Inference of Locus-Specific Population Mixtures From Linked Genome-Wide Allele Frequencies.

Admixture between populations and species is common in nature. Since the influx of new genetic material might be either facilitated or hindered by selection, variation in mixture proportions along the genome is expected in organisms undergoing recombination. Various graph-based models have been developed to better understand these evolutionary dynamics of population splits and mixtures. However, current models assume a single mixture rate for the entire genome and do not explicitly account for linkage. Here, we introduce TreeSwirl, a novel method for inferring branch lengths and locus-specific mixture proportions by using genome-wide allele frequency data, assuming that the admixture graph is known or has been inferred. TreeSwirl builds upon TreeMix that uses Gaussian processes to estimate the presence of gene flow between diverged populations. However, in contrast to TreeMix, our model infers locus-specific mixture proportions employing a Hidden Markov Model that accounts for linkage. Through simulated data, we demonstrate that TreeSwirl can accurately estimate locus-specific mixture proportions and handle complex demographic scenarios. It also outperforms related D- and f-statistics in terms of accuracy and sensitivity to detect introgressed loci.

Tax Policy-An Understudied Approach to Reducing Cannabis Use.

This Viewpoint discusses the potential of state taxation of cannabis products to curb use and raise revenue for public services.

Overdose, Behavioral Health Services, and Medications for Opioid Use Disorder After a Nonfatal Overdose.

Importance: Recognizing and providing services to individuals at highest risk for drug overdose are paramount to addressing the drug overdose crisis. Objective: To examine receipt of medications for opioid use disorder (MOUD), naloxone, and behavioral health services in the 12 months after an index nonfatal drug overdose and the association between receipt of these interventions and fatal drug overdose. Design, Setting, and Participants: This cohort study was conducted in the US from January 2020 to December 2021 using claims, demographic, mortality, and other data from the Centers for Medicare & Medicaid Services, the Centers for Disease Control and Prevention, and other sources. The cohort comprised Medicare fee-for-service beneficiaries aged 18 years or older with International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes for a nonfatal drug overdose. Data analysis was performed from February to November 2023. Exposures: Demographic and clinical characteristics, substance use disorder, and psychiatric comorbidities. Main Outcomes and Measures: Receipt of MOUD, naloxone, and behavioral health services as well as subsequent nonfatal and fatal drug overdoses. Results: The cohort consisted of 136 762 Medicare beneficiaries (80 140 females [58.6%]; mean (SD) age of 68.2 [15.0] years) who experienced an index nonfatal drug overdose in 2020. The majority of individuals had Hispanic (5.8%), non-Hispanic Black (10.9%), and non-Hispanic White (78.8%) race and ethnicity and lived in metropolitan areas (78.9%). In the 12 months after their index nonfatal drug overdose, 23 815 beneficiaries (17.4%) experienced at least 1 subsequent nonfatal drug overdose and 1323 (1.0%) died of a fatal drug overdose. Opioids were involved in 72.2% of fatal drug overdoses. Among the cohort, 5556 (4.1%) received any MOUD and 8530 (6.2%) filled a naloxone prescription in the 12 months after the index nonfatal drug overdose. Filling a naloxone prescription (adjusted odds ratio [AOR], 0.70; 95% CI, 0.56-0.89), each percentage of days receiving methadone (AOR, 0.98; 95% CI, 0.98-0.99) or buprenorphine (AOR, 0.99; 95% CI, 0.98-0.99), and receiving behavioral health assessment or crisis services (AOR, 0.25; 95% CI, 0.22-0.28) were all associated with reduced adjusted odds of fatal drug overdose in the 12 months after the index nonfatal drug overdose. Conclusions and Relevance: This cohort study found that, despite their known association with reduced risk of a fatal drug overdose, only a small percentage of Medicare beneficiaries received MOUD or filled a naloxone prescription in the 12 months after a nonfatal drug overdose. Efforts to improve access to behavioral health services; MOUD; and overdose-prevention strategies, such as prescribing naloxone and linking individuals to community-based health care settings for ongoing care, are needed.

Allergic inflammation triggers dyslipidemia via IgG signalling.

BACKGROUND: Allergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. METHODS: We used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TGs) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction. RESULTS: We found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TGs and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TGs in 59 patients after undergoing an allergic reaction. CONCLUSION: Overall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.

Variation and plasticity in life-history traits and fitness of wild Arabidopsis thaliana populations are not related to their genotypic and ecological diversity.

BACKGROUND: Despite its implications for population dynamics and evolution, the relationship between genetic and phenotypic variation in wild populations remains unclear. Here, we estimated variation and plasticity in life-history traits and fitness of the annual plant Arabidopsis thaliana in two common garden experiments that differed in environmental conditions. We used up to 306 maternal inbred lines from six Iberian populations characterized by low and high genotypic (based on whole-genome sequences) and ecological (vegetation type) diversity. RESULTS: Low and high genotypic and ecological diversity was found in edge and core Iberian environments, respectively. Given that selection is expected to be stronger in edge environments and that ecological diversity may enhance both phenotypic variation and plasticity, we expected genotypic diversity to be positively associated with phenotypic variation and plasticity. However, maternal lines, irrespective of the genotypic and ecological diversity of their population of origin, exhibited a substantial amount of phenotypic variation and plasticity for all traits. Furthermore, all populations harbored maternal lines with canalization (robustness) or sensitivity in response to harsher environmental conditions in one of the two experiments. CONCLUSIONS: Overall, we conclude that the environmental attributes of each population probably determine their genotypic diversity, but all populations maintain substantial phenotypic variation and plasticity for all traits, which represents an asset to endure in changing environments.

Copolymerization of ß-Butyrolactones into Functionalized Polyhydroxyalkanoates Using Aluminum Catalysts: Influence of the Initiator in the Ring-Opening Polymerization Mechanism.

Within bioplastics, natural poly(3-hydroxybutyrate) (PHB) stands out as fully biocompatible and biodegradable, even in marine environments; however, its high isotacticity and crystallinity limits its mechanical properties and hence its applications. PHB can also be synthesized with different tacticities via a catalytic ring-opening polymerization (ROP) of rac-ß-butyrolactone (BBL), paving the way to PHB with better thermomechanical and processability properties. In this work, the catalyst family is extended based on aluminum phenoxy-imine methyl catalyst [AlMeL2], that reveals efficient in the ROP of BBL, to the halogeno analogous complex [AlClL2]. As well, the impact on the ROP mechanism of different initiators is further explored with a particular focus in dimethylaminopyridine (DMAP), a hardly studied initiator for the ROP of BBL. A thorough mechanistic study is performed that evidences the presence of two concomitant DMAP-mediated mechanisms, that lead to either a DMAP or a crotonate end-capping group. Besides, in order to increase the possibilities of PHB post-polymerization functionalization, the introduction of a side-chain functionality is explored, establishing the copolymerization of BBL with ß-allyloxymethylene propiolactone (BPLOAll), resulting in well-defined P(BBL-co-BPLOAll) copolymers.

Alcohol-Related Deaths of US Health Care Workers.

This cohort study investigates the risk of alcohol-related death among US health care workers compared with non­health care workers.

Regulation of TSC2 lysosome translocation and mitochondrial turnover by TSC2 acetylation status.

Sirtuin1 (SIRT1) activity decreases the tuberous sclerosis complex 2 (TSC2) lysine acetylation status, inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) signalling and concomitantly, activating autophagy. This study analyzes the role of TSC2 acetylation levels in its translocation to the lysosome and the mitochondrial turnover in both mouse embryonic fibroblast (MEF) and in mouse insulinoma cells (MIN6) as a model of pancreatic ß cells. Resveratrol (RESV), an activator of SIRT1 activity, promotes TSC2 deacetylation and its translocation to the lysosome, inhibiting mTORC1 activity. An improvement in mitochondrial turnover was also observed in cells treated with RESV, associated with an increase in the fissioned mitochondria, positive autophagic and mitophagic fluxes and an enhancement of mitochondrial biogenesis. This study proves that TSC2 in its deacetylated form is essential for regulating mTORC1 signalling and the maintenance of the mitochondrial quality control, which is involved in the homeostasis of pancreatic beta cells and prevents from several metabolic disorders such as Type 2 Diabetes Mellitus.

Fentanyl-Related Substance Use Patterns, Morbidity, and Mortality Among Adolescents and Young Adults: Implications for Behavioral Health Services Research.

This commentary discusses best practices for responding to fentanyl-related overdose deaths in adolescents and young adults, and it outlines the current state of knowledge about them. Various types of approaches to fentanyl-related overdoses in this age group may need to be developed based on the different risk factors that are emerging from the existing data. We describe the National Institute on Drug Abuse (NIDA) behavioral health services research priorities connected with fentanyl-related overdoses in youth. We highlight a key target for intervention and discuss research opportunities related to early intervention with youth with identifiable risk factors. NIDA's research agenda is a means of assisting communities that experience fentanyl-related overdoses by providing scientific information that can be translated into clear recommendations for public action.

The Role of Extracellular Vesicles in Metabolic Diseases.

Extracellular vesicles represent a group of structures with the capacity to communicate with different cells and organs. This complex network of interactions can regulate multiple physiological processes in the organism. Very importantly, these processes can be altered during the appearance of different diseases including cancer, metabolic diseases, etc. In addition, these extracellular vesicles can transport different cargoes, altering the initiation of the disease, driving the progression, or even accelerating the pathogenesis. Then, we have explored the implication of these structures in different alterations such as pancreatic cancer, and in different metabolic alterations such as diabetes and its complications and non-alcoholic fatty liver disease. Finally, we have explored in more detail the communication between the liver and the pancreas. In summary, extracellular vesicles represent a very efficient system for the communication among different tissues and permit an efficient system as biomarkers of the disease, as well as being involved in the extracellular-vesicle-mediated transport of molecules, serving as a potential therapy for different diseases.

Effects of enzymatic hydrolysis combined with pressured heating on tree nut allergenicity.

Hazelnut, pistachio and cashew are tree nuts with health benefits but also with allergenic properties being prevalent food allergens in Europe. The allergic characteristics of these tree nuts after processing combining heat, pressure and enzymatic digestion were analyzed through in vitro (Western blot and ELISA) and in vivo test (Prick-Prick). In the analyzed population, the patients sensitized to Cor a 8 (nsLTP) were predominant over those sensitized against hazelnut seed storage proteins (Sprot, Cor a 9 and 14), which displayed higher IgE reactivity. The protease E5 effectively hydrolyzed proteins from hazelnut and pistachio, while E7 was efficient for cashew protein hydrolysis. When combined with pressured heating (autoclave and Controlled Instantaneous Depressurization (DIC)), these proteases notably reduced the allergenic reactivity. The combination of DIC treatment before enzymatic digestion resulted in the most effective methodology to drastically reduce or indeed eliminate the allergenic capacity of tree nuts.

Associations of cannabis use, use frequency, and cannabis use disorder with violent behavior among young adults in the United States.

BACKGROUND: Most violent crimes (52 %) are committed by adults aged 18-34, who account for 23 % of the US population and have the highest prevalence of cannabis use and cannabis use disorder (CUD). We examined whether and how associations of cannabis use, use frequency, and CUD with violent behavior (i.e., attacking someone with the intent to harm seriously) vary by sex in U.S. young adults. METHODS: Data were from 113,454 participants aged 18-34 in the 2015-2019 US National Surveys on Drug Use and Health, providing nationally representative data on cannabis use, CUD (using DSM-IV criteria), and violent behavior. Descriptive analyses and bivariate and multivariable logistic regression analyses were conducted. RESULTS: Among U.S. adults aged 18-34, 28.9 % (95 % CI = 28.5-29.2 %) reported past-year cannabis use (with/without CUD), including 20.5 % (95 % CI = 20.2-20.8 %) with non-daily cannabis without CUD, 4.7 % (95 % CI = 4.5-4.8 %) with daily cannabis use without CUD, 2.1 % (95 % CI = 1.9-2.2 %) with non-daily cannabis use and CUD, and 1.7 % (95 % CI = 1.5-1.8 %) with daily cannabis use and CUD. Past-year adjusted prevalence of violent behavior was higher among males with daily cannabis use but without CUD (2.9 %, 95 % CI = 2.4-2.7 %; adjusted prevalence ratio (PR) = 1.7, 95 % CI = 1.3-2.2) and males with daily cannabis use and CUD (3.1 %, 95 % CI = 2.3-4.0 %; adjusted PR = 1.8, 95 % CI = 1.3-2.4) than males without past-year cannabis use (1.7 %, 95 % CI = 1.6-1.9 %). Adjusted prevalence of violent behavior was higher among females with cannabis use regardless of daily cannabis use/CUD status (adjusted prevalence = 1.6-2.4 %, 95 % CIs = 0.9-3.2 %; adjusted PRs = 1.6-2.4, 95 % CI = 1.3-3.2) than females without past-year cannabis use (1.0 %, 95 % CI = 0.9-1.1 %). CONCLUSIONS: Research is needed to ascertain the directionality of the associations between cannabis use and violent behavior and underlying sex-specific mechanism(s). Our results point to complex sex-specific relationships between cannabis use frequency, CUD, and violent behavior and highlight the importance of early screening for and treatment of CUD and of preventive interventions addressing cannabis misuse.

The trichome pattern diversity of Cardamine shares genetic mechanisms with Arabidopsis but differs in environmental drivers.

Natural variation in trichome pattern (amount and distribution) is prominent among populations of many angiosperms. However, the degree of parallelism in the genetic mechanisms underlying this diversity and its environmental drivers in different species remain unclear. To address these questions, we analyzed the genomic and environmental bases of leaf trichome pattern diversity in Cardamine hirsuta, a relative of Arabidopsis (Arabidopsis thaliana). We characterized 123 wild accessions for their genomic diversity, leaf trichome patterns at different temperatures, and environmental adjustments. Nucleotide diversities and biogeographical distribution models identified two major genetic lineages with distinct demographic and adaptive histories. Additionally, C. hirsuta showed substantial variation in trichome pattern and plasticity to temperature. Trichome amount in C. hirsuta correlated positively with spring precipitation but negatively with temperature, which is opposite to climatic patterns in A. thaliana. Contrastingly, genetic analysis of C. hirsuta glabrous accessions indicated that, like for A. thaliana, glabrousness is caused by null mutations in ChGLABRA1 (ChGL1). Phenotypic genome-wide association studies (GWAS) further identified a ChGL1 haplogroup associated with low trichome density and ChGL1 expression. Therefore, a ChGL1 series of null and partial loss-of-function alleles accounts for the parallel evolution of leaf trichome pattern in C. hirsuta and A. thaliana. Finally, GWAS also detected other candidate genes (e.g. ChETC3, ChCLE17) that might affect trichome pattern. Accordingly, the evolution of this trait in C. hirsuta and A. thaliana shows partially conserved genetic mechanisms but is likely involved in adaptation to different environments.

Hepatitis C virus infection and co-infection with HIV among persons who inject drugs in 10 U.S. cities-National HIV Behavioral Surveillance, 2018.

BACKGROUND: Characterizing acute and chronic hepatitis C virus (HCV) infection and HIV/HCV co-infection among persons who inject drugs (PWID) can inform elimination efforts. METHODS: During 2018 National HIV Behavioral Surveillance in 10 U.S. metropolitan statistical areas (MSAs), PWID were recruited using respondent-driven sampling and offered a survey, HIV testing, and HCV antibody and RNA testing. We examined prevalence and associated characteristics of HCV infection and HIV/HCV co-infection. Associations were assessed using log-linked Poisson regression models with robust standard errors accounting for clustering by recruitment chain and adjusting for MSA and network size. RESULTS: Overall, 44.2% had current HCV infection (RNA detected), with 3.9% classified as acute infection (HCV antibody non-reactive/RNA detected) and 40.3% as chronic (HCV antibody reactive/RNA detected). Four percent had HIV/HCV co-infection. Current HCV infection was significantly higher among PWID who were male, White, injected >1 time/day, shared syringes in past year, and shared injection equipment in past year. PWID who were transgender, injecting >5 years, and most often injected speedball (heroin and cocaine together) or stimulants alone were more likely to have HIV/HCV co-infection. Among PWID who never previously had HCV infection, 9.9% had acute HCV infection. Among PWID who started injecting ≤5 years ago, 41.5% had already acquired HCV infection. CONCLUSIONS: Acute and chronic HCV infections were substantial among a sample of PWID in 10 U.S. MSAs. Accessibility to HCV RNA testing, promoting safer practices, and intervening early with harm reduction programs for recent injection initiates will be critical to disease elimination efforts for PWID.

Mental Health Impairment and Outpatient Mental Health Care of US Children and Adolescents.

Importance: Despite a federal declaration of a national child and adolescent mental health crisis in 2021, little is known about recent national trends in mental health impairment and outpatient mental health treatment of US children and adolescents. Objective: To characterize trends in mental health impairment and outpatient mental health care among US children and adolescents from 2019 to 2021 across demographic groups and levels of impairment. Design, Setting, and Participants: Survey study with a repeated cross-sectional analysis of mental health impairment and outpatient mental health care use among youth (ages 6-17 years) within the 2019 and 2021 Medical Expenditure Panel Surveys, nationally representative surveys of US households. Race and ethnicity were parent reported separately from 15 racial categories and 8 ethnic categories that were aggregated into Black, non-Hispanic; Hispanic; Other, non-Hispanic; and White, non-Hispanic. Exposure: Time period from 2019 to 2021. Main Outcomes and Measures: Age- and sex-adjusted differences between 2019 and 2021 in mental health impairment measured with the Columbia Impairment Scale (a score ≥16 indicates severe; 1-15, less severe; and 0, no impairment) and age-, sex-, and Columbia Impairment Scale strata-adjusted differences in the use of any outpatient mental health care in 2019 and 2021. Results: The analysis involved 8331 participants, including 4031 girls and 4300 boys; among them, 1248 were Black and 3385 were White. The overall mean (SE) age was 11.6 (3.4) years. The percentage of children and adolescents with severe mental health impairment was 9.7% in 2019 and 9.4% in 2021 (adjusted difference, -0.3%; 95% CI, -1.9% to 1.2%). Between 2019 and 2021, there was also no significant difference in the percentage of children and adolescents with less severe impairment and no impairment. The overall annual percentages of children with any outpatient mental health care showed little change: 11.9% in 2019 and 13.0% in 2021 (adjusted difference, 1.3%; 95% CI, -0.4% to 3.0%); however, this masked widening differences by race. Outpatient mental health care decreased for Black youth from 9.2% in 2019 to 4.0% in 2021 (adjusted difference, -4.3%; 95% CI, -7.3% to -1.4%) and increased for White youth from 15.1% to 18.4% (adjusted difference, 3.0%; 95% CI, 0.0% to 6.0%). Conclusions and Relevance: Between 2019 and 2021, there was little change in the overall percentage of US children and adolescents with severe mental health impairment. During this period, however, there was a significant increase in the gap separating outpatient mental health care of Black and White youth.

Trends in Psychological Distress and Outpatient Mental Health Care of Adults During the COVID-19 Era.

BACKGROUND: In addition to the physical disease burden of the COVID-19 pandemic, concern exists over its adverse mental health effects. OBJECTIVE: To characterize trends in psychological distress and outpatient mental health care among U.S. adults from 2018 to 2021 and to describe patterns of in-person, telephone, and video outpatient mental health care. DESIGN: Cross-sectional nationally representative survey of noninstitutionalized adults. SETTING: United States. PARTICIPANTS: Adults included in the Medical Expenditure Panel Survey Household Component, 2018 to 2021 (n = 86 658). MEASUREMENTS: Psychological distress was measured with the Kessler-6 scale (range of 0 to 24, with higher scores indicating more severe distress), with a score of 13 or higher defined as serious psychological distress, 1 to 12 as less serious distress, and 0 as no distress. Outpatient mental health care use was measured via computer-assisted personal interviews. RESULTS: Between 2018 and 2021, the rate of serious psychological distress among adults increased from 3.5% to 4.2%. Although the rate of outpatient mental health care increased from 11.2% to 12.4% overall, the rate decreased from 46.5% to 40.4% among adults with serious psychological distress. When age, sex, and distress were controlled for, a significant increase in outpatient mental health care was observed for young adults (aged 18 to 44 years) but not middle-aged (aged 45 to 64 years) and older (aged >65 years) adults and for employed adults but not unemployed adults. In 2021, 33.4% of mental health outpatients received at least 1 video visit, including a disproportionate percentage of young, college-educated, higher-income, employed, and urban adults. LIMITATION: Information about outpatient mental health service modality (in-person, video, telephone) was first fully available in the 2021 survey. CONCLUSION: These trends and patterns underscore the persistent challenges of connecting older adults, unemployed persons, and seriously distressed adults to outpatient mental health care and the difficulties faced by older, less educated, lower-income, unemployed, and rural patients in accessing outpatient mental health care via video. PRIMARY FUNDING SOURCE: None.

Lifetime Suicide Attempts in Otherwise Psychiatrically Healthy Individuals.

Importance: Not all people who die by suicide have a psychiatric diagnosis; yet, little is known about the percentage and demographics of individuals with lifetime suicide attempts who are apparently psychiatrically healthy. If such suicide attempts are common, there are implications for suicide risk screening, research, policy, and nosology. Objective: To estimate the percentage of people with lifetime suicide attempts whose first attempt occurred prior to onset of any psychiatric disorder. Design, Setting, and Participants: This cross-sectional study used data from the US National Epidemiologic Study of Addictions and Related Conditions III (NESARC-III), a cross-sectional face-to-face survey conducted with a nationally representative sample of the US civilian noninstitutionalized population, and included persons with lifetime suicide attempts who were aged 20 to 65 years at survey administration (April 2012 to June 2013). Data from the NESARC, Wave 2 survey from August 2004 to September 2005 were used for replication. Analyses were performed from April to August 2023. Exposure: Lifetime suicide attempts. Main Outcomes and Measures: The main outcome was presence or absence of a psychiatric disorder before the first lifetime suicide attempt. Among persons with lifetime suicide attempts, the percentage and 95% CI of those whose first suicide attempt occurred before the onset of any apparent psychiatric disorders was calculated, weighted by NESARC sampling and nonresponse weights. Separate analyses were performed for males, females, and 3 age groups (20 to <35, 35-50, and >50 to 65 years). Results: In the total sample of 36 309 respondents, 1948 persons had lifetime suicide attempts; 66.8% (95% CI, 64.1%-69.4%) were female, and 6.2% (95% CI, 4.9%-7.4%) had no apparent lifetime psychiatric diagnoses when surveyed. In addition, 13.4% (95% CI, 11.6%-15.2%) made their first suicide attempt prior to psychiatric disorder onset. Thus, an estimated 19.6% of respondents first attempted suicide without an antecedent psychiatric disorder. No significant age or sex differences were detected in the percentage of those with lifetime suicide attempts absent psychiatric disorders, although females were more likely than males to attempt suicide in the year of psychiatric disorder onset (14.9% [95% CI, 12.5%-17.3%] vs 8.6% [95% CI, 6.0%-11.2%]; P < .001), and attempts were less frequent among those older than 50 to 65 years (3.9% [95% CI, 3.5%-4.4%] vs 6.1% [95% CI, 5.4%-6.8%] for 35-50 years and 6.2% [95% CI, 5.6%-6.9%] for 20 to <35 years; P < .001). Conclusions and Relevance: In this study, an estimated 19.6% of individuals who attempted suicide did so despite not meeting criteria for an antecedent psychiatric disorder. This finding challenges clinical notions of who is at risk for suicidal behavior and raises questions about the safety of limiting suicide risk screening to psychiatric populations.