Biological Insights from Schizophrenia-associated Loci in Ancestral Populations.

Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals - near PLXNA4, PMAIP1, and TRPA1 - are the first to be independently identified in populations of predominantly African ancestry. Joint analyses of African, European, and East Asian ancestries across 86,981 cases and 303,771 controls, yielded 376 distinct autosomal loci, which were refined to 708 putatively causal variants via multi-ancestry fine-mapping. Utilizing single-cell functional genomic data from human brain tissue and two complementary approaches, transcriptome-wide association studies and enhancer-promoter contact mapping, we identified a consensus set of 94 genes across ancestries and pinpointed the specific cell types in which they act. We identified reproducible associations of schizophrenia polygenic risk scores with schizophrenia diagnoses and a range of other mental and physical health problems. Our study addresses a longstanding gap in the generalizability of research findings for schizophrenia across ancestral populations, underlining shared biological underpinnings of schizophrenia across global populations in the presence of broadly divergent risk allele frequencies.

Centralized Quality Assurance of Stereotactic Body Radiation Therapy for the Veterans Affairs Cooperative Studies Program Study Number 2005: A Phase 3 Randomized Trial of Lung Cancer Surgery or Stereotactic Radiotherapy for Operable Early-Stage Non-Small Cell Lung Cancer (VALOR).

BACKGROUND: The phase III Veterans Affairs Lung cancer surgery Or stereotactic Radiotherapy (VALOR) study implemented centralized quality assurance (QA) to mitigate risks of protocol deviations. This report summarizes quality and compliance for the first 100 participants treated with SBRT in this study. METHODS: A centralized QA program was developed to credential and monitor study sites to ensure standard-of-care lung stereotactic body radiation therapy (SBRT) treatments are delivered to participants. Requirements were adapted from protocols established by the National Cancer Institute's Image and Radiation Oncology Core, which provides oversight for clinical trials sponsored by the NCI's National Clinical Trials Network. RESULTS: The first 100 lung SBRT treatment plans were reviewed from April 2017 to October 2022. Tumor contours were appropriate in all submissions. PTV expansions were less than the minimum 5 mm requirement in 2% of cases. Critical organ-at-risk (OAR) structures were contoured accurately for the proximal bronchial tree, trachea, esophagus, spinal cord, and brachial plexus in 75%, 92%, 100%, 100%, and 95% of cases. Prescriptions were appropriate in 98% of cases; two central tumors were treated using a peripheral tumor dose prescription while meeting OAR constraints. PTV V100% values were above the protocol-defined minimum of 94% in all but one submission. The median Dmax within the PTV was 125.4% (105.8% - 149.0%, standard deviation ±8.7%). High-dose conformality (<1.2) and intermediate-dose compactness (R50% and D2cm) indices were acceptable or deviation acceptable in 100% and 94% of cases, respectively. CONCLUSIONS: The first 100 participants randomized to SBRT in this study were appropriately treated without safety concerns. A response to the incorrect prescriptions led to preventative measures without further recurrences. The program was developed in a healthcare system without prior experience with a centralized RT QA program and may serve as a reference for other institutions.

Exoskeletal-Assisted Walking in Veterans With Paralysis: A Randomized Clinical Trial.

Importance: Robotic exoskeletons leverage technology that assists people with spinal cord injury (SCI) to walk. The efficacy of home and community exoskeletal use has not been studied in a randomized clinical trial (RCT). Objective: To examine whether use of a wheelchair plus an exoskeleton compared with use of only a wheelchair led to clinically meaningful net improvements in patient-reported outcomes for mental and physical health. Design, Setting, and Participants: This RCT of veterans with SCI was conducted at 15 Veterans Affairs medical centers in the US from September 6, 2016, to September 27, 2021. Data analysis was performed from March 10, 2022, to June 20, 2024. Interventions: Participants were randomized (1:1) to standard of care (SOC) wheelchair use or SOC plus at-will use of a US Food and Drug Administration (FDA)-cleared exoskeletal-assisted walking (EAW) device for 4 months in the home and community. Main Outcomes and Measures: Two primary outcomes were studied: 4.0-point or greater improvement in the mental component summary score on the Veterans RAND 36-Item Health Survey (MCS/VR-36) and 10% improvement in the total T score of the Spinal Cord Injury-Quality of Life (SCI-QOL) physical and medical health domain and reported as the proportion who achieved clinically meaningful changes. The primary outcomes were measured at baseline, post randomization after advanced EAW training sessions, and at 2 months and 4 months (primary end point) in the intervention period. Device usage, reasons for not using, and adverse events were collected. Results: A total of 161 veterans with SCI were randomized to the EAW (n = 78) or SOC (n = 83) group; 151 (94%) were male, the median age was 47 (IQR, 35-56) years, and median time since SCI was 7.3 (IQR, 0.5 to 46.5) years. The difference in proportion of successes between the EAW and SOC groups on the MCS/VR-36 (12 of 78 [15.4%] vs 14 of 83 [16.9%]; relative risk, 0.91; 95% CI, 0.45-1.85) and SCI-QOL physical and medical health domain (10 of 78 [12.8%] vs 11 of 83 [13.3%]; relative risk, 0.97; 95% CI, 0.44-2.15) was not statistically different. Device use was lower than expected (mean [SD] distance, 1.53 [0.02] miles per month), primarily due to the FDA-mandated companion being unavailable 43.9% of the time (177 of 403 instances). Two EAW-related foot fractures and 9 unrelated fractures (mostly during wheelchair transfers) were reported. Conclusions and Relevance: In this RCT of veterans with SCI, the lack of improved outcomes with EAW device use may have been related to the relatively low device usage. Solutions for companion requirements and user-friendly technological adaptations should be considered for improved personal use of these devices. Trial Registration: ClinicalTrials.gov Identifier: NCT02658656.

Abdominal Noncontrast Computed Tomography Scanning to Screen for Kidney Cancer and Other Abdominal Pathology Within Community-based Computed Tomography Screening for Lung Cancer: Results of the Yorkshire Kidney Screening Trial.

BACKGROUND AND OBJECTIVE: The Yorkshire Kidney Screening Trial (YKST) assessed the feasibility of adding abdominal noncontrast computed tomography (NCCT) to lung cancer screening to screen for kidney cancer and other abdominal pathology. METHODS: A prospective diagnostic study offered abdominal NCCT to 55-80-yr-old ever-smokers attending a UK randomised lung cancer screening trial (May 2021 to October 2022). The exclusion criteria were dementia, frailty, previous kidney/lung cancer, and computed tomography (CT) of the abdomen and thorax within previous 6 and 12 mo, respectively. Six-month follow-up was undertaken. KEY FINDINGS AND LIMITATIONS: A total of 4438 people attended lung screening, of whom 4309 (97%) were eligible for and 4019 (93%) accepted abdominal NCCT. Only 3.9% respondents regretted participating. The additional time to conduct the YKST processes was 13.3 min. Of the participants, 2586 (64%) had a normal abdominal NCCT, whilst 787 (20%) required an abdominal NCCT imaging review but no further action and 611 (15%) required further evaluation (investigations and/or clinic). Of the participants, 211 (5.3%) had a new serious finding, including 25 (0.62%) with a renal mass/complex cyst, of whom ten (0.25%) had histologically proven kidney cancer; ten (0.25%) with other cancers; and 60 (1.5%) with abdominal aortic aneurysms (AAAs). Twenty-five (0.62%) participants had treatment with curative intent. Of the participants, 1017 (25%) had nonserious findings, most commonly benign renal cysts (727 [18%]), whereas only 259 (6.4%) had nonserious findings requiring further tests. The number needed to screen to detect one serious abdominal finding was 18; it was 93 to detect one suspicious renal lesion and 402 to detect one histologically confirmed renal cancer. Limitations of the cohort were fixed age range and being prior lung cancer screening attendees. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this first prospective risk-stratified screening study of abdominal NCCT offered alongside CT thorax, uptake and participant satisfaction were high. The prevalence of serious findings, cancers, and AAAs, is in the range of established screening programmes such as bowel cancer. Longer-term outcomes and cost effectiveness should now be evaluated.

Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

The power and pitfalls of underpowered studies.

This article reflects on the potential value and many pitfalls of underpowered studies to help authors and readers consider whether and how they contribute meaningfully to the published literature. A basic introduction to power and sample size calculations is provided. Several problems that can arise in analysis and publication of underpowered studies are described. In addition, features of underpowered studies that may provide value are proposed, including when the hypothesis test of interest is a limited part of the story, the data is rich enough to showcase interesting features of the population of interest, when the rarity or ubiquity of events is an important finding, and when the study is preregistered to reduce the impact of publication bias. Several reporting guidelines for underpowered studies are also suggested.

How recovery definitions vary by service use pathway: Findings from a national survey of adults.

OBJECTIVE: How people define recovery may affect their recovery goals, service use, and ultimately their outcomes. We examined recovery definitions among adults in recovery from an alcohol use disorder (AUD) who had different service use histories. METHOD: We analyzed online survey data from 1,492 adults with resolved lifetime AUD in "treated recovery" (any use of specialty services, such as inpatient or outpatient rehabilitation; n = 375), "assisted recovery" (any use of lay services, such as mutual-help groups, and no use of specialty services; n = 174), or "independent recovery" (no use of specialty or lay services; n = 943). Surveys assessed recovery definitions using the 39-item What Is Recovery? (WIR) scale. We compared endorsement of WIR domains and individual recovery elements across groups using survey-weighted chi-square tests and logistic regression. RESULTS: Endorsement of WIR scale domains was significantly lower among the independent than treated and assisted groups, but few differences emerged between the treated and assisted groups. Two recovery elements were endorsed by approximately equivalent majorities of all groups: "being honest with myself" (92.7%-94.8%) and "taking care of my physical health" (87.4%-90.9%). Five additional elements were similarly endorsed by large majorities (≥ 85%) in each group, albeit at lower levels in the independent group. CONCLUSIONS: People who have experienced AUD and have not obtained alcohol services may have a narrower definition of recovery compared to those accessing treatment or attending mutual-help groups. This suggests a need to broaden alcohol services to better match varied recovery definitions; however, some highly endorsed elements suggest commonalities across recovery pathways. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Identifying the facilitators and barriers to implementation of renal tumour biopsy in the diagnostic pathway for small renal masses.

OBJECTIVES: To understand the facilitators and barriers to the implementation of renal tumour biopsy (RTB) in the diagnostic pathway for renal tumours in England. PATIENTS AND METHODS: Participants consisted of patients who had a renal tumour diagnosed and/or treated at one of five tertiary centres in England, healthcare professionals involved in the direct care of patients diagnosed with renal tumours, and clinical service managers and commissioners. The study employed a mixed-methods research methodology consisting of individual interviews and an on-line survey that explored the types of facilitators and barriers individuals perceived and experienced and the frequency in which these were reported. A public dissemination event took place following the completion of data collection; to facilitate discussion of potential solutions to implementing RTB. RESULTS: There were 50 participant interviews (23 patients, 22 clinicians, and five health service commissioners/operations managers). The patient on-line survey received 52 responses, and the clinician survey received 22 responses. Patients most frequently reported influences in choosing whether to undergo RTB pertained to wanting to know the diagnosis of their kidney mass (40%), the advice or information provided by healthcare professionals (40%), and not wishing to delay treatment (23%). Clinicians most frequently reported barriers to recommending RTB related to their uncertainty of diagnostic accuracy (56%), availability of appointments or hospital beds (52%), concerns of risk of bleeding (44%), risk of seeding (41%), and delays in meeting national cancer pathway targets (41%). The dissemination event was attended by 18 participants (seven patients and 11 clinicians). Suggestions to improve implementation included reducing variation and promotion of standardisation of practice by a consensus statement, increasing the evidence base (clinicians) and improved communication by developing better patient aids such as videos and diagrams (patients and clinicians). CONCLUSION: Implementation of RTB may be dependent on the quality of information provided, its format and perceived reliability of the information. Increased utilisation of RTB may be improved by development of a consensus statement on the role of biopsy, with patients expressing a preference for alternative information aids such as patient videos.

Acceptability of adding a non-contrast abdominal CT scan to screen for kidney cancer and other abdominal pathology within a community-based CT screening programme for lung cancer: A qualitative study.

OBJECTIVES: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal malignancies to community-based CT screening for lung cancer within the Yorkshire Lung Screening Trial (YLST). This study explored the acceptability of the combined screening approach to participants and healthcare professionals (HCPs) involved in the trial. METHODS: We conducted semi-structured interviews with eight HCPs and 25 participants returning for the second round of scanning within YLST, 20 who had taken up the offer of the additional abdominal CT scan and five who had declined. Transcripts were analysed using thematic analysis, guided by the Theoretical Framework of Acceptability. RESULTS: Overall, combining the offer of a non-contrast abdominal CT scan alongside the low-dose thoracic CT was considered acceptable to participants, including those who had declined the abdominal scan. The offer of the additional scan made sense and fitted well within the process, and participants could see benefits in terms of efficiency, cost and convenience both for themselves as individuals and also more widely for the NHS. Almost all participants made an instant decision at the point of initial invitation based more on trust and emotions than the information provided. Despite this, there was a clear desire for more time to decide whether to accept the scan or not. HCPs also raised concerns about the burden on the study team and wider healthcare system arising from additional workload both within the screening process and downstream following findings on the abdominal CT scan. CONCLUSIONS: Adding a non-contrast abdominal CT scan to community-based CT screening for lung cancer is acceptable to both participants and healthcare professionals. Giving potential participants prior notice and having clear pathways for downstream management of findings will be important if it is to be offered more widely.

Incremental Application of Positive End-Expiratory Pressure for the Evaluation of Atelectasis During RP-EBUS and Bronchoscopy (I-APPEAR).

BACKGROUND: CT-to-body divergence-described as the difference between preprocedural CT scans and intraprocedural lung architecture-is a significant barrier to improving diagnostic yield during navigational bronchoscopy. A major proposed contributor to CT-to-body divergence is the development of atelectasis, which can confound visualization of peripheral lung lesions via radial probe endobronchial ultrasound (RP-EBUS). High positive end-expiratory pressure (PEEP) ventilatory strategies have been used to decrease atelectasis, allowing the lesion to re-APPEAR on intraprocedure imaging. However, standardized PEEP levels may not be appropriate for all patients due to hemodynamic and ventilatory impacts. METHODS: We performed a multicenter, prospective observational study in which patients were imaged with RP-EBUS under general anesthesia to determine if subsegmental atelectasis would resolve as incremental increases in PEEP were applied. Resolution of atelectasis was based on the transition from a non-aerated pattern to an aerated appearance on RP-EBUS. RP-EBUS images were reviewed by 3 experienced operators to determine correlation. RESULTS: Forty-three patients underwent RP-EBUS examination following navigational bronchoscopy. Thirty-seven patients underwent incremental PEEP application and subsequent RP-EBUS imaging. Atelectasis was determined to have resolved in 33 patients (88.2%) following increased PEEP. The intraclass correlation coefficient between reviewers was 0.76. A recruitment maneuver was performed in 7 (16.3%) patients after atelectasis persisted at maximal PEEP. Atelectasis was not identified in the examined subsegments in 6 (10.8%) patients despite zero PEEP. CONCLUSION: RP-EBUS is an effective tool to monitor what pressure atelectasis within a lung segment has resolved with increasing levels of PEEP.

The Troubling Rise of Scurvy: A Review and National Analysis of Incidence, Associated Risk Factors, and Clinical Manifestations.

INTRODUCTION: In the era of modern medicine, scurvy has been thought of as a rare disease of ancient times because of improved emphasis on diet and nutrition; however, isolated case reports are plentiful. This investigation presents a comprehensive review of scurvy, including an analysis on its rising incidence, with specific focus on its orthopaedic manifestations and commonly associated diagnoses. METHODS: This comprehensive review includes a retrospective analysis of 19,413,465 pediatric patients in the National Inpatient Sample database from 2016 through 2020. Patients with scurvy were identified by the ICD-10 code, and an estimated incidence of scurvy in the inpatient pediatric population was calculated. Concurrent diagnoses, musculoskeletal reports, and demographic variables were collected from patient records. Comparisons were made using analysis of variance or chi-square with Kendall tau, where appropriate. RESULTS: The incidence of scurvy increased over the study period, from 8.2 per 100,000 in 2016 to 26.7 per 100,000 in 2020. Patients with scurvy were more likely to be younger (P < 0.001), male (P = 0.010), in the lowest income quartile (P = 0.013), and obese (P < 0.001). A majority (64.2%) had a concomitant diagnosis of autism spectrum disorder. Common presenting musculoskeletal reports included difficulty walking, knee pain, and lower limb deformity. Burden of disease of scurvy was markedly greater than that of the average inpatient population, with these patients experiencing greater total charges and longer hospital stays. CONCLUSION: Clinicians should be aware of the increasing incidence of scurvy in modern medicine. In cases of vague musculoskeletal reports without clear etiology, a diagnosis of scurvy should be considered, particularly if risk factors are present. TRIAL REGISTRATION NUMBER: NA.

High-resolution and highly accelerated MRI T2 mapping as a tool to characterise renal tumour subtypes and grades.

BACKGROUND: Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades. METHODS: Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades. RESULTS: High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037). CONCLUSIONS: Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03741426 . Registered on 13 November 2018. RELEVANCE STATEMENT: The newly developed T2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses.

Wombat burrows are hotspots for small vertebrates in a landscape subject to gigafire.

Ecosystem engineers modify their environment and influence the availability of resources for other organisms. Burrowing species, a subset of allogenic engineers, are gaining recognition as ecological facilitators. Burrows created by these species provide habitat for a diverse array of other organisms. Following disturbances, burrows could also serve as ecological refuges, thereby enhancing ecological resistance to disturbance events. We explored the ecological role of Common Wombat (Vombatus ursinus) burrows using camera traps in forests of southeastern Australia. We compared animal activity at paired sites with and without burrows, from the same fire severity class and habitat. We examined how animal activity at Common Wombat burrows was affected by the 2019-20 Black Summer bushfires in Australia. We predicted that burrows would serve as hotspots for animal activity and as refuges in burned areas. The activity of several species including Bush Rat (Rattus fuscipes), Agile Antechinus (Antechinus agilis), Lace Monitor (Varanus varius), Painted Button-quail (Turnix varius), and Grey Shrike-thrush (Colluricincla harmonica) increased at sites where Common Wombat burrows were present, while other species avoided burrows. Species that were more active at burrows tended to be smaller mammal and bird species that are vulnerable to predation, whereas species that avoided burrows tended to be larger mammals that might compete with Common Wombat for resources. Species composition differed between sites with and without burrows, and burrow sites had higher native mammal species richness. The association of several species with burrows persisted or strengthened in areas that burned during the 2019-20 Black Summer bushfires, suggesting that Common Wombat burrows may act as ecological refuges for animals following severe wildfire. Our findings have relevance for understanding how animals survive, persist, and recover following extreme wildfire events.

Effects of spaceflight on the brain.

The number of long duration human spaceflights has increased substantially over the past 15 years, leading to the discovery of numerous effects on the CNS. Microgravity results in headward fluid shifts, ventricular expansion, an upward shift of the brain within the skull, and remodelling of grey and white matter. The fluid changes are correlated with changes to perivascular space and spaceflight associated neuro-ocular syndrome. Microgravity alters the vestibular processing of head tilt and results in reduced tactile and proprioceptive inputs during spaceflight. Sensory adaptation is reflected in postflight effects, evident as transient sensorimotor impairment. Another major concern is that galactic cosmic radiation, which spacefarers will be exposed to when going beyond the magnetosphere around Earth, might have a negative effect on CNS function. Research with rodents points to the potential disruptive effects of space radiation on blood-brain barrier integrity and brain structures. More work is needed to understand and mitigate these effects on the CNS before humans travel to Mars, as the flight durations will be longer than anyone has previously experienced.

Mapping the Evolutionary Space of SARS-CoV-2 Variants to Anticipate Emergence of Subvariants Resistant to COVID-19 Therapeutics.

New sublineages of SARS-CoV-2 variants-of-concern (VOCs) continuously emerge with mutations in the spike glycoprotein. In most cases, the sublineage-defining mutations vary between the VOCs. It is unclear whether these differences reflect lineage-specific likelihoods for mutations at each spike position or the stochastic nature of their appearance. Here we show that SARS-CoV-2 lineages have distinct evolutionary spaces (a probabilistic definition of the sequence states that can be occupied by expanding virus subpopulations). This space can be accurately inferred from the patterns of amino acid variability at the whole-protein level. Robust networks of co-variable sites identify the highest-likelihood mutations in new VOC sublineages and predict remarkably well the emergence of subvariants with resistance mutations to COVID-19 therapeutics. Our studies reveal the contribution of low frequency variant patterns at heterologous sites across the protein to accurate prediction of the changes at each position of interest.

Realising a global One Health disease surveillance approach: insights from wastewater and beyond.

One Health is a recognition of the shared environment inhabited by humans, animals and plants, and the impact of their interactions on the health of all organisms. The COVID-19 pandemic highlighted the need for a framework of pathogen surveillance in a tractable One Health paradigm to allow timely detection and response to threats to human and animal health. We present case studies centered around the recent global approach to tackle antimicrobial resistance and the current interest in wastewater testing, with the concept of "one sample many analyses" to be further explored as the most appropriate means of initiating this endeavor.

Identifying Veterans Who Benefit From Nirmatrelvir-Ritonavir: A Target Trial Emulation.

BACKGROUND: Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed. METHODS: We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir-ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model. RESULTS: Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], -0.50% points [95% confidence interval {CI}: -.69 to -.35]) and death (0.11% vs 0.30%; RD, -0.20 [95% CI: -.24 to -.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD -2.85 [95% CI: -3.94 to -1.76]), immunocompromised persons (RD -1.91 [95% CI: -3.09 to -.74]), and persons aged ≥75 years (RD -1.16 [95% CI: -1.73 to -.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years. CONCLUSIONS: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death.