (6.98) to the first year post intervention (3.52; p < 0.008) but plateaued without further significant decrease in the final cohort (3.0; p = 0.73), whereas the mortality decreased from 22.4 (std 0.42) to 9.5% (std 0.29): p value: 0.002 (confidence intervals: 0.05;0.21). The regression model that examined age, sex, diagnosis and severity of illness (via aggregate Pediatric Risk of Mortality (PRISM) scores between epochs) yielded an adjusted R-squared (adjusting for the number of predictors) value of 0.046, indicating that approximately 4.6% of the variance in mortality was explained by the predictors included in the model. The overall significance of the regression model was supported by an F-statistic of 3.198 (p = 0.00828). age, weight, diagnosis, and severity of illness. 15 new and locally driven quality practices were observed in the PICU compared to the initial post-implementation time period. The Impact Pathway model suggested multiple unique potential pathways connecting the improved patient outcomes with the intervention components. Sustained improvements were seen in the care of intubated pediatric patients. While some of this improvement may be attributable to the intervention, it appears likely that the change is multifactorial, as evidenced by a significant number of new quality improvement projects initiated by the local clinical team. Although currently limited by available data, the use of Driver Diagram and Impact Pathway models demonstrates several proposed causal pathways and holds potential for further elucidating the complex dynamics underlying such improvements.

Pain Self-Efficacy Can Improve During a Visit With an Orthopedic Surgeon.

Greater pain self-efficacy (PSE) is associated with reduced pain, fewer limitations, and increased quality of life after treatment for orthopedic conditions. The aims of this study were to (1) assess if PSE improves during a visit with an orthopedic surgeon and (2) identify modifiable visit factors that are associated with an increase in PSE. We performed a prospective observational study of orthopedic clinic visits at a multispecialty clinic from February to May 2022. New patients who presented to one of six orthopedic surgeons were approached for the study. Patients who provided consent completed a pre-visit questionnaire including the Pain Self-Efficacy Questionnaire (PSEQ) and demographic questions. A trained research member recorded the five-item Observing Patient Involvement in Decision Making Instrument (OPTION-5) score, number of questions asked, and visit duration. Immediately after the visit, patients completed a post-visit questionnaire consisting of the PSEQ and Perceived Involvement in Care Scale (PICS). Of 132 patients enrolled, 61 (46%) had improved PSE after the orthopedic visit, with 38 (29%) having improvement above a clinically significant threshold. There were no significant differences between patients with increased PSE and those without increased PSE when comparing the PICS, OPTION-5, questions asked, or visit duration. Almost half of the patients had improvement in PSE during an orthopedic visit. The causal pathway to how to improve PSE and the durability of the improved PSE have implications in strategies to improve patient outcomes in orthopedic surgery, such as communication methods and shared decision-making. Future research can focus on studying different interventions that facilitate improving PSE. [Orthopedics. 2024;47(4):e197-e203.].

Causal and common risk pathways linking childhood maltreatment to later intimate partner violence victimization.

Childhood maltreatment and intimate partner violence (IPV) victimization are major psychiatric risk factors. Maltreatment substantially increases the likelihood of subsequent IPV victimization, but what drives this association is poorly understood. We analyzed retrospective self-reports of maltreatment and IPV in 12794 participants (58% women, 42% men) from the Twins Early Development Study at ages 21 and 26 using quantitative genetic methods. We estimated the etiological influences common to maltreatment and IPV, and the direct causal effect of maltreatment on IPV beyond such common influences. Participants exposed to maltreatment (~7% of the sample) were 3 times more likely to experience IPV victimization than their peers at age 21, 4 times more likely at 26. The association between maltreatment and IPV was mostly due to environmental influences shared by co-twins (42-43%) and genetic influences (30-33%). The association between maltreatment and IPV was similar for women and men, but its etiology partly differed by sex. Maltreatment had a moderate-to-large effect on IPV in phenotypic models (β = 0.23-0.34), decreasing to a small-to-moderate range in causal models accounting for their common etiology (β = 0.15-0.21). Risk factors common to maltreatment and IPV victimization are largely familial in origin, environmental and genetic. Even considering common risk factors, experiencing maltreatment is causally related to subsequent IPV victimization. Interventions promoting safe intimate relationships among young adults exposed to maltreatment are warranted and should address family-level environmental risk and individual-level risk shaped by genetics.

Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression

The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.

Adverse childhood experiences are associated with HIV risk factors in Agbogbloshie, Ghana

ABSTRACT Adverse Childhood Experiences (ACEs) have been associated with increased risk factors for HIV transmission, but the causal pathway is uncertain. This study documents the prevalence of ACEs by gender and their association with HIV risk factors and assesses depressive symptoms as mediating this relationship. A cross-sectional survey was conducted in 2019 among a representative sample of men and women, aged 18–24 years, living in an informal settlement in Accra, Ghana. Data on sociodemographic characteristics, ACEs, ten HIV risk factors (five sexual behaviors, HIV/AIDS knowledge, sexual assault, three substance use behaviors), and depressive symptoms were collected. Multiple logistic regression models were estimated to assess the independent association between four or more ACEs and each of the ten HIV risk factors. Structural equation models examined depressive symptoms as a mediator in these associations. A third (34.6%) of participants reported four or more ACEs, and among those who experienced four or more ACEs 60% were men and 40% were women. Gender did not modify the effect of the association between four or more ACEs and HIV factors and therefore the multiple regression analysis was not stratified by gender. After controlling for sociodemographic covariates and depressive symptoms, having experienced four or more ACEs was associated with alcohol use (OR = 3.88; 95% CI: 1.34, 11.21), injection drug use (OR = 2.78; 95% CI: 1.15, 6.73), low knowledge of HIV (OR = 3.59; 95% CI: 1.43, 9.00), sexually transmitted infection (OR = 3.70; 95% CI: 1.15, 11.96), and sexual assault (OR = 3.58; 95% CI: 1.07, 12.05). There was some evidence that depressive symptoms could be mediating the association between reporting four or more ACEs and ever having a sexually transmitted infection. The mitigation of ACEs and depressive symptoms has the potential to decrease HIV risk factors and thus reduce the risk for HIV transmission among youth living in informal settlements.

Shared Genetic Architectures between Coronary Artery Disease and Type 2 Diabetes Mellitus in East Asian and European Populations.

Coronary artery disease (CAD) is a common comorbidity of type 2 diabetes mellitus (T2DM). However, the pathophysiology connecting these two phenotypes remains to be further understood. Combined analysis in multi-ethnic populations can help contribute to deepening our understanding of biological mechanisms caused by shared genetic loci. We applied genetic correlation analysis and then performed conditional and joint association analyses in Chinese, Japanese, and European populations to identify the genetic variants jointly associated with CAD and T2DM. Next, the associations between genes and the two traits were also explored. Finally, fine-mapping and functional enrichment analysis were employed to identify the potential causal variants and pathways. Genetic correlation results indicated significant genetic overlap between CAD and T2DM in the three populations. Over 10,000 shared signals were identified, and 587 were shared by East Asian and European populations. Fifty-six novel shared genes were found to have significant effects on both CAD and T2DM. Most loci were fine-mapped to plausible causal variant sets. Several similarities and differences of the involved genes in GO terms and KEGG pathways were revealed across East Asian and European populations. These findings highlight the importance of immunoregulation, neuroregulation, heart development, and the regulation of glucose metabolism in shared etiological mechanisms between CAD and T2DM.