👤 Roberta A Gottlieb

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioural assays (locomotor activity and conditioned place preference), alcohol intake paradigms (intermittent access two-bottle choice, drinking in the dark and the alcohol deprivation effect), and molecular analyses (microdialysis, electrophysiology and proteomics) in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release (P < 0.001). Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption (P < 0.001), prevented binge (P < 0.01) and relapse-like drinking (P < 0.001), and maintained efficacy during repeated administration (P < 0.001). Finally, tirzepatide induced sustained synaptic depression in the lateral septum (P < 0.05) and further altered histone regulatory proteins in this region (P < 0.05), suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight (P < 0.001), adipose tissue mass (P < 0.01), hepatic triglycerides (P < 0.01) and circulating pro-inflammatory cytokines (P < 0.05). Together, our findings suggest tirzepatide modulates alcohol-related behaviours through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatide's established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. The study is supported by grants from the Swedish Research Council (2023-2600, 2020-00559, 2020-01463, 2024-03054), LUA/ALF (723941 & 1005347) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), National Institutes of Health (NIH) (P50 AA010761 & U01 AA014095), U.S. Department of Veterans Affairs Office of Research and Development (BLR&D I01BX000813 & IK6BX006299), Herbert & Karin Jacobssons Foundation (2024-Forskning-225), Adlerbertska Research Foundation (2024-791), Wilhelm & Martina Lundgren's Research Foundation (2024-SA-4698), Åke Wibergs Foundation (M24-0216), Swedish Diabetes Foundation (DIA 2024-898) and Mary von Sydow Foundation (2024-36 & 2024-185). Thaynnam A Emous held an international internship scholarship from the São Paulo Research Foundation (FAPESP), Process Number #2023/18470-5, while conducting research at the University of Gothenburg. Show less

Sleep traits, including sleep apnoea (SA), insomnia, daytime sleepiness, and snoring, frequently co-occur with cardiometabolic diseases (CMDs), with shared genetic factors suspected to underlie these associations. However, the contribution of shared genetic determinants to these associations is not fully understood. We conducted a genome-wide pleiotropic association study applying sequential genetic methods to identify shared genetic variants, genes, pathways and causal associations between the four sleep traits and seven CMDs, including LDSC, high-definition likelihood analysis, colocalisation, gene-based tests, enrichment analysis and Mendelian randomisation. Next, validation of those pleiotropic variants was performed in individuals from the All of Us and MVP studies. Among 28 pairs of sleep traits and CMDs, 25 showed significant genetic correlations. Pleiotropic analysis identified 754 independent SNPs (691 unique) and 102 colocalized loci (85 unique). Among these, 47 SNPs (44 unique) were validated as significantly associated with both traits in the pairs, and notably, rs429358 (19q13.32, APOE) demonstrated pleiotropic effects across SA, insomnia and type 2 diabetes (T2D). Forty-eight annotated genes were validated by gene-based tests. Shared genes were enriched in phenotypes related to mortality and growth. Pathway analysis highlighted Cushing syndrome, hormone secretion, and cGMP-PKG, Ras and calcium signalling pathways. After adjusting for glycaemic traits and blood pressure, genetically predicted T2D increased risk of SA, sleepiness, and snoring. Conversely, SA was positively associated with heart failure and T2D independently. This study of sleep traits and CMDs reveals shared genetic determinants that may partially explain their epidemiologic association and suggests potential treatment targets. Described in Acknowledgements. Show less

Complex PTSD (CPTSD) is often associated with prolonged or repeated trauma exposure and the experience of intimate partner and childhood abuse. CPTSD includes the criteria for PTSD (re-experiencing, avoidance, and sense of threat) in addition to three criteria for self-organization disturbances (affective dysregulation, negative self-concept, and relational disturbance). This study aimed to assess profiles of CPTSD symptoms and their association with psychiatric distress among people with co-occurring Serious Mental Illness (SMI; schizophrenia/schizoaffective, bipolar, and treatment-refractory major depression). Treatment-seeking participants ( A model with three classes best fit the data with the most parsimonious interpretation: 26.7% ( The results demonstrate the heterogeneity in symptom presentation across the PTSD classes and that, despite similar diagnoses, individuals may present with varying symptom patterns. This emphasizes the importance of studying CPTSD in subpopulations of persons with SMI. Show less

The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing. Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033). Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes. Show less

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression. A family in which a young man had a clinical diagnosis of HCM underwent clinical and genetic investigations. The coding regions of the MYH7, MYBPC3 and TNNT2 genes were sequenced and analyzed. The proband present a malignant manifestation of the disease, and is the only one to express HCM in his family. The genetic analysis through direct sequencing of the three main genes related to this disease identified a compound heterozygous variant (p.E542Q and p.D610H) in MYBPC3. A family analysis indicated that the p.E542Q and p.D610H alleles have paternal and maternal origin, respectively. No family member carrier of one of the variant alleles manifested clinical signs of HCM. We suggest that the MYBPC3-biallelic heterozygous expression of p.E542Q and p.D610H may cause the severe disease phenotype seen in the proband. Resumo A cardiomiopatia hipertrófica (CMH) é uma doença autossômica dominante causada por mutações em genes que codificam as proteínas dos sarcômeros. É a principal causa de morte súbita cardíaca em atletas jovens de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A associação entre genótipo e fenótipo em CMH tem sido objeto de diversos estudos desde a descoberta da origem genética dessa doença. Este trabalho apresenta o efeito de uma mutação composta em MYBPC3 na expressão fenotípica da CMH. Uma família na qual um jovem tem o diagnóstico clínico de CMH foi submetida à investigação clínica e genética. As regiões codificadoras dos genes MYH7, MYBPC3 e TNNT2 foram sequenciadas e analisadas. O probando apresenta uma manifestação maligna da doença e é o único em sua família a desenvolver CMH. A análise genética pelo sequenciamento direto dos três principais genes relacionados à essa doença identificou uma variante em heterozigose composta (p.E542Q e p.D610H) em MYBPC3. A análise da família mostrou que os alelos p.E542Q e p.D610H tem origem paterna e materna, respectivamente. Nenhum familiar portador de um dos alelos variantes manifestou sinais clínicos de CMH. Sugerimos que a expressão heterozigótica bialélica de p.E542Q e p.D610H pode ser responsável pelo fenótipo severo da doença encontrada no probando. Show less

Clinical Question Does the addition of cyclobenzaprine or oxycodone with acetaminophen to naproxen result in improved functional outcomes at one week when compared to placebo in patients with acute low back pain? Article Chosen Friedman B, Dym A, Davitt, M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA 2015:20;314(15):1572-80. Study Objective The primary objective of this study was to compare functional outcomes at one week and three months after emergency department (ED) presentation for acute low back pain among patients prescribed naproxen plus one of the following: (1) oxycodone/acetaminophen; (2) cyclobenzaprine; or (3) placebo. Show less