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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.

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 [...]

Coronavirus disease 2019 (COVID-19) is associated with enlarged luminal areas of large conducting airways. In 10–30% of patients with acute COVID-19 infection, symptoms persist for more than 4 wk (referred to as post-acute sequelae of COVID 19, or PASC), and it is unknown if airway changes are associated with this persistence. Thus, we aim to investigate whether luminal area of large conducting airways is different between patients with PASC and COVID-19 and healthy controls. In this retrospective case-control study, 75 patients with PASC (48 females) were age-, height-, and sex-matched to 75 patients with COVID-19 and 75 healthy controls. Using three-dimensional digital reconstruction from computed tomography imaging, we measured luminal areas of seven conducting airways, including trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi. Kruskal–Wallis H test was used to compare measurements between the three groups, as appropriate. Airway luminal areas between COVID-19 and PASC groups were not different (all, P > 0.66). There were no group differences in airway luminal area (PASC vs. control) for trachea and right main bronchus. However, in the remaining five airways, airway luminal areas were 12–39% larger among patients with PASC than in controls (all, P < 0.05). Patients diagnosed with COVID-19 and PASC have greater airway luminal area in most large conducting airways compared with healthy controls. No differences in luminal area between patients with COVID-19 and PASC suggest persistence of changes or insufficient time for reversal of changes. NEW & NOTEWORTHY: Three-dimensional reconstruction of airways has shown increased luminal area in patients with COVID-19 and post-acute sequelae of COVID-19 when compared with healthy controls. These findings suggest the role of large conducting airways in the pathogenesis of post-acute sequelae of COVID 19. [ABSTRACT FROM AUTHOR]

Background: Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Methods: Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. Results: GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes. Conclusions: Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology. [ABSTRACT FROM AUTHOR]

The immobilisation of artificial metalloenzymes (ArMs) holds promise for the implementation of new biocatalytic reactions. We present the synthesis of cross-linked artificial metalloenzyme aggregates (CLArMAs) with excellent recyclability, as an alternative to carrier-based immobilisation strategies. Furthermore, iron-siderophore supramolecular anchoring facilitates redox-triggered cofactor release, enabling CLArMAs to be recharged with alternative cofactors for diverse selectivity. [ABSTRACT FROM AUTHOR]

This study aims to design and pilot an empirically based mobile application (ActiviDaily) to increase daily activity in persons with apathy and ADRD and test its feasibility and preliminary efficacy. ActiviDaily was developed to address impairments in goal-directed behaviour, including difficulty with initiation, planning, and motivation that contribute to apathy. Participants included patients with apathy and MCI, mild bvFTD, or mild AD and their caregivers. In Phase I, 6 patient-caregiver dyads participated in 1-week pilot testing and focus groups. In Phase II, 24 dyads completed 4 weeks of at-home ActiviDaily use. Baseline and follow-up visits included assessments of app usability, goal attainment, global cognition and functioning, apathy, and psychological symptoms. App use did not differ across diagnostic groups and was not associated with age, sex, education, global functioning or neuropsychiatric symptoms. Patients and care-partners reported high levels of satisfaction and usability, and care-partner usability rating predicted app use. At follow-up, participants showed significant improvement in goal achievement for all goal types combined. Participant goal-directed behaviour increased after 4 weeks of ActiviDaily use. Patients and caregivers reported good usability and user satisfaction. Our findings support the feasibility and efficacy of mobile-health applications to increase goal-directed behaviour in ADRD. [ABSTRACT FROM AUTHOR]

Study Design: Systematic Review. Objectives: To determine the efficacy and overall outcomes of iFactor/ABM/P-15 following lumbar spine surgery. Methods: We performed a search of the Cochrane Library, Medline Ovid, PubMed, and SCOPUS databases from inception until August 2023. Eligible studies included outcomes of patients receiving iFactor following lumbar spine surgery. The primary outcomes of interest were fusion rates and iFactor efficacy after lumbar surgery in patients who received iFactor. Secondary outcomes included patient-reported outcomes and complication rates. Results: A total of 766 titles were initially screened. After inclusion criteria were applied, 5 studies (388 patients) were included, which measured overall outcomes of iFactor/ABM/P-15 following lumbar spine surgery. These studies showed acceptable reliability for inclusion based on the Methodical Index for Non-Randomized studies and Critical Appraisal Skills Programme assessment tools. iFactor/ABM/P-15 facilitated significantly faster bone development in various procedures while maintaining favorable clinical outcomes compared to traditional grafts. Conclusions: This systematic review found that iFactor/ABM/P-15 use for lumbar spine surgery maintains similar managing patient-reported outcomes relative to other grafting methods. In regard to rates of fusion, iFactor/ABM/P-15 showed a significantly faster rate of fusion when compared to traditional grafts including allograft, autograft, demineralized bone matrix (DBM), and recombinant human bone morphogenetic protein-2 (rhBMP-2). Future multicenter randomized control trials with larger sample sizes are recommended to further assess iFactor/ABM/P-15 efficacy in lumbar spine surgery. [ABSTRACT FROM AUTHOR]

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction. [ABSTRACT FROM AUTHOR]

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, and shared neurobiological and genetic influences may in part explain these associations. Links between sensation seeking and alcohol use disorder (AUD) may primarily manifest via increased alcohol consumption rather than through direct effects on increasing problems and consequences. Here the overlap among sensation seeking, alcohol consumption, and AUD was examined using multivariate modelling approaches for genome‐wide association study (GWAS) summary statistics in conjunction with neurobiologically informed analyses at multiple levels of investigation. Meta‐analytic and genomic structural equation modelling (GenomicSEM) approaches were used to conduct GWAS of sensation seeking, alcohol consumption, and AUD. Resulting summary statistics were used in downstream analyses to examine shared brain tissue enrichment of heritability and genome‐wide evidence of overlap (e.g., stratified GenomicSEM, RRHO, genetic correlations with neuroimaging phenotypes), and to identify genomic regions likely contributing to observed genetic overlap across traits (e.g., H‐MAGMA and LAVA). Across approaches, results supported shared neurogenetic architecture between sensation seeking and alcohol consumption characterised by overlapping enrichment of genes expressed in midbrain and striatal tissues and variants associated with increased cortical surface area. Alcohol consumption and AUD evidenced overlap in relation to variants associated with decreased frontocortical thickness. Finally, genetic mediation models provided evidence of alcohol consumption mediating associations between sensation seeking and AUD. This study extends previous research by examining critical sources of neurogenetic and multi‐omic overlap among sensation seeking, alcohol consumption, and AUD which may underlie observed phenotypic associations. Sensation seeking is associated with greater alcohol consumption which, in turn, can increase risk for alcohol use disorder. We found substantial overlap of neurogenetic and multi‐omic influences underlying sensation seeking and alcohol consumption and evidence that alcohol consumption mediates genetic links between sensation seeking and alcohol use disorder. [ABSTRACT FROM AUTHOR]

Background: Acute alcohol‐associated hepatitis (AH) is associated with high mortality. CT‐derived liver surface nodularity (LSN) is a robust prognostic biomarker in other chronic liver diseases. The aim of this study was to determine relationships between LSN, disease severity, and mortality in AH. Methods: Adults hospitalized with AH from January 2016 to March 2020 were included if an abdominal CT was performed between 8 weeks prior to 72 h after hospitalization. LSN was measured using quantitative methods (Liver Surface Nodularity Software version 0.88, Birmingham, AL, USA). Cox proportional hazards models, logistic regression and AUROC analysis were used to examine relationships between LSN and 180‐day transplant‐free survival. Results: Of 386 patients hospitalized with AH during the study period, 230 had CT scans performed, and 205 met inclusion criteria. Mean transplant‐free survival was 127 days (95% CI 118–137). Within each cohort, patients were grouped into low [LSN‐LOW, N = 109 (53.2%)] and high [LSN‐HIGH, N = 96 (46.8%)] LSN strata based on an optimal cutoff of 2.86 derived from unadjusted ROC curves. Patients with high LSN had features of portal hypertension, which included encephalopathy [53 (55.2%) vs. 43 (39.4%), p = 0.017], ascites on CT [81 (84.4%) vs. 69 (63.3%), p = 0.001] and portosystemic shunts [78 (81.2%) vs. 69 (63.3%), p = 0.003]. High LSN, ascites and MELD were independently associated with lower likelihood of 180‐day transplant‐free survival, and inclusion of a score assigning 1 point each for high LSN or ascites on CT (AHRADS score) to MELD enhanced diagnostic accuracy of AUROC for 180‐day survival compared to MELD alone [AUROC 0.782 (95% CI 0.719–0.845) vs. 0.735 (0.667–0.802), p = 0.023]. Conclusions: CT‐derived factors that include LSN and ascites are radiographic biomarkers associated with 180‐day transplant‐free survival in alcohol‐associated hepatitis. [ABSTRACT FROM AUTHOR]

Objectives: The investigation of morphological variation in animals is widely used in taxonomy, ecology, and evolution. Using large datasets for meta‐analyses has dramatically increased, raising concerns about dataset compatibilities and biases introduced by contributions of multiple researchers. Materials and Methods: We compiled morphological data on 13 variables for 3073 individual mouse lemurs (Cheirogaleidae, Microcebus spp.) from 25 taxa and 153 different sampling locations, measured by 48 different researchers. We introduced and applied a filtering pipeline and quantified improvements in data quality (Shapiro‐Francia statistic, skewness, and excess kurtosis). The filtered dataset was then used to test for genus‐wide sexual size dimorphism and the applicability of Rensch's, Allen's, and Bergmann's rules. Results: Our pipeline reduced inter‐observer bias (i.e., increased normality of data distributions). Inter‐observer reliability of measurements was notably variable, highlighting the need to reduce data collection biases. Although subtle, we found a consistent pattern of sexual size dimorphism across Microcebus, with females being the larger (but not heavier) sex. Sexual size dimorphism was isometric, providing no support for Rensch's rule. Variations in tail length but not in ear size were consistent with the predictions of Allen's rule. Body mass and length followed a pattern contrary to predictions of Bergmann's rule. Discussion: We highlighted the usefulness of large multi‐researcher datasets for testing ecological hypotheses after correcting for inter‐observer biases. Using genus‐wide tests, we outlined generalizable patterns of morphological variability across all mouse lemurs. This new methodological toolkit aims to facilitate future large‐scale morphological comparisons for a wide range of taxa and applications. [ABSTRACT FROM AUTHOR]

The article in the Journal of Physiology explores the determinants of muscle maximal oxygen uptake (VO2max) after endurance exercise training. The study by Broxterman et al. involved sedentary young men undergoing 8 weeks of training, measuring oxygen transport and utilization parameters using advanced techniques. The findings suggest a transition in muscle VO2max determinants from oxygen utilization to oxygen delivery after training. The study provides valuable insights into how individuals adapt to endurance training, highlighting the importance of VO2max trainability. [Extracted from the article]

Background: Educational attainment (EduA) is correlated with life outcomes, and EduA itself is influenced by both cognitive and non-cognitive factors. A recent study performed a 'genome-wide association study (GWAS) by subtraction,' subtracting genetic effects for cognitive performance from an educational attainment GWAS to create orthogonal 'cognitive' and 'non-cognitive' factors. These cognitive and non-cognitive factors showed associations with behavioral health outcomes in adults; however, whether these correlations are present during childhood is unclear., Methods: Using data from up to 5517 youth (ages 9-11) of European ancestry from the ongoing Adolescent Brain Cognitive Development SM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and cognition, risk tolerance, decision-making & personality, substance initiation, psychopathology, and brain structure (e.g. volume, fractional anisotropy [FA]). Within-sibling analyses estimated whether observed genetic associations may be consistent with direct genetic effects., Results: Both PGSs were associated with greater cognition and lower impulsivity, drive, and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk tolerance, increased odds of choosing delayed reward, and decreased likelihood of ADHD and bipolar disorder; the non-cognitive PGS was associated with lack of perseverance and reward responsiveness. Cognitive PGS were more strongly associated with larger regional cortical volumes; non-cognitive PGS were more strongly associated with higher FA. All associations were characterized by small effects., Conclusions: While the small sizes of these associations suggest that they are not effective for prediction within individuals, cognitive and non-cognitive PGS show unique associations with phenotypes in childhood at the population level.

Binge drinking is a relatively common pattern of alcohol use among youth with normative frequency trajectories peaking in emerging and early adulthood. Frequent binge drinking is a critical risk factor for not only the development of alcohol use disorders (AUDs) but also increased odds of alcohol-related injury and death, and thus constitutes a significant public health concern. Changes in binge drinking across development are strongly associated with changes in impulsive personality traits (IPTs) which have been hypothesized as intermediate phenotypes associated with genetic risk for heavy alcohol use and AUD. The current study sought to examine the extent to which longitudinal changes in binge drinking and intoxication frequency across adolescence and early adulthood are associated with genetic influences underlying dual-systems IPTs (i.e., top-down [lack of self-control] and bottom-up [sensation seeking and urgency] constructs) alongside genetic risk for alcohol consumption and AUD. Associations were tested using conditional latent growth curve polygenic score (PGS) models in three independent longitudinal samples ( N =10,554). Results suggested consistent significant and independent associations across all samples between sensation seeking PGSs and model intercepts (i.e., higher frequency of binge drinking at first measurement occasion) and alcohol consumption PGSs and model slopes (i.e., steeper increases toward peak binge drinking frequency). Urgency PGSs were not significantly associated with changes in binge drinking or intoxication frequency. Collectively, these findings highlight the role of unique but correlated IPT and alcohol-specific genetic factors in the emergence and escalation of binge drinking during adolescence and early adulthood.

Alcohol Use Disorder (AUD) is a heterogenous category with many unique configurations of symptoms. Previous investigations of AUD heterogeneity using molecular genetics methods studied the association between genetic liability and individual AUD symptoms at the latent level or focusing on a small number of genetic variants. Notably, these studies did not investigate potential severity differences between symptoms in their genetic analyses. Therefore, the current study aimed to examine the genetic risk for individual AUD symptom criteria by using a polygenic risk score (PRS) approach to assess the relative severity of each AUD symptom and test for associates with AUD symptoms above and beyond a unidimensional AUD construct. An AUD PRS was created using summary statistics obtained from published genome-wide association studies (GWAS), and Multiple Indicators Multiple Causes (MIMIC) models were employed to examine the effect of the PRS on overall AUD severity as well as on individual symptoms after accounting for this overall effect. The phenotypic severity of AUD symptoms was highly correlated with the genetic severity of AUD symptoms ( r = 0.78). Results of MIMIC models indicated that the AUD PRS significantly predicted the AUD factor. Regression paths testing the unique, direct effects of the PRS on individual AUD symptoms, independent of the latent AUD factor, were not significant. These results imply that PRSs derived from GWAS of AUD influence symptom expression through a single genetic factor that is highly correlated with the relative severity of individual symptoms when measured at the phenotypic level. Item-level GWAS of AUD symptoms are needed to further parse heterogeneous symptom expression and allow for more nuanced tests of these conclusions., Competing Interests: We have no conflicts of interests to disclose.

Objective: A propensity for aggression or alcohol use may be associated with alcohol-related aggression. Previous research has shown genetic overlap between alcohol use and aggression but has not looked at how alcohol-related aggression may be uniquely influenced by genetic risk for aggression or alcohol use. The present study examined the associations of genetic risk for trait aggression, alcohol use, and alcohol use disorder (AUD) with alcohol-related aggression using a polygenic risk score (PRS) approach., Method: Using genome-wide association study summary statistics, PRSs were created for trait aggression, alcohol consumption, and AUD. These PRSs were used to predict the phenotype of alcohol-related aggression among drinkers in two independent samples: the University of California at San Francisco (UCSF) Family Alcoholism Study ( n = 1,162) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; n = 4,291)., Results: There were significant associations between the AUD PRS and lifetime alcohol-related aggression in the UCSF study sample. Additionally, the trait aggression PRS was associated with three or more experiences of hitting anyone else and getting into physical fights while under the influence of alcohol, along with a composite score of three or more experiences of alcohol-related aggression, in the UCSF study sample. No significant associations were observed in the Add Health sample. Limited sex-specific genetic effects were observed., Conclusions: These results provide preliminary evidence that genetic influences underlying alcohol use and aggression are uniquely associated with alcohol-related aggression and suggest that these associations may differ by type and frequency of alcohol-related aggression incidents. (PsycInfo Database Record (c) 2024 APA, all rights reserved).