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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.

Abstract Background Ventricular tachycardia storm is a syndrome defined by the presence of at least three episodes of ventricular tachycardia over a 24-h period, requiring termination by intervention. Standard therapy consists initially of using intravenous betablockers (if left ventricular ejection fraction is preserved) and Amiodarone, in addition to intravenous Lidocaine (in case of ischemic etiology) and light sedation. In the present case, a ventricular tachycardia storm episode is terminated by Esmolol, a particular intravenous betablocker, despite acute decompensated heart failure. Case presentation We report the case of an 89-year-old patient presenting for a ventricular tachycardia storm and acute heart failure with reduced left ventricle ejection fraction of coronary ischemic origin that persisted despite coronary revascularization, oral betablocker, intravenous Amiodarone and Lidocaine, light sedation, and multiple electrical cardioversion. Emergency catheter ablation was not feasible due to meteorological conditions. We decided to use an intravenous betablocker despite the presence of acute heart failure. We favored use of intravenous Esmolol over other intravenous betablockers due to its short half-life and thus his rapid elimination, a unique characteristic for Esmolol. Intravenous Esmolol has successfully terminated the ventricular tachycardia without causing cardiogenic shock. Conclusions Intravenous Esmolol can be used safely in patients with acute decompensated heart failure to terminate an electrical storm after failure of other measures. Close monitoring of the patient remains essential.

Abstract Recent research has identified multiple immune systems that bacteria use to protect themselves from viral infections. However, little is known about the mechanisms by which these systems horizontally spread, especially among bacterial pathogens. Here, we investigate antiviral defenses in staphylococci, opportunistic pathogens that constitute leading causes of antibiotic-resistant infections. We show that these organisms harbor a variety of anti-phage defenses encoded within or near SCC (staphylococcal cassette chromosome) mec cassettes, mobile genomic islands that confer methicillin resistance. Importantly, we demonstrate that SCCmec-encoded recombinases mobilize not only SCCmec, but also tandem SCC-like cassettes enriched in genes coding for diverse defense systems. Further, we show that phage infection stimulates cassette mobilization (i.e. excision and circularization). Thus, our findings indicate that SCC/SCCmec cassettes not only spread antibiotic resistance but can also play a role in mobilizing anti-phage defenses.

Abstract Background Hospitalization of patients with heart failure makes it possible to optimize drug therapy, considerably improving the prognosis of this serious condition. Methods We conducted a retrospective descriptive study of patients with reduced left ventricular ejection fraction (≤ 40%) in the Cardiology Department of a community hospital center in France to measure the prescription rate of heart failure medications in hospitalized patients with reduced ejection fraction heart failure and identify their limiting factors. The primary endpoint was the prescription on the discharge prescription of the following four drug classes: beta-blockers, renin–angiotensin–aldosterone system blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter inhibitors. Results From September 1, 2022, to March 31, 2023, 73 patients were included in the study. About one-third of patients were discharged with the recommended four drug classes. Those discharged with all 4 drug classes were younger and had preserved renal function. Conclusions The low rate of prescription of heart failure medications after hospitalization is a reminder of the need to develop a specialized follow-up structure to optimize the drug treatment of reduced ejection fraction heart failure, even in the most fragile patients.

Abstract Background Conus artery occlusion is a rare life-threatening event, typically secondary to iatrogenic etiology, and is treated mainly with conservative therapy and/or balloon angioplasty without stenting. However, treatment remains challenging. Case presentation We report the case of a 60-year-old man with a known history of coronary artery disease presenting with multiple internal defibrillator cardioversions due to an electrical storm (recurrent ventricular fibrillation). The coronary angiography showed an acute occlusion of the conus artery arising from the proximal segment of the right coronary artery, treated by percutaneous transluminal coronary angioplasty with stenting (drug-eluting stent) without any serious complications. Conclusions To our knowledge, this is the first case in the literature where a non-iatrogenic occlusion of the conus artery causing a ST-segment elevation myocardial infarction and electrical storm was treated with percutaneous coronary intervention with drug-eluting stenting. Graphical abstract

Abstract Background The term end-stage renal disease (ESRD) refers to the final stage of chronic kidney disease. Not all ESRD patients are suitable for dialysis treatment, which despite its advantages, is not without risks. Shared nephrologist-patient decision-making could be beneficial at this stage, yet little is known about such practices in Israel. This study aimed at examining the practice of shared decision-making (SDM) between nephrologists and ESRD patients in Israel, while exploring related conflicts, ethical dilemmas, and considerations. Methods The descriptive-quantitative approach applied in this study included a validated questionnaire for nephrologists, based on Emanual and Emanual (1992). The survey, which was distributed via social-media platforms and snowball sampling, was completed by 169 nephrologists. Data analysis included t-tests for independent samples, f-tests for analysis of variance, and t-tests and f-tests for independence. Descriptive analysis examined attitudes towards SDM in end-of-life care for ESRD patients. Results The findings show that the research sample did not include nephrologists who typically act according to the paternalistic decision-making style. Rather, 53% of the respondents were found to act in line with the informative decision-making style, while 47% act according to the interpretive decision-making style. Almost 70% of all respondents reported their discussing quality-of-life with patients; 63.4% provide prognostic assessments; 61.5% inquire about the patient’s desired place of death; 58.6% ask about advance directives or power-of-attorney; and 57.4% inquire about cultural and religious beliefs in end-of-life treatment. Additionally, informative nephrologists tend to promote the patients’ autonomy over their health (P

Abstract Background Children and adolescents are exposed to a high volume of unhealthy food marketing across digital media. No previous Canadian data has estimated child exposure to food marketing across digital media platforms. This study aimed to compare the frequency, healthfulness and power of food marketing viewed by children and adolescents across all digital platforms in Canada. Methods For this cross-sectional study, a quota sample of 100 youth aged 6–17 years old (50 children, 50 adolescents distributed equally by sex) were recruited online and in-person in Canada in 2022. Each participant completed the WHO screen capture protocol where they were recorded using their smartphone or tablet for 30-min in an online Zoom session. Research assistants identified all instances of food marketing in the captured video footage. A content analysis of each marketing instance was then completed to examine the use of marketing techniques. Nutritional data were collected on each product viewed and healthfulness was determined using Health Canada’s 2018 Nutrient Profile Model. Estimated daily and yearly exposure to food marketing was calculated using self-reported device usage data. Results 51% of youth were exposed to food marketing. On average, we estimated that children are exposed to 1.96 marketing instances/child/30-min (4067 marketing instances/child/year) and adolescents are exposed to 2.56 marketing instances/adolescent/30-min (8301 marketing instances/adolescent/year). Both children and adolescents were most exposed on social media platforms (83%), followed by mobile games (13%). Both age groups were most exposed to fast food (22% of marketing instances) compared to other food categories. Nearly 90% of all marketing instances were considered less healthy according to Health Canada’s proposed 2018 Nutrient Profile Model, and youth-appealing marketing techniques such as graphic effects and music were used frequently. Conclusions Using the WHO screen capture protocol, we were able to determine that child and adolescent exposure to the marketing of unhealthy foods across digital media platforms is likely high. Government regulation to protect these vulnerable populations from the negative effects of this marketing is warranted.

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

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.

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.

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.

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 [...]

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.

Abstract Eating disorders (EDs) are serious, deadly disorders that emerge in adolescence and early adulthood. Further, reported incidences of EDs are increasing worldwide. As such, accessible, affordable, and effective early intervention and prevention efforts are critical. The Body Project is a well-established ED prevention program with demonstrated success at reducing ED symptom severity and the risk of onset of EDs in young females. However, it has not yet been formally evaluated in an Australian population, nor have the benefits of the treatment for young people of all genders been thoroughly investigated. This protocol paper outlines the design for a study which aims to investigate the outcomes and feasibility of the Body Project as a brief ED prevention program within an Australian youth mental health service: headspace Camperdown. This pragmatic trial will compare outcomes between a Body Project treatment group and a Treatment-as-usual control group. Primary outcomes include body image concerns, ED symptomatology and general psychological distress, measured pre- and post-treatment, and at one-month follow-up. All young people attending headspace Camperdown for care are eligible for participation in the trial. The Body Project program is comprised of four group-based 1.5 h sessions run over 4 consecutive weeks. Overall, a trial of the Body Project as an ED prevention program is warranted to investigate the outcomes of the intervention in this sample and will provide valuable information about the feasibility for widespread implementation of the treatment as part of a stepped-care approach to intervention for EDs at youth mental health service locations across Australia. ANZCTR Trial Registration Number: ACTRN12623000695606 (registered 29 June 2023).

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.

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.

BackgroundCognition is robustly associated with substance involvement. This relationship is attributable to multiple factors, including genetics, though such contributions show inconsistent patterns in the literature. For instance, genome-wide association studies point to potential positive relationships between educational achievement and common substance use but negative relationships with heavy and/or problematic substance use.MethodsWe estimated associations between polygenic risk for substance involvement (i.e., alcohol, tobacco, and cannabis use and problematic use) and cognition subfacets (i.e., general ability, executive function, learning/memory) derived from confirmatory factor analysis among 3205 substance naïve children (ages 9-10) of European ancestry who completed the baseline session of the Adolescent Brain Cognitive Development (ABCD) Study.FindingsPolygenic risk for lifetime cannabis use was positively associated with all three facets of cognitive ability (Bs ≥ 0.045, qs ≤ 0.044). No other substance polygenic risk scores showed significant associations with cognition after adjustment for multiple testing (|Bs|≤0.033, qs ≥ 0.118).ConclusionsPolygenic liability to lifetime cannabis use, but not use disorder, was positively associated with cognitive performance among substance-naïve children, possibly reflecting shared genetic overlap with openness to experience or the influence of genetic variance associated with socioeconomic status. Our lack of findings for the other polygenic scores may reflect ascertainment differences between the genome-wide association study (GWAS) samples and the current sample and/or the young age of the present sample. As longitudinal data in ABCD are collected, this sample may be useful for disentangling putatively causal or predispositional influences of substance use and misuse on cognition.