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BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives.

Abstract Eye movement desensitization and reprocessing (EMDR) has demonstrated promise as a treatment for eating disorders (ED). The present study aimed to systematically evaluate the current evidence regarding the use of EMDR therapy in the treatment of EDs, ED symptomatology and body image concerns. Included articles were original studies that described the use of EMDR therapy in the treatment of EDs, published in the English language in a peer‐review journal. The search was conducted using four electronic databases: PsycINFO, MedLine, Embase, and Web of Science. Two independent reviewers conducted screening, selection, risk of bias assessment and data extraction. Of the initial search of 109 potential studies, eight met inclusion criteria, including six case studies, one quasi‐experimental study, and one randomised control trial (RCT). The RCT indicated that including an EMDR component did not have benefits over standard treatment for core ED symptoms, whereas the quasi‐experimental study demonstrated some benefits for inclusion of EMDR as a treatment adjunct for anorexia nervosa patients. Case studies indicated some promising outcomes for patients with various presentations. Despite EMDR being an available treatment for several decades now, there is limited clinical evidence regarding its efficacy in the treatment of EDs. These findings highlight a critical need for more clinical research in this area to ensure clinical practice is guided and supported by evidence‐based outcomes.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes — CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR — involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

Background: Device-related thrombosis (DRT) occurs in up to 4% of patients undergoing left atrial appendage occlusion (LAAO) and is associated with substantial morbidity and mortality. However, its pathophysiology, predictors, and optimal management remain unclear. Objectives: This study aims to assess flow dynamic factors correlating to DRT. Methods: A multicenter registry of patients who underwent LAAO and had pre- and post-computed tomography imaging was used. Patient-specific 3-dimensional digital models of the left atrium were created, and finite element simulations were performed to implant an LAAO device into each model in a position that matched the clinical deployment. Computational fluid dynamic simulations were performed to quantify the following flow dynamic parameters: time averaged wall shear stress, oscillatory shear index, and endothelial cell activation potential. Results: A total of 38 patients (19 with DRT and 19 without DRT) were included. Left atrium volumes and mitral valve areas were larger in the DRT cohort compared with controls. Patients with DRT had a significantly lower time averaged wall shear stress (1.76 ± 1.24 Pa vs 2.90 ± 2.70 Pa), a higher oscillatory shear index (0.19 ± 0.11 vs 0.17 ± 0.11), and a higher endothelial cell activation potential (0.23 ± 0.58 Pa–1 vs 0.17 ± 0.30 Pa−1) than the controls (P

Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.

The anomalous origin of the left vertebral artery from the aorta is the second most common anatomical alteration of the aortic arch. We present a case of a patient with a descending thoracic aortic aneurysm and an anomalous origin of a dominant left vertebral artery. The artery was treated by transposition to the left common carotid artery via a cervical approach, followed by endovascular correction of the thoracic aortic aneurysm using a subclavian branched thoracic endoprosthesis. The patient had a good postoperative recovery with complete occlusion of the aneurysm and patency of the carotid-vertebral shunt and left subclavian artery.

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call meta-loci, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci.

Background: Mortality due to ischemic heart disease (IHD) is heterogeneously distributed globally, and identifying the sites most affected by it is essential in developing strategies to mitigate the impact of the disease, despite the complexity resulting from the great diversity of variables involved. Objective: To analyze the predictability of IHD mortality using machine learning (ML) techniques in combination with geospatial analysis in southern Brazil. Methods: Ecological study using secondary and retrospective data on mortality due to ischemic heart disease (IHD) obtained from the Mortality Information Systems (SIM-DATASUS) de 2018 a 2022, covering 1,191 municipalities in the states of Paraná (399), Santa Catarina (295), and Rio Grande do Sul (497). Ordinary Least Squares Regression (OLS), Geographically Weighted Regression (GWR), Random Forest (RF), and Geographically Weighted Random Forest (GWRF) analyses were performed to verify the model with the best performance capable of identifying the most affected sites by the disease based on a set of predictors composed by variables of procedures and access to health. Results: In the analyzed period, there were 59,093 deaths, 65% of which were men, 82.7% were white, and 72.8% occurred between 60 and 70 years of age. Ischemic heart disease presented the highest mortality rates in the northwest and north regions of the state of Paraná, and in the central-east, southwest and southeast regions of Rio Grande do Sul, the latter state accounting for 41% of total deaths. The GWRF presented the best performance with R2 = 0.983 and AICc = 2298.4, RMSE: 3.494 and the most important variables of the model in descending order were electrocardiograph rate, cardiac catheterization rate, access index to hemodynamics, access index of pre-hospital mobile units, cardiologists rate, myocardial scintigraphy rate, stress test rate, and stress echocardiogram rate. Conclusion: The GWRF identified spatial heterogeneity in the variation of geographic predictors, contrasting the limitation of linear regression models. The findings showed patterns of vulnerability in southern Brazil, suggesting the formulation of health policies to improve access to diagnostic and therapeutic resources, with the potential to reduce IHD mortality.

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10-8) lead SNPs-one at FURIN (rs11372849; p = 9.54 × 10-10) and two OPRM1 variants (rs1799971, p = 4.92 × 10-09; rs79704991, p = 1.11 × 10-08; r2 = 0.02). Rs1799971 (p = 4.91 × 10-08) and another OPRM1 variant (rs9478500; p = 1.95 × 10-08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10-47) and AUD (rg = 0.77; p = 6.36 × 10-78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10-16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10-13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

The critical importance of technological innovation in home care for older adults is indisputable. Less well understood is the question of how to measure its performance and impact on the delivery of healthcare to older adults who are living with chronic illness and disability. Knowing how well digital technologies, such as smartphones, tablets, wearable devices, and Ambient Assisted Living Technologies (AAL) systems “work” should certainly include assessing their impact on older adults’ health and ability to function in daily living but that will not guarantee that it will necessarily be adopted by the user or implemented by a healthcare facility or the healthcare system. Technology implementation is a process of planned and guided activities to launch, introduce and support technologies in a certain context to innovate or improve healthcare, which delivers the evidence for adoption and upscaling a technology in healthcare practices. Factors in addition to user acceptance and clinical effectiveness require investigation. Failure to appreciate these factors can result in increased likelihood of technology rejection or protracted procurement decision at the “adoption decision” stage or delayed or incomplete implementation or discontinuance (following initial adoption) during implementation. The aim of our research to analyze research studies on the effectiveness of digital health technologies for older adults to answer the question, “How well do these studies address factors that affect the implementation of technology?” We found common problems with the conceptualization, design, and methodology in studies of digital technology that have contributed to the slow pace of implementation in home care and long-term care. We recommend a framework for improving the quality of research in this critical area.Systematic Review Registration:https://archive.org/details/osf-registrations-f56rb-v1, identifier osf-registrations-f56rb-v1.

Abstract Objective To gather real‐world evidence on antiseizure medications (ASMs) treatment patterns and related outcomes in patients with drug‐resistant focal epilepsy. Methods Medical insurance claims from the start of 2014 till the end of 2019 were used. Patient selection criteria included International Classification of Diseases (ICD) codes followed by documented ASM use. Baseline patient demographics along with ASM and rescue medication use patterns and related patient outcome were documented for first (index) ASM regimen. Patients who failed the first regimen and then failed the second regimen were considered drug resistant. Multivariate analyses were performed to identify risks and other characteristics for positive or negative treatment outcomes. Results Study cohort consisted of 46 474 patients with a mean age of 47.23 (SD: 16.94). Levetiracetam was the most first‐encountered ASM (37.94%). At baseline, 87.14% were treated with ASMs prior to having study‐confirmed diagnoses. Mental comorbidities were present in 37.86% of patients. After first‐year ASM treatment, 34.61% of patients persisted on their index regimen and 5.91% were seizure‐free. Patients failing first ASM regimen numbered 12 868 (27.69%). Drug‐resistant patients who failed first and then second ASM regimens numbered 6335 (49.23%). Percentages of patients who had successful second treatment and seizure‐free were 21.32 and 3.65, respectively. Initiating patients on lamotrigine or carbamazepine (relative to levetiracetam), baseline use of index ASM, rescue medications, and older age or male gender all lowered the risk for treatment failure. Having higher comorbidity, comorbid mental illness, headache, or neoplasty increased such a risk. Baseline use of index ASM, depressive episode, or anxiety disorder all entailed higher risk of failing second ASM treatment. Significance Overall, reported findings indicated that patient history at baseline and the early selection of an ASM all influenced treatment outcomes. Findings pointed to the complex nature of ASM treatment in drug‐resistant focal epilepsy patients calling for additional research to identify the optimal treatment to achieve beneficial patient outcomes.

Abstract Background Although eating disorder (ED) models display some differences in theory and treatment approach, cognitive-behavioural, schema-focused, and disorder-specific models all highlight the fundamental nature of cognitions as key factors in ED development and maintenance processes. As such, it is vital that ED cognitions continue to be assessed and monitored as therapeutic targets and treatment outcomes as well as being examined as constructs in empirical research. This review aimed to systematically identify and evaluate the psychometric properties of existing self-report measures of ED cognitions. Methods A systematic review protocol was registered using the international prospective register of systematic reviews (PROSPERO; CRD42023440840). Included studies described the development, validation and/or the psychometric evaluation of a measure (or subscale) that was specifically developed to solely assess ED cognitions (that is thoughts, expectations, assumptions, or beliefs), in English-speaking, adult populations. The search was conducted using three electronic databases: PsycINFO, MedLine, and Embase. Two independent reviewers conducted screening, selection and evaluation of the psychometric properties of relevant measures using a standardised, well-established quality appraisal tool. Results Of the initial search of 7581 potential studies, 59 met inclusion criteria and described the psychometric evaluation of 31 measures (or subscales) of ED cognitions. The findings from the current review indicate that of the included measures, none currently meet all nine criteria of adequate psychometric properties. The Eating Beliefs Questionnaire (EBQ; and EBQ-18), and the Eating Disorder Inventory Body Dissatisfaction subscale (EDI [BD]) currently possess the most evidence supporting their validity, reliability, and clinical utility. Conclusions The findings of the current systematic review provide guidance for future researchers to focus efforts on improving evidence for the validity, reliability and utility of self-report measures of ED cognitions. Overall, the present study has provided a detailed and systematic evaluation to support researchers and clinicians in future selection of measures of ED cognitions dependent on the specific aims of their research and treatment.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs., Introduction Use of psychoactive substances constitutes a significant and growing international health concern. More than 4% of the global burden of disease and injury is attributable to substance use, and [...]