5071 Background: Olaparib, a targeted therapy for metastatic castration-resistant prostate cancer (mCRPC), has demonstrated clinical benefits in patients with homologous recombination repair (HRR) gene alterations, as shown in the PROfound trial. As the largest integrated healthcare system in the US, the Veteran’s Health Administration (VHA) offers insights into olaparib use among a diverse population. We characterized the treatment patterns and outcomes of patients with mCRPC treated with olaparib. Methods: We identified all VHA patients with mCRPC who received olaparib between May 2020 and December 2023. We then performed a retrospective chart review of data from May 2018 to June 2025 to capture pre- and post-treatment data. Demographics, baseline characteristics, biomarker testing and treatment sequencing were summarized. We analyzed time to event outcomes: time to next therapy (TTNT), and overall survival (OS) via Kaplan-Meier methods, both starting from olaparib initiation. Results: We identified 477 mCRPC patients receiving olaparib. Median age at initiation was 75, older than subjects in PROfound (median age 69). Most patients were non-Hispanic White (69%), followed by Black/African American (20%) and Hispanic/Latino (6%). Between 2020 and 2023, olaparib was most commonly initiated in ≥5th line after prostate cancer diagnosis (46%), followed by 4 th (25%), 3 rd (22%), and 2 nd line (6.5%). All patients had received an androgen receptor pathway inhibitor prior to olaparib. Median time from HRR testing to olaparib initiation was 5 months. Median TTNT was 7 months; OS was 12 months. Use of olaparib in an earlier line post first NHA was associated with numerically longer OS (17 months for 1st line vs. 8 months for 4th or later). Conclusions: Within the VHA, olaparib showed favorable outcomes despite older age and late-line use, supporting effectiveness in routine practice and in a more diverse population with substantially higher representation of Black/African American and Hispanic/Latino individuals than in clinical trials. Understanding these treatment patterns provides insight into clinical practice and helps guide towards optimal integration of olaparib into management of mCRPC. Kaplan-Meier estimates for time to event outcomes. #Events/Total Median Time (95% CI) (months) Time to Next Treatment - All Patients 449/477 7 (6-8) - Olaparib Line of Treatment Post NHA 1st line 100/111 9 (7-10) 2nd line 151/162 8 (7-10) 3rd line 92/96 6 (5-8) 4th line or later 91/92 5 (4-6) Overall Survival - All Patients 395/477 12 (11-13) - Olaparib Line of Treatment Post NHA 1st line 79/111 17 (12-22) 2nd line 133/162 15 (12-17) 3rd line 85/96 10 (8-12) 4th line or later 88/92 8 (6-9)

BACKGROUND:Hepatitis C virus (HCV) disproportionately affects incarcerated individuals, and effective interventions are needed to improve HCV care within prisons to achieve global elimination targets. This review aimed to identify and synthesise evidence on interventions to improve HCV testing, linkage to care, and direct-acting antiviral (DAA) treatment initiation among people in prison and post-release. METHODS:We systematically searched MEDLINE (PubMed), Scopus, Web of Science, Cochrane CENTRAL, and PsycINFO for studies assessing non-pharmaceutical interventions with a comparator or control group. Outcomes were HCV antibody testing, HCV RNA testing, linkage to HCV care, and treatment initiation. Randomised controlled trials (RCTs) and controlled non-randomised studies were included; data were extracted and risk of bias assessed in duplicate using standard tools (RoB 2 and ROBINS-I). This analysis was restricted to studies of interventions evaluated in prison settings or among people recently released from prison. Searches had no date restriction and were updated November 2024. This review is registered in PROSPERO (CRD42020178035). FINDINGS:Of 20,643 unique records, 22 studies were included (19 non-randomised; three RCTs). Simplified testing modalities had the most evidence of impact on testing and treatment outcomes: dried blood spot (DBS) testing improved antibody testing uptake in three studies (two RCTs and one non-randomised study; OR 2.90, 95 % CI 1.43-5.86) and point-of-care RNA testing improved treatment initiation in three non-randomised studies (OR 9.60, 95 % CI 3.38-27.32). Simplified opt-out screening strategies also increased antibody testing uptake in three studies (OR 20.41, 95 % CI 1.88-221.19). Other interventions simplifying testing (e.g., reflex RNA testing, broadened testing criteria) were effective in individual studies, but pooled analyses for broadened testing criteria were not statistically significant due to high heterogeneity. Single studies also showed improvements in treatment initiation using DBS testing, nurse-led care, and no-cost coverage of HCV medications. INTERPRETATION:Several interventions, particularly those to enhance testing, may be successful in increasing HCV testing and treatment in prisons. However, the heterogeneity of interventions, methodological limitations of included studies, and limited number of studies underscore the need for further robust research, particularly RCTs, to optimise care in this setting.

Efficient and secure integration of epidemiological data with pathogen genome sequence data is essential for identification of transmission clusters, monitoring of emerging mutations and targeting public health responses. However, this information is often collected across different organisations: epidemiological data is collected by public health units while genome sequence data is collected by diagnostic laboratories. Linking these sources often requires manual or semi-manual approaches, leading to unnecessary delays in identifying emerging outbreaks. To address this, we developed a proof-of-concept privacy-preserving distributed platform, SecureEpiLink, for automatic linkage of pathogen genome sequences and notification data across public health and diagnostic laboratories. SecureEpiLink uses cryptographic hashing to establish linkage, without exposing personal identifying information. This ensures that the resulting linked data can be used to identify the emergence of transmission clusters without identification of individuals comprising each cluster. The original identifiable data can continue to be stored at source labs. We benchmarked SecureEpiLink against manual linkage and another linkage service using HIV and HCV datasets from New South Wales, Australia. SecureEpiLink performed similarly to manual linkage and outperformed previously used linkage algorithms, with all errors attributable to data entry errors in the underlying dataset. Lastly, we demonstrate how SecureEpiLink can be integrated with automated genomic epidemiology pipelines. SecureEpiLink is available from https://github.com/jolenefarrell/SecureEpiLink. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by an Australian Government Department of Health and Aged Care Medical Research Future Fund (MRFF) grant (FSPGN000047). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: St Vincent's Hospital Human Research Ethics Committee approved following study 2024/ETH00857: Assessing the systems for HCV molecular epidemiology in H2Seq I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Memory stem CD8+ T cells (TSCM) are a long-lived T-cell subset with stem cell-like properties, playing a key role in antiviral immunity. Despite their importance, comprehensive single-cell transcriptomic profiling of antigen-specific TSCM has not been previously conducted. In this study, an in vitro single-cell colony expansion protocol was used to investigate human CD8+ T-cell clones specific for cytomegalovirus (CMV) epitopes. Clonal lineages from selected donors were generated by single-cell sorting of dextramer-positive CD8+ T cells with varied effector and memory phenotypes, all specific for one of 2 HLA-restricted CMV epitopes. Phenotypic and functional characterization of clonal lineages derived from antigen-specific TSCM revealed differentiated memory and effector subsets (TCM, TEM, TEMRA) as well as TSCM, with the latter subset featuring multi-potentiality and multi-cytokine production. Studying TSCM-derived progeny of these varied differentiation phenotypes in single-cell transcriptomic analysis revealed strong progenitor-to-progeny effects, whereby daughter cells from a shared progenitor clustered closely regardless of progeny differentiation phenotype, suggesting a dominant impact associated with heritable genes. TSCM-derived progeny that retained a TSCM phenotype expressed canonical early-memory genes such as IL7R, CCR7, SELL, and CD27, along with novel transcripts consistently shared across donors and epitopes. The transcriptional features of clonal lineages are strongly dependent on the progenitor cell, but TSCM have an additional transcriptomic signature, likely underpinning their unique differentiation and functional characteristics. These findings have important implications for identification of long-lived and multipotent CD8 T cells for immunotherapy and immunization against viral infections.

Health state values, often in the form of value sets that list values applied to particular health states, are used in cost-effectiveness analyses of health care to calculate gains in quality-adjusted life-years. These values are subject to several sources of uncertainty, arising from the fact that values are not constants but variables and are of different types including variability, heterogeneity, statistical uncertainty, and methodological variation. Currently, these sources are not fully documented and are not fully accounted for when creating and analyzing economic evaluation models. This may provide to users of such models a false sense of the precision of quality-adjusted life-year gain estimates and therefore of cost-effectiveness. This article provides a comprehensive account of such sources of uncertainty and how they interact. It also provides a more detailed account of how uncertainty arises in studies that elicit and model value sets. Its aim is to encourage research to measure and report uncertainty around health state values so it can be better accounted for in cost-effectiveness analyses.HighlightsHealth state values (HSVs) used in cost-effectiveness analysis are subject to multiple types of uncertainty, including variability, heterogeneity, statistical uncertainty, and methodological variation.Current reporting and guidelines often fail to fully document or address all sources of uncertainty in HSVs, which can mislead users about the precision of QALY and cost-effectiveness estimates.Valuation studies should report measures of uncertainty (such as standard errors or variance/covariance matrices) for HSVs, not just point estimates.Researchers, decision modellers, and guideline developers should recognise, measure, and report HSV uncertainty more thoroughly to improve the reliability of cost-effectiveness analyses.

Background & Aims Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD. Methods In an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS). Results Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale. Conclusion PROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD. Impact and implications Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group). Clinical trial registration ClinicalTrials.gov Identifier, NCT03852719

Background Understanding whether apathy in older adults is related to incident dementia and mortality could help identify at-risk individuals, and inform public health efforts. This study aimed to investigate associations between apathy and these outcomes over long-term follow-up, and their independence from the overlapping symptoms of depression and fatigue. Methods In an Australian population-based cohort of 1,030 community-dwelling older adults aged 70-90, without dementia at baseline, apathy was assessed using the self-report Geriatric Depression Scale-3A subscale. Incident dementia was established via consensus diagnosis over 12 year follow-up, and mortality by record linkage over 18 years. We calculated hazard ratios (HRs) using Cox proportional hazards analyses. We repeated analyses adjusting for depression, fatigue and covariates, accounting for competing risk of mortality, and excluding short-term cases. Findings Unadjusted primary analyses showed the presence of self-reported apathy was associated with higher risk of dementia (HR 1.45, 95% confidence interval (CI) 1.05-2.00) and mortality (HR 1.76, 95% CI 1.43-2.16). Participants with apathy developed dementia a year earlier, and died three years earlier. These findings remained significant when adjusting for depression. The association with dementia was no longer significant when adjusting for fatigue or covariates, nor when taking mortality into account or excluding those cases where dementia developed in the shorter term. Interpretation The presence of apathy may represent an important risk indicator for dementia and mortality in older adults without dementia, independent of depression. Its association with dementia may reflect reverse causality. Future studies are needed to better understand the causal relationships that may underpin this observed association in the short and long-term, and the utility of apathy for screening in public health settings. ### Competing Interest Statement H.B. is or has been an advisory board member or consultant to Biogen, Eisai, Eli Lilly, Medicines Australia, Roche, and Skin2Neuron. P.S.S. was a member of the Expert Advisory Committees for Biogen and Roche Australia in 2020-22, unrelated to the current work. He is supported by an NHMRC Investigator Grant. J.R. has received honorarium from Merck Sharp & Dohme (MSD) for giving educational talks to health professionals. All other authors declare they have no competing interests. ### Funding Statement This doctoral research was supported by co-funding from Dementia Australia Research Foundation-Dementia Collaborative Research Centres Half-Funded PhD Scholarship and the Centre for Healthy Brain Ageing (CHeBA), and top-up scholarships from CHeBA Josh Woolfson Memorial Scholarship and Kwan Fung and Yuet Ying Fung Healthy Brain Ageing Research Award Fund and Brain Sciences UNSW Collaborative PhD Grant-In-Aid. The Sydney Memory and Ageing Study has been funded by three National Health & Medical Research Council (NHMRC) Program Grants (ID No. ID350833, ID568969, and APP1093083). DNA samples were extracted by Genetic Repositories Australia, an Enabling Facility, which was supported by an NHMRC Grant (ID No. 401184). Blood samples were collected by South-Eastern Area Laboratory Service (SEALS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of the University of New South Wales and South-Eastern Sydney and Illawarra Health Service gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes De-identified individual participant data collected during the Sydney Memory and Ageing Study are available to researchers who provide a methodologically sound proposal. Proposals should be directed to the Centre for Healthy Brain Ageing; to gain access, data requestors will need to sign a data access agreement.

OBJECTIVE:To qualitatively explore the perceptions of general practitioners in regional New South Wales, Australia, on diagnosing, managing and preventing Q fever. SETTING:Q fever is a prevalent zoonosis in regional New South Wales, but diagnosis may be missed as patients have symptoms similar to influenza or COVID. Perspectives of general practitioners who are the primary health care providers in rural areas are important to understand the logistical difficulties in providing optimum care to Q fever patients. PARTICIPANTS:General practitioners practicing outside of metropolitan Sydney in regional postcodes of New South Wales, Australia. METHODS:Eligible general practitioners were interviewed online using a semi-structured interview guide on their approach to diagnosis, management and prevention of Q fever. The data were transcribed, coded using NVivo software, and analysed to identify emerging overarching themes. RESULTS:Thematic saturation was achieved after 11 interviews. Diagnostic delays due to prioritising more common differential diagnoses for an influenza-like illness, difficulties in navigating the complex serological test interpretations for diagnosis, logistical difficulties in arranging immunisation, and the need for continuing medical education were the broad themes emerging from the data analysis. CONCLUSIONS:Investment in continuing medical education and expansion of the reference resources made available to general practitioners regarding the diagnosis and management of Q fever will improve health care for people suffering from and at risk of Q fever in regional New South Wales.

Potent and broadly neutralizing antibodies (NAbs) are important for clearance of RNA virus infections. However, NAbs generated in response to RNA viruses exhibit diverse profiles of potency and breadth. In this study, we conducted a comparative analysis of NAbs targeting HIV, hepatitis C virus (HCV), SARS-CoV-2, and influenza based on their potency, measured by IC50 values, and breadth, assessed through the genetic diversity of the viruses neutralized by the NAbs. Our results reveal that while anti-HCV NAbs show a high breadth of neutralization, they are less potent and demonstrate inconsistent potency across different virus variants. These findings highlight the challenges in eliciting broad and potent antibody responses, which are essential for the development of effective vaccine strategies against HCV.

BACKGROUND:Injecting drug use following treatment for hepatitis C virus (HCV) may result in reinfection, potentially reversing individual, and population benefits of HCV treatment. The aim of this study was to evaluate the incidence of HCV reinfection following successful direct acting antiviral (DAA) therapy among people with recent injecting drug use. METHODS:This analysis used data from an observational cohort study of people with recent injecting drug use (previous six months) following successful DAA treatment in Australia, Canada, and New Zealand. Participants were either recruited prior to commencing DAA therapy or after a documented sustained virological response (SVR). Participants were assessed three-monthly for HCV reinfection. Reinfection was defined as recurrence of virus distinct from the initial infecting strain or recurrence after confirmed cure at or after 12 weeks post-treatment. Person-time of observation and Cox proportional hazard models were used to calculate reinfection incidence and associated factors. RESULTS:Among 112 participants who contributed follow-up time at risk of reinfection (113 person-years of follow-up time), the median age was 43 years, 34 % were female, and 86 % reported injecting drug use in the month prior to enrolment. Eleven cases of reinfection were observed for an incidence of 9.7/100 person-years (95 % confidence interval [CI], 5.4-17.4) overall, 11.1/100 person-years (95 % CI, 6.1-20.0) among people who reported injecting drugs during follow-up, and 24.3/100 person-years (95 % CI, 7.8-75.3) among those who reported sharing needles/syringes during follow-up. All cases of HCV reinfection occurred among people reporting injecting drug use during the study. CONCLUSIONS:The relatively high incidence of reinfection seen in this study underscores the importance of targeted harm reduction measures and monitoring for HCV reinfections within the first year following successful treatment among people who inject drugs. Additional research into integrated models of care incorporating harm reduction and supporting reducing risk of reinfection and HCV treatment are needed.

BACKGROUND:Hepatitis C virus (HCV) is prevalent among people who are incarcerated. Provision of opioid agonist treatment (OAT) has been shown to reduce risk of HCV transmission in the community. Little is known about the navigation of HCV (re-)exposure in prisons, and people's experiences and utilisation of OAT as a risk reduction strategy while incarcerated. METHODS:Semi-structured interviews were completed with n=25 men incarcerated in an urban reception (intake) and remand (awaiting sentencing) prison in New South Wales, Australia. De-identified transcripts were coded deductively and analysed thematically, informed by a fragile treatment environment lens focused on OAT treatment as a risk mitigation strategy for HCV (re-)exposure. RESULTS:Overall, 25 men were included (all had previously been diagnosed with HCV, 13 were receiving long-acting injectable buprenorphine). Participants viewed risk of HCV (re-)exposure as part of injecting drug use in prison. Participants who were prescribed long-acting injectable buprenorphine described the treatment as supporting reduced injection drug use while incarcerated. However, OAT dosage was not always experienced as 'adequate', with some participants reporting supplementing with 'the yard program' (injecting drug use in the yard/cells) as the prescribed OAT dose lacked effectiveness to sustain until the next dose. Continuity of care was tenuous as people cycled from prison to community to prison, with people being removed from their OAT program after missing a scheduled dose in the community often due to a participant being 'on the run'. CONCLUSION:Continuity of OAT and HCV care remains a fragile experience for people who cycle in and out of incarceration. People who miss their OAT appointment in the community might wait several months upon re-incarceration to re-enter the OAT program. This leaves people vulnerable to injection sharing in custody and, subsequently, increased risk of HCV (re-)exposure while waiting to recommence OAT or to return to the optimal dosing level.

Background: Chronic graft-versus-host disease (cGvHD) - a potentially debilitating complication of allogeneic hematopoietic stem cell transplantation - is a rare condition. Objectives: This vignette-based study aimed to generate utility values to inform an economic model via an online survey wherein cGvHD health state (HS) vignettes were valued by the general UK population using the EQ-5D-5L and the EQ-5D-visual analog scale (EQ-5D VAS). Methods: This non-interventional health-related quality of life (HRQoL) study was conducted in 3 stages across the UK: the development, validation, and valuation of HS vignettes to generate utility values for cGvHD. Four HS for cGvHD were defined based on an economic model partitioning different treatment level responses in patients with cGvHD receiving third-line (3L) therapy (HS1: complete response, HS2: partial response, HS3: lack of response, and HS4: recurrent cGvHD). Draft vignettes were developed for each HS based on 4 previously published GvHD vignettes. The contents of the draft vignettes were reviewed for all aspects of cGvHD symptoms and functional impact and validated through semistructured interviews with 5 clinical experts. The 4 finalized HS vignettes were valued by 300 participants from the UK general population using EQ-5D-5L and EQ-5D VAS. Results: Previously published vignettes were used to develop the vignettes for the current study that described GvHD in the context of blood cancer and other rare blood disorders (n = 2 each) and included symptoms, functioning, and quality of life for a patient in the HS. The highest and lowest mean EQ-5D-5L utility scores were observed for HS1 (mean [95% CI]: 0.577 [0.558-0.595]) and HS4 (0.061 [0.034-0.088]), respectively. The EQ-5D-VAS showed the highest and lowest mean utility scores for HS1 (46.8 [44.9-48.6]) and HS4 (25.6 [23.4-27.7]), respectively. Conclusion: This study generated utility values for HS vignettes describing symptoms, functioning, and HRQoL for patients with cGvHD receiving 3L therapy. The utility values highlighted a substantial burden of cGvHD and HRQoL impact associated with the treatment response level. However, assessing concordance between utility estimates derived from the vignette-based method in a general population and those from patients with cGvHD is further warranted.

Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. This definition can be divided into intrinsic fitness—fitness without immune pressure—and effective fitness, which includes immune influence. Co-occurring mutations outside immune-targeted epitope regions may also affect variant survival (epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Using a rare cohort of subjects recently infected with HCV, we build on prior work by integrating mathematical modeling and experimental data to examine the interplay between transmitted/founder (T/F) viruses, immune responses, fitness, and co-occurring mutations. We show that viral fitness declines during the first 90 days post-infection (DPI), associated with the magnitude of CD8 +T cell responses and early diversification. Fitness then rebounds in a complex pattern marked by co-occurring mutations. Finally, we demonstrate that an early, strong CD8 +T cell response in the absence of neutralizing antibodies (nAbs) exerts strong selective pressure, allowing escape and chronic infection. These insights support HCV vaccine strategies that elicit broad T and B cell immunity.

Limited surveillance data have hindered understanding of SARS-CoV-2 transmission within prisons. We integrated routine surveillance data with viral sequencing to investigate transmission dynamics and associated factors during a Delta variant outbreak in a maximum-security prison in Sydney, New South Wales, Australia. Infection incidence and associated factors were determined by using person-time and Cox regression. We generated transmission chains by integrating epidemiologic and viral sequencing data. Of 1,562 patients, SARS-CoV-2 infection was diagnosed in 169 (11%), predominantly acquired in prison and asymptomatic. Prisonwide testing identified substantial unrecognized transmission, and 4 subvariants indicated multiple viral introductions. Infection was associated with housing location, having a cellmate (regardless of infection status), and vaccination status. Our findings underscore the inadequacy of symptom-based testing and the efficacy of entry-quarantine, strategic housing, extensive testing, and vaccination in reducing transmission. This integrated approach to surveillance and genomic sequencing offers a valuable model for enhancing infectious disease surveillance in correctional settings.

Background Complaints of chronic fatigue lasting weeks or longer are common during adolescence. Little is known about factors associated with chronic fatigue in youth with mood disorders or potential sex-specific associations. Methods 496 young people (mean age = 18.36-years, SD = 3.22; 69 % female) seeking help for mental healthcare were assessed on psychological symptoms, lifestyle, and sleep at baseline and 12-months later. Fatigue was defined as a score of ≥3 on the somatic subscale of the Somatic and Psychological Health Report. Logistic regression models were used to examine associations between clinical, lifestyle, and related factors and chronic fatigue caseness, including main effects and sex interactions. Results Half (52 % [N = 260]) of the sample reported fatigue at both baseline and 12-month follow-up (“chronic fatigue”). Univariately, chronic fatigue cases were more commonly at later clinical stages of mental disorder and had worse mental health, sleep disturbance, and disability at baseline and follow-up. In covariate-adjusted analyses, being a chronic fatigue case was associated with persistently elevated anxiety and, at 12-month follow-up, more disability, weight gain, and shorter sleep duration. In sex-interaction analyses, chronic fatigue in females was associated with longer sleep latency at follow-up (OR = 1.97), but not in males. Conclusion Chronic fatigue was common and associated with poorer mental health and functioning longitudinally. While there were no sex differences in the rates of chronic fatigue, there were some sex differences in the factors associated with it. Systematic screening and early intervention for chronic fatigue, considering sex-specific factors, may improve multidimensional outcomes in youth with emerging mood disorders.

Hepatitis C virus (HCV) exists as a heterogenous quasispecies, but the phenotypic consequences of viral variability are widely unexplored. Here we identify a replication enhancing domain (ReED) in non-structural protein 5A conferring high replication fitness to clinical isolates. Accumulation of mutations in the ReED mediates high genome replication capacity. In a cohort of liver transplant patients, high replicator variants are exclusively found in individuals with severe disease outcome, suggesting that high viral replication fitness is associated with increased viral pathogenesis. Analysis of large sequence cohorts reveals that overall only 10% of viral genomes show genetic signatures of high replicators, which are enriched in recipients of liver transplantations, patients developing hepatocellular carcinoma and in HIV coinfected individuals. Overall, our data suggests that low replication fitness is a hallmark of HCV, contributing to establishment of persistence, whereas high replicators appear to have an advantage under conditions of immune suppression, thereby enforcing pathogenesis.

BACKGROUND:AADCd is a rare neurometabolic disorder presenting in infancy. Children with AADCd have motor dysfunction and development delays that result in the need for lifelong care; quality of life is greatly impacted. Current characterizations of health-related quality of life and associated health state utilities (HSUs) may be underestimated in AADCd. Accurate characterization of AADCd burden is important when evaluating the benefits of treatment, especially the improvements observed with the recently approved disease-modifying therapy eladocagene exuparvovec. Time-trade-off (TTO) vignette methods may be used to elicit HSUs in AADCd for assessing the value of new treatments. This study aimed to first update previously published health state vignettes, then estimate AADCd HSUs in the United States (US). METHODS:Existing vignettes for five AADCd health states were updated based on the review of published literature and clinician/caregiver input. Health states included: "bedridden/no motor function," "head control," "sitting unassisted," "standing with support," "walking with assistance." Online composite TTO interviews were conducted 1:1 with adults from the US general public. Participants ranked health states in order of preference using a visual analog scale, then were presented with health state vignettes to elicit utilities using TTO. Mean TTO scores were calculated for each health state, and regression models were used to estimate disutility associated with use of feeding tube. RESULTS:Following revision of the vignettes, 120 participants completed the TTO task (mean age: 47 years; 50% female; 70% White); characteristics were not significantly different from US population norms in terms of age, sex, race or ethnicity. Six participants who appeared to misunderstand the exercise were excluded. Mean (SD) HSUs were: -0.258 (0.534) for bedridden state, -0.155 (0.569) for head control, 0.452 (0.523) for sitting unassisted, 0.775 (0.242) for standing with support, and 0.796 (0.235) for walking with assistance. The need for a feeding tube was associated with a disutility of 0.07. CONCLUSIONS:This study implemented TTO methods to estimate utilities for five health states which reflect the burden and impact of AADCd. The range in values from the most to least severe health state suggests that there is potential for effective treatments to substantially improve quality of life in these patients.