Vincent Lo Re

Background: Steatotic liver disease (SLD) is highly prevalent in people with HIV (PWH), but factors influencing progression to hepatocellular carcinoma (HCC) and hepatic decompensation (HD) remain unclear. It is unknown if the risk of these outcomes associated with SLD differs by HIV status. Methods: Patients from the Veterans Aging Cohort Study-HIV (includes matched people without HIV [PWoH]) who underwent an ultrasound, computed tomography, or magnetic resonance imaging between 2001–2017 were included. Patients with diagnosed cirrhosis or chronic viral hepatitis were excluded. SLD was defined by a natural language processing algorithm; primary outcome of composite of HCC or HD was defined using International Classification of Diseases 9/10 codes and national cancer registry. Follow-up began on imaging study date and continued until incident HCC/HD, death, or 31 December 2024. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of HCC/HD associated with SLD and HIV status were calculated. Results: Among 19 546 patients (mean age: 54 years; 96.6% male; 28.6% PWH), 13 617 (69.7%) had SLD identified by natural language processing. Rates of HCC/HD were lowest in PWoH and no SLD (18.0/10 000 person-years) and highest among PWH and SLD (46.8/10 000 person-years). When compared to PWoH without SLD, risk of HCC/HD was increased among PWH with SLD (aHR: 2.71; 95% CI: 2.10–3.49) and PWH without SLD (aHR: 1.62; 95% CI: 1.14–2.29), although no interaction between HIV and SLD was observed (P = .25). Conclusions: Among people without cirrhosis or chronic viral hepatitis, radiographic findings of SLD were associated with increased rates of HCC/HD, with the highest rate among PWH and SLD, independent of cardiometabolic factors, alcohol, and tobacco.

Purpose: Alcohol use disorder (AUD) remains a major public health problem, with few effective treatments. L‐type calcium channel blockers (LTCCBs) have genetic and preclinical support as potential treatments for AUD. Methods: We evaluated whether brain penetrant (BP)‐LTCCBs are associated with reduced alcohol consumption in two preregistered observational cohort studies using electronic health records from the US Department of Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC). New users of BP‐LTCCBs (nifedipine or felodipine) were compared with new users of a non‐BP‐LTCCB (amlodipine) and with unexposed patients from the same clinics, requiring a 180‐day washout and ≥ 60 days' supply. Propensity score matching was performed across all exposure contrasts. The primary outcome was change in drinks per week from pre‐index to end of follow‐up using difference‐in‐differences (DiD) models, with prespecified subgroup analyses by AUD diagnosis, drinking level, and sex. Results: Across both health systems, BP‐LTCCB initiation was not associated with greater reductions in drinks per week than either comparator, with broadly consistent findings across all subgroups; though some subgroups were small and imprecise. In the VA, the DiD comparing BP‐LTCCB with non‐BP‐LTCCB was 0.14 drinks/week (95% CI −0.06, 0.34), and versus unexposed was 0.00 (95% CI −0.18, 0.19). Similar results were observed in KPNC (BP‐LTCCB vs. non‐BP‐LTCCB: 0.31, 95% CI −0.48, 1.11; BP‐LTCCB vs. unexposed: 0.16, 95% CI −0.67, 0.99). Conclusions: In two large, preregistered EHR‐based cohorts, we found no evidence that BP‐LTCCBs were associated with reduced drinking relative to comparators. Despite compelling genetic and preclinical evidence, these findings do not support repurposing BP‐LTCCBs for AUD and instead prioritize alternative pharmacologic targets.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is known to cause acute liver injury (ALI) in COVID‐19 patients. This study explores the association between ALI patterns and the occurrence of long‐term hepatic complications in patients with and without existing chronic liver disease (CLD). Methods: Within the Veterans Health Administration system, we identified patients testing positive for SARS‐CoV‐2. ALI was categorised based on injury type within the first 30 days post‐infection into hepatocellular, cholestatic, or mixed patterns. Cox regression was employed to analyse the link between ALI types and hepatic complications post‐acute COVID‐19 phase in patients with and without pre‐existing CLD. Results: Of 173 111 COVID‐19 patients, 1843 (1.1%) suffered from ALI: 1542 hepatocellular, 180 cholestatic and 121 mixed. Among these, 51 291 (29.6%) had pre‐existing CLD. Post‐acute hepatic dysfunction was notably higher in ALI patients, with adjusted hazard ratios (aHR) of 2.19 for hepatocellular, 1.57 for cholestatic and 5.75 for mixed injuries. Patients with pre‐existing alcohol‐associated liver disease had a significantly increased risk of decompensation (aHR = 6.86), followed by those with Metabolic Dysfunction‐Associated Steatotic Liver Disease (MASLD) (aHR = 1.56). Conclusions: COVID‐19–associated ALI was associated with increased risk of post‐acute hepatic dysfunction and decompensation, with the highest risk observed among patients with a mixed hepatocellular‐cholestatic injury pattern. Among patients with pre‐existing CLD, ALD was most strongly associated with subsequent hepatic decompensation, while MASLD showed a more modest association.

The Veterans Aging Cohort Study (VACS)‐National is a large, longitudinal real‐world data resource derived from electronic health records within the Department of Veterans Affairs (VA), the largest integrated healthcare system in the United States. As of December 2025, VACS‐National includes > 14.9 million Veterans who have received care in the VA since 2000. It captures information on VA‐related outpatient and inpatient care and includes structured (e.g., diagnostic codes, laboratory results, vital signs, dispensed medical products), semi‐structured (e.g., radiology and pathology reports) and unstructured (e.g., progress notes) fields, collected from over 1300 points of care nationwide. Its longitudinal structure supports extended follow‐up across demographically and clinically diverse populations within an integrated healthcare system. Key features for pharmacoepidemiological research include near real‐time availability of data on dispensed medications, including biologics, vaccines, and devices; routinely‐collected laboratory measurements; and computable phenotypes, including validated natural language phenotypes. The resource includes linkages to Centers for Medicare and Medicaid Services (CMS) data, VA Community Care data, National Death Index, and deeply phenotyped VACS sub‐cohorts with an extensive library of biomarkers and survey data. VACS‐National has supported a wide range of research, including drug utilization, drug safety, comparative effectiveness, and epidemiologic and health outcomes research. Strengths include its national scale, longitudinal follow‐up, and rich clinical record; limitations include a small proportion of women and potential incomplete capture of care outside the system or not recoverable through linked datasets. VACS‐National provides a comprehensive platform for generating real‐world evidence to inform clinical, regulatory, and public health decision‐making.

Background: Prolonged exposure to hepatotoxic antiretroviral therapy (ART) could lead to chronic liver injury, which might increase risk of hepatocellular carcinoma (HCC). We used causal inference methods to evaluate if cumulative exposure to ART with known mechanisms of chronic liver injury is associated with HCC among people with HIV (PWH), by chronic liver disease (CLD) status. Methods: We conducted a cohort study of antiretroviral-naïve PWH with and without diagnosed CLD who initiated ART in the Veterans Affairs (VA) between 1999-2023. Exposure to ART with known mechanism of chronic liver injury (mitochondrial toxicity or accumulation of toxic intermediates) was determined monthly via prescription fills. Incident HCC was identified by VA National Cancer Registry and/or recorded diagnoses. Marginal structural models estimated odds ratios (ORs) with 95% confidence intervals (CIs) of HCC associated with cumulative exposure to chronic liver injury-inducing ART compared to ART without chronic liver injury mechanisms, by CLD status. Results: Among 11,854 PWH without CLD and 6,771 PWH with CLD, we observed 112 and 378 HCC events, respectively. Among PWH without CLD, ≥4 years of exposure to chronic liver injury-inducing ART was associated with HCC when compared to ≥4 years of use of ART without chronic liver injury mechanisms (OR=4.02 [95% CI, 1.00-16.24]). Among PWH with CLD, ≥4 years of exposure to chronic liver injury-inducing ART was not associated with HCC (OR=1.36; 95% CI, 0.68-2.72). Conclusion: Four or more years of ART with a chronic liver injury mechanism was associated with HCC among PWH without CLD, but not those with CLD.

Background: Evidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England. Methods: We conducted a matched-cohort study among adults aged ≥65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36). In a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type. Results: Across all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: ( fit to : mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to : moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to : severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection. Interpretation: Severe infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline. Research in context: Evidence before this study: We searched PubMed (inception to May 08, 2026), for published articles evaluating the association between infections and frailty progression with multistate modelling including studies that focused on one transition only with no language restrictions. We used the search terms [(infection OR infectious) AND (frailty OR frail) AND optional (progression OR multistate OR multi-state OR transition)]. We identified five longitudinal studies that compared transition hazard rates from a baseline fit state to pre-frailty or frailty during follow-up between individuals with specific infections (SARS-CoV-2, HIV, history of 20 infections based on International Classification of Diseases [ICD] codes and prescribed medications, cytomegalovirus antibody concentration quartiles, and seropositivity of herpes viruses [HSV 1 and 2, varicella-zoster, and Epstein-Barr]) versus those without infection. The studies found that infection or infection history increased the hazards of transition from a fit/pre-frail state to frailty after adjusting for confounders. The hazards of frailty recovery from frail to fit state was higher among individuals with HIV infection than those without. None of the studies accounted for the competing risk of death, and all modelled transitions along a single pathway between fit/pre-frail and frail states. Furthermore, frailty was conceptualised as a binary outcome, whereas validated frailty risk prediction models typically define frailty in progressive categories of deterioration, commonly classified as fit, mild, moderate, and severe. There is limited evidence on the risk of transition from baseline and intermediate frailty states to more advanced states following infection, while accounting for competing risk of death. To identify subgroups for targeted care, it is important to determine whether frailty deterioration after severe infection varies by infection type (sepsis, urinary tract infection, skin and soft tissue infection, meningitis/encephalitis, lower respiratory tract infection, and gastroenteritis), age, sex, social deprivation, diabetes, and dementia. Added value of this study: Our study compared rates of transition to greater frailty or death between older adults with and without severe infection (hospitalisation primarily for infection). We found that severe infection increased the hazards of transition from baseline and intermediate frailty states to more advanced frailty states or death. From each same starting frailty state, outgoing transition hazards increased progressively towards more advanced frailty states or death. The hazards of progression to greater frailty or death also varied by infection type, with the strongest associations observed for LRTI, followed by sepsis, UTI, meningitis/encephalitis, gastroenteritis, and skin and soft tissue infections. Implications of all the available evidence: Our findings underscore the importance of infection prevention in reducing the risk of frailty progression in older age. Additional studies are required to explore other wider life-course influences on frailty, to guide the development of comprehensive preventive strategies.

Background: Building an academic career in pharmacoepidemiology requires intentional planning but can be challenging, particularly for new learners, trainees, and early faculty members who may lack awareness of the skills and benchmarks expected at each career stage. This paper provides reflections on designing a purposeful and sustainable academic career. Perspectives: The first part of the article focuses on four foundational elements: (1) setting aside time for regular reflection to clarify values and priorities; (2) developing a clear vision and defining missions for each professional and personal role; (3) prioritizing activities systematically to maintain alignment with one's vision, missions, and goals; (4) seeking and maintaining mentorship throughout one's career to obtain feedback and guide decision‐making. We describe concrete strategies, tools, and authors' personal approaches for implementing these elements. The second part of the article outlines key skills to acquire and benchmarks to achieve during key career stages, including competencies such as time management, team‐building, project management, research dissemination, research grant writing, mentorship, and leadership. In the final part, we note that structural, institutional, and life‐course factors (e.g., gender, race/ethnicity, resource access, and major life events) may shape the feasibility and impact of these strategies, underscoring the importance of supportive environments, inclusive mentorship, and flexibility for sustainable careers. Implications: Our goal is not to prescribe a single pathway but to offer a reference that promotes individual reflection and catalyzes open discussion among peers, mentors, and colleagues to enhance satisfaction and success in an academic career in pharmacoepidemiology.

Background: We investigated frailty progression after severe infections in adults (≥65 years) in the US and England. Methods: We conducted parallel matched cohort studies using: US Veterans Aging Cohort Study (VACS-National, 2008-2019; median age 74 years; 98% male); and English Clinical Practice Research Datalink (2006-2019; median age 76 years; 45% male). Adults hospitalised primarily for infection (i.e., severe infection) were matched in calendar date order to individuals without severe infection on age, sex, care site, and US only, plus race and ethnicity. We measured frailty using VACS Index 2·0 (US) and Electronic Frailty Index (eFI; England). We estimated annual conditional mean frailty differences between adults with versus without severe infection using linear regression adjusting for baseline frailty, demographics, lifestyle factors, infection history, and US only, comorbidities. Results: Mean baseline frailty was higher in those with severe infection than those without (US: 57 v 48; England: 0·17 v 0·12). At Year 1, adjusted mean frailty was higher among adults with severe infections than those without (US: VACS Index +2·0, 95% CI 1·9-2·0; England: eFI +0·005, 95% CI 0·005-0·006). At Years 2-5, adjusted mean frailty remained higher after severe infection; however, compared to Year 1, differences were smaller in US, and larger in England. Effects varied by infection type (strongest for lower respiratory tract infections, meningoencephalitis (UK only), urinary tract infections, and sepsis). Interpretation: Individuals with severe infections had higher frailty at baseline and follow up than those without. Preventing both frailty and infections is important for improving health in older age. Funding: Wellcome Research in context: Evidence before this study: We searched PubMed (inception to October 27, 2025), for published articles evaluating the association between infections and frailty, with no language restrictions. We used the search terms [(infection OR infectious) AND (frailty OR frail)]. We found fifteen observational studies investigating associations between individual infections (including: HIV, cytomegalovirus, SARS-CoV-2, acute respiratory infection, urinary tract infection, and influenza) and frailty in adults. Frailty measures varied: eight studies used Fried’s phenotype index, six used versions of the cumulative deficit index (i.e., Edmonton Frail Scale, FRAIL-NH Scale, Hospital Frailty Risk Score, Clinical Frailty Score, Veterans Affairs Frailty Index, Vulnerable Elders Survey-13), and one study used the Timed Up and Go Test. Results from identified studies were mixed, with nearly half (7/15) reporting a positive association between the infection studied and frailty, and the remaining eight finding no evidence of association. In cross-sectional analyses, HIV, SARS-CoV-2, cytomegalovirus, and urinary tract infection, were each associated with higher mean frailty scores or frailty prevalence. In longitudinal analysis, hospitalisation for acute respiratory infection was followed by higher mean hospital frailty risk scores two years post-discharge. SARS-CoV-2 infection was associated with early onset (i.e., higher hazard) of frailty over three years follow-up. However, other studies found no association between HIV, SARS-CoV-2, acute respiratory infection and influenza, and frailty prevalence, incidence, or transition between frailty states. These mixed findings may reflect methodological differences between the studies, including variation in frailty measures, and study limitations. Frailty exists along a continuum of vulnerability, and progression after infection may be an important outcome, yet current evidence is scarce. It remains unclear whether severe infections or different types of infection, are associated with faster frailty deterioration. Similarly, it is uncertain whether post-infection frailty risk varies by pathogen (bacterial, viral, parasitic, fungal), infection type (sepsis, urinary tract infection, skin and soft tissue infection, meningitis/encephalitis, lower respiratory tract, gastroenteritis), or by age, sex, social deprivation, and pre-existing comorbidities. Added value of this study: Our study compared frailty progression over a five-year period between adults aged ≥65 years with severe infection (hospitalisation primarily due to infection) versus comparators without severe infection. We found higher baseline frailty at severe infection onset than in matched comparators. We saw evidence of increased frailty progression over time in people following severe infections compared to those without, however, these differences were small. We also saw higher risk of worsening frailty progression in older adults and those with dementia. Further, worsening frailty progression varied by infection type (strongest for lower respiratory tract infections, meningoencephalitis (UK only), urinary tract infections, and sepsis). Implications of all the available evidence: Our findings underscore the importance of both frailty and infection prevention in improving health in older age. Additional studies are required to explore other wider life-course influences on frailty, to guide the development of comprehensive preventive strategies.

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications and suboptimal adherence. L-type calcium channel blockers (LTCCBs) have genetic and preclinical support as potential treatments for AUD. We evaluated whether brain penetrant (BP)-LTCCBs are associated with reduced alcohol consumption by conducting two preregistered ( https://osf.io/huawv ) observational cohort studies using electronic health records (EHRs) from the US Department of Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC). New users of BP-LTCCBs (nifedipine or felodipine) were compared with new users of a non-BP-LTCCB (amlodipine) and with unexposed patients sampled from the same clinics, following a 180-day washout and requiring at least 60 days’ supply. Propensity score matching was conducted separately for BP-LTCCB versus unexposed, non-BP-LTCCB versus unexposed, and BP-versus non-BP-LTCCB. The primary outcome was change in drinks per week from the most recent pre-index screen to end of follow-up, estimated using difference-in-differences (DiD) models. Prespecified subgroup analyses were conducted by AUD diagnosis, baseline drinking level, and sex. Across both health systems, BP-LTCCB initiation was not associated with greater reductions in drinks per week than either comparator, with broadly consistent findings across all subgroups. In two large, preregistered EHR-based cohorts with rigorous confounding control, BP-LTCCBs were not associated with reduced drinking relative to comparators. Despite compelling genetic and preclinical evidence, these results do not support repurposing BP-LTCCBs for AUD, highlighting the need to prioritize alternative pharmacologic targets, potentially within etiologically informed subgroups.

Background: It remains unclear if cure of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) leads to change in liver fat fraction and if this change differs from people without HCV observed over similar time. We evaluated the change in three-dimensional volumetric liver fat fraction by magnetic resonance imaging (MRI) prior to DAA treatment and 18 months following initiation and compared changes in uninfected controls over 18 months. Methods: We conducted a cohort study of 35 participants who initiated DAAs and achieved cure and 42 without HCV infection as controls. At enrollment and 18 months later, participants had measurements of height, body weight, and three-dimensional volumetric liver fat fraction and cross-sectional area of abdominal subcutaneous and visceral adipose tissue by MRI. Multivariable linear regression was used to estimate group differences in mean changes in liver fat fraction. Results: Mean change in three-dimensional volumetric liver fat fraction between Months 0 and 18 was +2.89% (95% CI: + 0.89%, + 4.88%) among participants with cured HCV and +0.48% (95% CI: -1.02%, + 1.97%) among controls (between group difference p-value=0.05). After adjustment for age, sex, smoking, and change in body mass index, the mean difference in liver fat fraction change between Months 0 and 18 was +3.11% (95% CI: + 0.46%, + 5.76%; p = 0.022) higher for participants with HCV versus controls. Conclusions: Three-dimensional volumetric liver fat fraction by MRI significantly increased between Months 0 and 18 following successful treatment of HCV infection, but this finding was not observed from Month 0 to 18 among participants without HCV infection.