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Importance Transthyretin amyloid cardiomyopathy (ATTR-CM) is underdiagnosed despite expanding treatment options. Objective To develop and evaluate an artificial intelligence (AI)–augmented clinical program for ATTR-CM detection. Design, Setting, and Participants This nonrandomized clinical trial involved constructing an AI model, ATTRACTnet, using electrocardiogram waveforms, echocardiographic measurements, demographics, and diagnosis codes for orthopedic manifestations of amyloidosis. A single-system, multisite, single-arm, open-label trial was conducted to evaluate its real-world performance. The model was trained and validated at a large academic referral site for ATTR-CM with external validation at an academic site. The trial was conducted as a single-system, multisite trial. Patients with left ventricular (LV) wall thickness 12 mm or more and an ATTRACTnet score 0.5 or higher were eligible. Exclusions included prior ATTR-CM testing, hypertrophic cardiomyopathy, expected life span less than 1 year, nursing home residence, advanced dementia, or LV wall thickness less than 14 mm explained by uncontrolled hypertension or moderate/severe aortic stenosis. Intervention Eligible patients were notified and offered nuclear scintigraphy testing, monoclonal protein testing, and follow-up care on agreement from the treating physician. Main Outcomes and Measure The primary outcome was a diagnosis of ATTR-CM by consensus criteria. ATTR-CM testing positivity was compared with historical and contemporary controls. Results ATTRACTnet was developed in an internal test set of 799 patients (mean [SD] age, 75.1 [11.1] years; 516 [64.7%] male and 283 [35.3%] female) using 5-fold cross-validation with an additional external test set of 422 patients. It had good discrimination for ATTR-CM detection with an area under the receiver operator characteristic curve of 0.85 (5-fold cross-validation, 0.77-0.85) in the internal set and 0.82 (95% CI, .81-0.83) in the external test set with similar performance in Hispanic, non-Hispanic Black, and non-Hispanic White patients. A total of 1471 patients were identified with positive AI model scores 0.5 or more during the study period, with 256 eligible patients who met study criteria. Of these patients, 50 underwent amyloidosis testing after physician and patient approval; 24 (48%) were diagnosed with ATTR-CM, and 21 (88%) initiated treatment within 3 months. The positivity rate was more than 2.8 times higher than historical controls (15.3%; 95% CI, 13.1%-17.9%; P < .001), with an 18% relative increase in new diagnoses vs the prior year. Conclusions and Relevance AI-augmented screening may improve ATTR-CM detection and identify patients who are missed by usual care. Prospective randomized trials are needed to determine if outcomes are improved. Trial Registration ClinicalTrials.gov Identifier: NCT06469372

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Abstract Key unanswered questions in biology center on the causes, consequences, and maintenance of sexual reproduction (“sex”). Genome-driven processes are central to the evolutionary and genetic mechanisms inherent to sex, making genomic resources a fundamental part of answering these questions. We present the first genome assembly for a species that is uniquely well-suited for the study of (a)sex in nature, Potamopyrgus antipodarum. This New Zealand snail is unusual in featuring multiple separate transitions from obligately sexual to obligately asexual reproduction, leading to the coexistence of phenotypically similar sexual and asexual forms, a feature that is required to directly study the maintenance of sex. These separately derived asexual lineages constitute separate evolutionary experiments, providing a powerful means of characterizing how the absence of sex affects genome evolution. Our genome assembly provides critical steps toward understanding the causes and consequences of sex in this system and important resources for the rapidly growing P. antipodarum and molluscan genomics research community. In characterizing this genome, we uncovered unexpected evidence for a recent whole-genome duplication (WGD) in P. antipodarum. This discovery sets the stage for using P. antipodarum to evaluate processes of rediploidization following WGD and to assess whether WGD might drive transitions to asexuality.

Importance The long-term outcomes of surgery for pediatric traumatic cataract are not well described; understanding these outcomes would inform parental expectations. Objective To report visual acuity (VA) outcomes and cumulative incidence of ocular complications by 5 years following lensectomy for pediatric traumatic cataract. Design, Setting, and Participants This prospective cohort study was conducted across 32 sites in the US and Canada among 75 children undergoing lensectomy from birth to less than 13 years of age for unilateral traumatic cataract. Of 75 children, 60 had primary intraocular lens (IOL) placement; 15 were left aphakic. Data were collected from August 2012 to February 2020. Data analysis was performed from October 2022 to May 2025. Exposure Lensectomy. Main Outcomes and Measures The primary outcomes were best-corrected VA 5 years after lensectomy; period prevalence of strabismus and glaucoma (including cases diagnosed before lensectomy); surgery for visual axis opacification (VAO); and cumulative incidence of ocular complications by 5 years. Annual data collection was from medical record reviews through 5 years following lensectomy. Results Among 75 participants, 28 (37%) were female, and median (range) age at lensectomy was 7.4 years (0.1-13 years). Median (IQR) best-corrected VA at 5 years (available for 37 participants [49%]) was 20/63 (20/35-20/159) in pseudophakic eyes (n = 29; mean [SD] age at surgery, 7.2 [3.0] years) and 20/258 (20/56-<20/800) in aphakic eyes (n = 8; mean [SD] age at surgery, 5.5 [4.3] years). Age-normal VA was achieved by 6 pseudophakic eyes (21%; 95% CI, 10%-38%) and 1 aphakic eye (13%; 95% CI, 2%-47%). The 5-year period prevalence of glaucoma was 9% in pseudophakic eyes (95% CI, 1%-16%) and 9% in aphakic eyes (95% CI, 0%-24%). The 5-year cumulative incidence of surgery for VAO was 47% in pseudophakic eyes (95% CI, 31%-60%) and 13% in aphakic eyes (95% CI, 0%-28%). The risk was greater in eyes that did not undergo an anterior vitrectomy (84%; 95% CI, 55%-94%) vs eyes that did (15%; 95% CI, 2%-26%) (age-adjusted hazard ratio, 11.4; 95% CI, 4.6-33.1; P < .001). Conclusions and Relevance In this cohort study, while only half of the study participants had a 5-year follow-up visit, achieving age-normal VA was uncommon among the cohort in whom a best-corrected VA was determined. The prevalence of glaucoma at 5 years was low among those with 5-year follow-up, while nearly half of the pseudophakic eyes needed surgery for VAO supporting the need to monitor these children.

Importance Metabolic dysfunction–associated steatohepatitis (MASH) represents a high, underprioritized burden among noncommunicable diseases (NCDs) and people living with type 2 diabetes (T2D). Objective To identify cost-effective management approaches to prevent, detect, and treat MASH and liver fibrosis in people living with T2D. Design, Setting, and Participants This economic evaluation consisted of a generalized cost-effectiveness analysis (GCEA) that was conducted for 12 countries (Brazil, Chile, Germany, Italy, Japan, Saudi Arabia, South Africa, Spain, Sweden, Tanzania, Thailand, and the United States), across all 6 World Health Organization (WHO) regions. A cohort state-transition model simulated liver disease development and its impact on a synthetic cohort, aged 19 years and older and living with T2D, over their lifespan across 10 liver health states. Exposures Using an 80% coverage level, 14 management approaches were compared, including screening via the Fibrosis-4 (FIB-4) test and Enhanced Liver Fibrosis (ELF) test or vibration-controlled transient elastography (VCTE) as well as treatment with pharmacological and nonpharmacological interventions. Main Outcomes and Measures The main outcomes were the average cost-effectiveness ratios (ACERs) and the incremental cost-effectiveness ratios (ICERs), which were used to construct care expansion paths by ranking the management approaches in order of cost-effectiveness. The main measures were the total incremental costs and the total incremental quality-adjusted life-years (QALYs) of each intervention. Results In this GCEA, the outcomes were evaluated with respect to country-specific willingness-to-pay thresholds. The standard of care had the lowest ACERs in 8 countries (not in Chile, Germany, Saudi Arabia, or the United States). Treatment with intensive lifestyle interventions (ILIs), after screening via ELF or VCTE, was cost-effective in all countries. ILIs and treatment with semaglutide was cost-effective in 11 countries (not in Tanzania); ILIs and treatment with resmetirom was cost-effective in 8 countries (not in Brazil, South Africa, Tanzania, or Thailand). Conclusion and Relevance In this economic evaluation, screening followed by ILIs was found to be a cost-effective management approach for MASH and liver fibrosis among people living with T2D in all countries. Screening followed by pharmacological treatment was cost-effective in most countries. These results can inform health policy decision-making and further the development of WHO recommended interventions to address NCDs.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.