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Exposure to post-transplant liver biopsies varies among pathology residencies and largely depends on the institution's training program, particularly if the hospital has a liver transplant program. The interpretation of biopsies from transplanted livers presents its own set of challenges, even for those with a solid understanding of non-transplant medical liver biopsies. In this review, we aim to provide a succinct, step-by-step approach to help you interpret liver transplant biopsies. This article may be beneficial for residents interested in liver pathology, gastrointestinal and liver pathology fellows in the early stages of training, clinical gastroenterology and hepatology fellows, hepatologists and general pathologists who are curious about this niche.

Abstract Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios.

ABSTRACT BACKGROUND: Viral hepatitis is a major public health concern worldwide. OBJECTIVES: This study aimed to analyze the factors that facilitate access to care for viral hepatitis. DESIGN AND SETTING: Using a sequential mixed method, this evaluation research was conducted in the state of Mato Grosso, Brazil. METHODS: Mapping of references and selection of regions were made based on the quantity and heterogeneity of services. The stakeholders, including the managers of the State Department of Health and professionals from reference services, were identified. Nine semi-structured interviews were conducted using content analysis and discussions guided by the dimensions of the analysis model of universal access to health services. RESULTS: In the political dimension, decentralizing services and adhering to the Intermunicipal Health Consortium are highly encouraged. In the economic-social dimension, a commitment exists to allocate public funds for the expansion of referral services and subsidies to support users in their travel for appointments, medications, and examinations. In the organizational dimension, the availability of inputs for testing, definition of user flow, ease of scheduling appointments, coordination by primary care in testing, collaboration following the guidelines and protocols, and engagement in extramural activities are guaranteed. In the technical dimension, professionals actively commit to the service and offer different opening hours, guarantee the presence of an infectious physician, expand training opportunities, and establish intersectoral partnerships. In the symbolic dimension, professionals actively listen to the experiences of users throughout their care trajectory and demonstrate empathy. CONCLUSIONS: The results are crucial for improving comprehensiveness, but necessitate managerial efforts to enhance regional governance.

ABSTRACT Objective: To analyze the spatial distribution and the temporal trend of the hepatitis mortality rate in Brazil from 2001 to 2020. Methods: Ecological, temporal, and spatial study on mortality from hepatitis in Brazil with data from the Mortality Information System (Sistema de Informações sobre Mortalidade – SIM/DATASUS). Information was stratified by year of diagnosis, region of the country, municipalities (of residence). Standardized mortality rates (SMR) were calculated. The temporal trend was estimated by Prais-Winsten regression and the spatial distribution by the Global Moran Index (GMI). Results: The highest SMR means in Brazil were for Chronic viral hepatitis with 0.88 deaths per 100,000 inhabitants (SD=0.16), followed by Other viral hepatitis with 0.22/100,000 (SD=0.11). In Brazil, the temporal trend of mortality from Hepatitis A was −8.11% per year (95%CI −9.38; −6.82), while for Hepatitis B it was −4.13% (95%CI −6.03; −2.20), of Other viral hepatitis of −7.84% (95%CI −14.11; −1.11) and of Unspecified Hepatitis −5.67% per year (95%CI −6.22; −5.10). Mortality due to chronic viral hepatitis increased by 5.74% (95%CI 3.47; 8.06) in the North and 4.95% in the Northeast (95%CI 0.27; 9.85). The Moran Index (I) for Hepatitis A was 0.470 (p

This is the first study to evaluate the adequacy and reliability of the ChatGPT and Gemini chatbots on viral hepatitis. A total of 176 questions were composed from three different categories. The first group includes "questions and answers (Q&As) for the public" determined by the Centers for Disease Control and Prevention (CDC). The second group includes strong recommendations of international guidelines. The third group includes frequently asked questions on social media platforms. The answers of the chatbots were evaluated by two different infectious diseases specialists on a scoring scale from 1 to 4. Cohen's kappa coefficient was calculated to assess inter-rater reliability. The reproducibility and correlation of answers generated by ChatGPT and Gemini were analyzed. ChatGPT and Gemini's mean scores (3.55 ± 0.83 vs. 3.57 ± 0.89, p = 0.260) and completely correct response rates (71.0% vs. 78.4%, p = 0.111) were similar. In addition, in subgroup analyses with the CDC questions Sect. (90.1% vs. 91.9%, p = 0.752), the guideline questions Sect. (49.4% vs. 61.4%, p = 0.140), and the social media platform questions Sect. (82.5% vs. 90%, p = 0.335), the completely correct answers rates were similar. There was a moderate positive correlation between ChatGPT and Gemini chatbots' answers (r = 0.633, p < 0.001). Reproducibility rates of answers to questions were 91.3% in ChatGPT and 92% in Gemini (p = 0.710). According to Cohen's kappa test, there was a substantial inter-rater agreement for both ChatGPT (κ = 0.720) and Gemini (κ = 0.704). ChatGPT and Gemini successfully answered CDC questions and social media platform questions, but the correct answer rates were insufficient for guideline questions., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Chronic hepatitis B is the leading cause of hepatocellular carcinoma and a significant global health issue, affecting over 296 million people worldwide, with 15 million people coinfected with hepatitis delta virus (HDV) suffering accelerated disease progression. Recent advances in single-cell sequencing and spatial transcriptomics offer promising insights to improve the understanding of the liver's immune responses and hepatitis B virus (HBV)-infected cell distribution, with the final goal being the achievement of an HBV 'functional cure'. In this issue of eGastroenterology , Cross et al used the GeoMx nanostring digital spatial profiling (DSP) technology to study gene expression in the liver tissues of three patients (one HBV-monoinfected, one HBV/HDV coinfected and one HBV/human immunodeficiency virus (HIV) coinfected). Unlike other spatial transcriptomics techniques, GeoMx DSP allows targeted selection of specific tissue regions (regions of interest) for analysis, enabling precise gene expression mapping. The study revealed spatially distinct transcriptomic signatures related to immune features and viral burden, identifying a component of underinvestigated immune cells. Despite the small sample size, this proof-of-concept study demonstrates the feasibility of spatial transcriptomics in analysing HBV infections. Future advances, such as integrating viral proteins and nucleic acids, will enhance the understanding of spatial viral replication. Challenges in tissue processing, data analysis and costs remain before spatial transcriptomics can be applied as a diagnostic tool, but ongoing multiomics approaches offer promise for improved diagnosis and therapy., Competing Interests: BT receives funding from Assembly Biosciences, Beam Therapeutics, BlueJay Therapeutics and Aligos., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract Infection by the hepatitis C virus is more prevalent in patients on dialysis than in the general population in Brazil, and has been associated with worse outcomes. Current therapy for hepatitis C is highly effective, safe, and widely available in Brazil, with coverage provided to dialysis patients with chronic kidney disease, which makes the elimination of hepatitis C a viable target. The Brazilian Society of Nephrology, the Brazilian Society of Hepatology, and the Brazilian Liver Institute developed the “Brazilian Registry for the Elimination of Hepatitis C in Dialysis Units”. This project aims to identify, treat, and monitor the response to treatment of patients on chronic dialysis infected with the hepatitis C virus in Brazil. This article presents the issue and invites Brazilian nephrologists to rally around the achievement of a significant goal.

Background and Aim: Liver cirrhosis is the primary risk factor for the development of hepatocellular carcinoma. Most conditions that lead to cirrhosis are treatable, or modifiable. Therefore, a community‐based screening program targeting high‐risk groups was designed for early diagnosis and intervention of liver disease, to offset the rising burden of hepatocellular carcinoma in Australia. Methods: Two nurse consultants from a tertiary liver center performed community screening of pre‐identified cohorts at risk of viral hepatitis and chronic liver disease, with transient elastography and/or serology testing for chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), in addition to standard blood tests. A positive screening result was defined as any of the following: liver stiffness measurement (LSM) ≥ 9.5 kPa, positive HCV RNA, or positive HBV surface antigen. Individuals who screened positive were linked to the liver center for management. Results: Nine hundred and twenty‐six subjects were screened over a 6‐year period, of which 122/926 (13.2%) had evidence of chronic liver disease. Chronic viral hepatitis was diagnosed in 91 participants (HBV = 23, HCV = 67, and co‐infection = 1), while non‐alcoholic fatty liver disease was diagnosed in 14 participants. Advanced fibrosis (LSM ≥ 9.5 kPa) was detected in 42/866 (4.9%) subjects with available LSM. Loss to follow‐up occurred in 36/91 (39.6%) participants with chronic viral hepatitis. Conclusions: Targeting high‐risk populations for community screening and intervention increases early identification of chronic liver disease. This may reduce the incidence of liver cirrhosis and hepatocellular carcinoma. Loss to follow‐up remains an ongoing challenge, requiring better strategies. [ABSTRACT FROM AUTHOR]

The paper presents an approach for overcoming modeling problems of typical life science applications with partly unknown mechanisms and lacking quantitative data: A model family of reaction-diffusion equations is built up on a mesoscopic scale and uses classes of feasible functions for reaction and taxis terms. The classes are found by translating biological knowledge into mathematical conditions and the analysis of the models further constrains the classes. Numerical simulations allow comparing single models out of the model family with available qualitative information on the solutions from observations. The method provides insight into a hierarchical order of the mechanisms. The method is applied to the clinics for liver inflammation such as metabolic dysfunction-associated steatohepatitis or viral hepatitis where reasons for the chronification of disease are still unclear and time- and space-dependent data is unavailable., (© 2024. The Author(s).)

Objective. To identify and summarize existing literature on the burden of HIV, sexually transmitted infections (STIs), and viral hepatitis (VH) in indigenous peoples and Afro-descendants in Latin America to provide a broad panorama of the quantitative data available and highlight problematic data gaps. Methods. Published and grey literature were systematically reviewed to identify documents published in English, Spanish, or Portuguese with data collected between January 2000 and April 2016 on HIV, STI, and VH disease burden among indigenous peoples and Afro-descendants in 17 Latin American countries. Results. Sixty-two documents from 12 countries were found. HIV prevalence was generally low (< 1%) but pockets of high prevalence (> 5%) were noted in some indigenous communities in Venezuela (Warao) (9.6%), Peru (Chayahuita) (7.5%), and Colombia (Wayuu females) (7.0%). High active syphilis prevalence (> 5%) was seen in some indigenous communities in Paraguay (11.6% and 9.7%) and Peru (Chayahuita) (6.3%). High endemicity (> 8%) of hepatitis B was found in some indigenous peoples in Mexico (Huichol) (9.4%) and Venezuela (Yanomami: 14.3%; Japreira: 29.5%) and among Afro-descendant quilombola populations in Brazil (Frechal: 12.5%; Furnas do Dionísio: 8.4% in 2008, 9.2% in 2003). Conclusions. The gaps in existing data on the burden of HIV, STIs, and VH in indigenous peoples and Afro-descendants in Latin America highlight the need to 1) improve national surveillance, by systematically collecting and analyzing ethnicity variables, and implementing integrated biobehavioral studies using robust methodologies and culturally sensitive strategies; 2) develop a region-wide response policy that considers the needs of indigenous peoples and Afro-descendants; and 3) implement an intercultural approach to health and service delivery to eliminate health access barriers and improve health outcomes for these populations.

Spatial analysis of infectious diseases can play an important role in mapping the spread of diseases and can support policy making at local level. Moreover, identification of disease clusters based on local geography and landscape forms the basis for disease control and prevention. Therefore, this study aimed to examine the spatial-temporal variations, hotspot areas, and potential risk factors of infectious diseases (including Viral Hepatitis, Typhoid and Diarrhea) in Ahmedabad city of India. We used Moran's I and Local Indicators of Spatial Association (LISA) mapping to detect spatial clustering of diseases. Spatial and temporal regression analysis was used to identify the association between disease incidence and spatial risk factors. The Moran's I statistics identified presence of positive spatial autocorrelation within the considered diseases, with Moran's I from 0.09 for typhoid to 0.21 for diarrhea (p < 0.001). This indicates a clustering of affected wards for each disease, suggesting that cases were not randomly distributed across the city. LISA mapping demonstrated the clustering of hotspots in central regions of the city, especially towards the east of the river Sabarmati, highlighting key geographical areas with elevated disease risk. The spatial clusters of infectious diseases were consistently associated with slum population density and illiteracy. Furthermore, temporal analysis suggested illiteracy rates could increase risk of viral hepatitis by 13 % (95 % Confidence Interval (CI): 1.01-1.26) and of diarrhea by 18 % (95 % CI: 1.07-1.31). Significant inverse association was also seen between viral hepatitis incidence and the distance of wards from rivers. Conclusively, the study highlight the impact of socio-economic gradients, such as slum population density (indicative of poverty) and illiteracy, on the localized transmission of water and foodborne infections. The evident social stratification between impoverished and affluent households emerges as a notable contributing factor and a potential source of differences in the dynamics of infectious diseases in Ahmedabad., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Among the three open reading frames (ORFs) of the HEV genome, the ORF3 protein is involved in virus release. However, the host proteins involved in HEV release need to be clarified. In this study, a host protein, thioredoxin domain-containing protein 5 (TXNDC5), interacted with the non-palmitoylated ORF3 protein by co-immunoprecipitation analysis. We determined that the overexpression or knockdown of TXNDC5 positively regulated HEV release from the host cells. The 17 FCL 19 mutation of the ORF3 protein lost the ability to interact with TXNDC5. The releasing amounts of HEV with the ORF3 mutation (FCL17-19SSP) were decreased compared with wild-type HEV. The overexpression of TXNDC5 can stabilize and increase ORF3 protein amounts, but not the TXNDC5 mutant with amino acids 1-88 deletion. Meanwhile, we determined that the function of TXNDC5 on the stabilization of ORF3 protein is independent of the Trx-like domains. Knockdown of TXNDC5 could lead to the degradation of ORF3 protein by the endoplasmic reticulum (ER)-associated protein degradation-proteasome system. However, the ORF3 protein cannot be degraded in the knockout-TXNDC5 stable cells, suggesting that it may hijack other proteins for its stabilization. Subsequently, we found that the other members of protein disulfide isomerase (PDI), including PDIA1, PDIA3, PDIA4, and PDIA6, can increase ORF3 protein amounts, and PDIA3 and PDIA6 interact with ORF3 protein. Collectively, our study suggested that HEV ORF3 protein can utilize TXNDC5 for its stability in ER to facilitate viral release., Importance: Hepatitis E virus (HEV) infection is the leading cause of acute viral hepatitis worldwide. After the synthesis and modification in the cells, the mature ORF3 protein is essential for HEV release. However, the host protein involved in this process has yet to be determined. Here, we reported a novel host protein, thioredoxin domain-containing protein 5 (TXNDC5), as a chaperone, contributing to HEV release by facilitating ORF3 protein stability in the endoplasmic reticulum through interacting with non-palmitoylated ORF3 protein. However, we also found that in the knockout-TXNDC5 stable cell lines, the HEV ORF3 protein may hijack other proteins for its stabilization. For the first time, our study demonstrated the involvement of TXNDC5 in viral particle release. These findings provide some new insights into the process of the HEV life cycle, the interaction between HEV and host factors, and a new direction for antiviral design., Competing Interests: The authors declare no conflict of interest.

Background & Aims: Little is known about the potential impact of statins on the progression of noncirrhotic chronic liver diseases (CLDs) to severe liver disease., Methods: Using liver histopathology data in a nationwide Swedish cohort, we identified 3862 noncirrhotic individuals with CLD and statin exposure, defined as a statin prescription filled for 30 or more cumulative defined daily doses. Statin users were matched to 3862 (statin) nonusers with CLD through direct 1:1 matching followed by propensity score matching. Cox regression was used to estimate hazard ratios (HRs) for the primary outcome of incident severe liver disease (a composite of cirrhosis, hepatocellular carcinoma, and liver transplantation/liver-related mortality)., Results: A total of 45.3% of CLD patients had nonalcoholic fatty liver disease, 21.9% had alcohol-related liver disease, 17.7% had viral hepatitis, and 15.1% had autoimmune hepatitis. During follow-up evaluation, 234 (6.1%) statin users vs 276 (7.1%) nonusers developed severe liver disease. Statin use was associated with a decreased risk of developing severe liver disease (HR, 0.60; 95% CI, 0.48-0.74). Statistically significantly lower rates of severe liver disease were seen in alcohol-related liver disease (HR, 0.30; 95% CI, 0.19-0.49) and in nonalcoholic fatty liver disease (HR, 0.68; 95% CI, 0.45-1.00), but not in viral hepatitis (HR, 0.76; 95% CI, 0.51-1.14) or autoimmune hepatitis (HR, 0.88; 95% CI, 0.48-1.58). Statin use had a protective association in both prefibrosis and fibrosis stages at diagnosis. Statin use was associated with lower rates of progression to cirrhosis (HR, 0.62; 95% CI, 0.49-0.78), hepatocellular carcinoma (HR, 0.44; 95% CI, 0.27-0.71), and liver-related mortality (HR, 0.55; 95% CI, 0.36-0.82)., Conclusions: Among individuals with noncirrhotic CLD, incident statin use was linked to lower rates of severe liver disease, suggesting a potential disease-modifying role., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Viral hepatitis-induced acute liver failure (ALF) is a preventable cause for liver-related mortality worldwide. Viruses are the most common cause for ALF in developing nations in contrast to the west, where acetaminophen is largely responsible. Viruses may be hepatotropic or affect the liver secondary to a systemic infection. In tropical countries, infections such as leptospirosis, scrub typhus and malaria can mimic the symptoms of ALF. Differentiating these ALF mimics is crucial because they require etiology-specific therapy. Treatment of viral hepatitis-induced ALF is two-pronged and directed towards providing supportive care to prevent organ failures and antiviral drugs for some viruses. Liver transplantation (LT) is an effective modality for patients deteriorating despite adequate supportive care. Early referral and correct identification of patients who require a transplant are important. Liver support devices and plasma exchange have evolved into "bridging modalities" for LT. Preventive strategies such as hand hygiene, use of clean and potable water and inclusion of vaccines against viral hepatitis in the national program are simple yet very effective methods focusing on the preventive aspect of this disease., (© 2024. Indian Society of Gastroenterology.)

Introduction: Liver disease is a significant public health problem in the United States, with notable racial disparities in mortality. This study examines liver disease mortality trends among Black and White populations during 1999-2020., Methods: We used CDC WONDER database to ascertain liver disease age-standardized mortality rates in Black and White Americans. Annual percent change was calculated. Age-standardized absolute rate difference and rate ratios were computed by subtracting and dividing the White population's rate from that of the Black population., Results: Liver diseases accounted for 171,627 Black and 1,314,903 White deaths during 1999-2020. Age-standardized mortality rates for Blacks decreased from 22.5 to 20.1 per 100,000 person-years (annual percentage change -0.4%, -0.6% to -0.2%), whereas an increase was observed for Whites, from 17.9 to 25.3 per 100,000 person-years (annual percentage change 1.4%, 1.4% to 1.7%). The rate ratio decreased from 1.26 (1.22-1.29) in 1999 to 0.79 (0.78-0.81) in 2020. This pattern was evident in all census regions, more pronounced among the younger (age 25-64 years) than older (age 65+ years) population and observed across different urbanization levels. The pattern may be attributable to increasing alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease-related deaths in Whites and tapering in viral hepatitis and primary liver cancer-related deaths in Blacks. Despite notable improvement, racial disparities persist in primary liver cancer and viral hepatitis among the Black population., Discussion: The rise in alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease-related deaths among Whites, and enduring liver cancer and viral hepatitis disparities in the Black population, underscores the urgent need for tailored public health interventions., (Copyright © 2023 by The American College of Gastroenterology.)

Introduction: Viral hepatitis C (HCV) and B (HBV) were at the top of Egypt's most significant public health challenges, with an estimated 14.7% of its population having antibodies to HCV in 2008. Egypt issued an ambitious action plan in 2014 to eliminate viral hepatitis through strengthening infection control and improving patient care. In 2018, an extensive HCV mass screening campaign was conducted for the entire country's population with treating more than 4 million patients with antivirals. This study aimed to evaluate the current prevalence of viral hepatitis in Egypt after all these efforts., Methods: A cross-sectional household cluster survey was conducted in all 27 Egyptian governorates to obtain a representative sample of Egypt's population. Subjects aged 1-70 years were interviewed using a standardised questionnaire that included demographics, viral hepatitis knowledge, previous infection and risk factors data. Laboratory testing was performed for all subjects for anti-HCV and HBsAg using chemiluminescence. Subjects positive for anti-HCV were further tested for HCV-RNA by RT-PCR. Prevalence rates were calculated by demographic groups and compared to the demographic health survey 2015 results., Results: Of 20 881 subjects interviewed, 48.8% were males, 20.2% were children <15 years of age, and 53.7% were residents of rural areas. Of all subjects, 92 (0.4%) were HCV-infected, 1577 (7.6%) were anti-HCV positive and 177 (0.8%) were HBV-chronically infected, including one patient who had mixed HBV and HCV current infection. The prevalence of HCV-current and HBV chronic infections decreased by 93% and 20%, respectively, compared to 2015., Conclusions: Egypt achieved the elimination of the viral hepatitis goal. To maintain low rates of viral hepatitis, community health education, in addition to maintaining infection control and blood safety programs, is essential., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs)., Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP)., Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020., Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt., Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records., Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C., Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.