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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

Background: Orthopaedic sports medicine fellowships are highly competitive, yet objective data defining characteristics of successful applicants remain limited. Hypothesis: It was hypothesized that greater academic productivity, top-tier residency training, and certain demographic factors would be associated with matching into a top-ranked orthopaedic sports medicine fellowship. Study Design: Cross-sectional study. Methods: We retrospectively reviewed applicants who matched into one of the top 10 orthopaedic sports medicine fellowships from 2020 to 2025, as identified by previous applicant preference rankings. Applicant data were obtained from publicly available sources and verified by 2 independent reviewers. Variables included sex, degree type, residency program ranking, geographic region, and research productivity (total publications, primary publication count, H-index, and sports-related publications). Multivariate logistic regression assessed predictors of matching into top 5 versus 6th- to 10th-ranked programs. Results: Among 226 matched applicants, 87.7% were male and 99.1% held a doctorate in medicine degree. The mean total publication count was 12.4, mean H-index was 8.2, and 30.5% trained at a top 20 orthopaedic residency. Applicants matching into top 5 programs had significantly higher research metrics than those in the 6th- to 10th-ranked programs: total publications (20.1 vs 4.7), primary publication count (6.2 vs 1.6), and sports-related publications (11.4 vs 1.9). On regression analysis, total publications, H-index, and residency ranking were independent predictors of matching into a top 5 program. Conclusion: Matching into a top orthopaedic sports medicine fellowship is associated with higher academic productivity and training at a top-tier residency program.

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.

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.

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.

Abstract Background In patients with heart failure with preserved ejection fraction (HFpEF), studies have described different HFpEF phenogroups based on medical comorbidities and variable echocardiographic, invasive hemodynamic, and biomarker data. We hypothesized that myocardial histopathologic findings may define phenogroups with differing clinical features and outcomes in patients with HFpEF. Methods We analyzed consecutive patients with left HF and EF ≥50% who underwent right ventricular septal endomyocardial biopsy (EMB) at our institution between 2001 and 2022 to investigate HF etiology. Patients with infiltrative or hypertrophic cardiomyopathy, sarcoidosis, myocarditis, primary valvular heart disease, constrictive pericarditis, isolated right HF, or insufficient EMB samples were excluded. Clinical, echocardiographic, and invasive hemodynamic data were collected. The severity of hypertrophy and fibrosis on EMB specimens was characterized (semiquantitative grading) by experienced cardiac pathologists based on standard histologic stains. Patients were stratified into four phenogroups based on EMB findings: "mild" (none/mild hypertrophy and fibrosis), "hypertrophy" (moderate/marked hypertrophy, minimal/mild fibrosis), "fibrosis" (moderate/marked fibrosis, none/mild hypertrophy), and "severe" (moderate/marked hypertrophy and fibrosis). Results Among the 121 patients analyzed, the median age was 67 years, 50% were female and cardiovascular conditions were common (Table 1). Fibrosis was graded as minimal in 21% (n=25), mild in 64% (n=77), moderate in 12% (n=15), and marked in 3% (n=4). Hypertrophy was graded as none in 4% (n=5), mild in 41% (n=50), moderate in 40% (n=48), and marked in 15% (n=18). Only one patient had the isolated "fibrosis" phenogroup and was excluded from further analysis, while 54 had the "mild", 48 had the "hypertrophy", and 18 had the "severe" phenogroup (Table 1). The "hypertrophy" phenogroup exhibited significantly higher rates of hypertension, diabetes, RV dilation, and higher pulmonary artery pressures. Over a median follow-up of 7.9 years (3.1–13.8), mortality rate varied according to the histopathologic phenogroups (Figure 1, p=0.034) with "severe" having the worst and "mild" having the best outcomes. Survival analyses based on fibrosis grades alone, hypertrophy grades alone, or echocardiographic hypertrophy did not reveal significant differences (all p = NS). Differences in survival remained significant adjusting for age (HR 3.39, 95% CI 1.20-9.58). Conclusions The integrated severity of histopathologic hypertrophic and fibrotic remodeling defined HFpEF phenogroups with variable prognosis. Clinical features did not reliably identify histopathologic phenogroups. These data suggest that advanced myocardial phenotyping (e.g., gene, protein, metabolism) may reveal unique HFpEF myocardial subtypes in need of specific therapies.Figure 1

The first Introduction to Clinical Research for Academic Anesthesiologists (ICRAA) Course took place from July 2024 through April 2025 via online interactive lectures. The 9-month course provided participants with the skills necessary to ethically design research proposals and conduct research projects. Some of the core principles taught included basics of biostatistics, ways to effectively communicate ideas to data analysts, how to write a grant, and tips on writing and analyzing scientific articles. In this report, we summarize the motivation, describe the content, and provide future directions for this initiative, which aims to foster high-quality clinical research among the next generation of academic anesthesiologists.

Background: Internalized HIV stigma (IHS) is associated with reductions in antiretroviral therapy (ART) adherence and HIV viremia mediated through depression. However, there is still a need to quantify the direct impact of IHS on ART adherence to inform interventions to improve medication adherence. Methods: The Center for AIDS Research Network of Integrated Clinical Systems is a longitudinal, US-based, multisite cohort of people with HIV who complete patient-reported outcome assessments as part of HIV-care visits. Patient-reported outcome data include IHS items, ART adherence, depression assessments, substance use, and other outcomes. We examined associations between IHS and ART adherence using generalized linear latent and mixed models with a nonparametric random effects intercept to accommodate repeated measures. Results were compared with analyses using generalized estimating equations and marginal structural models. Results: Among 13,119 people with HIV, the mean age was 47.4 years, 17.6% were women, and 59.3% were non-White. Across 33,139 observations, controlled for repeated measures on individuals, HIV medication adherence was reduced by 1.07% for every point increase in IHS after controlling for age, sex, ethnicity, geographic location, and substance use, and 0.58% when additionally adjusted for depression score. Marginal structural models and generalized estimating equations provided similar results. Conclusions: Our study demonstrates that IHS has a direct association with reductions in ART adherence, which could affect other comorbid health outcomes that are influenced by unsuppressed viremia over time. Developing a thorough understanding of the mechanisms through which IHS affects ART adherence is critical for developing interventions to mitigate IHS and improve health outcomes across the lifespan.

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.

ABSTRACT Objective We sought to characterize the sixth most common finding in our neuroimmunological laboratory practice (tissue assay‐observed unclassified neural antibodies [UNAs]), combining protein microarray and phage immunoprecipitation sequencing (PhIP‐Seq). Methods Patient specimens (258; 133 serums; 125 CSF) meeting UNA criteria were profiled; October 2022–September 2023. Top‐ranking candidate antigens were validated in silico, by dual‐staining confocal microscopy, and ≥ 1 protein‐specific assay. Clinical data were reviewed. Results Among 21 patients, 11 autoantibodies were characterized (serum, 19; CSF, all 9 available). Autoantigens were CACNA1I, 1; CAMK2B, 2; CLIP2, 1; FMN2, 2; MAP1A, 2; MAP2, 5; NECAB1, 1; SNAP91, 3; SRCIN1, 1; SYNJ1, 1; SYT3, 2. Analytical validation was by confocal TIIFA (all), western blot (10/10 available), and cell‐based assay (5/5 performed). Clinical accompaniments were: encephalitis, 6; brainstem encephalitis, 2; encephalomyelitis, 2; cerebellar ataxia, 2; longitudinally extensive transverse myelitis (LETM), 2; sensory neuronopathy, 1; peripheral neuropathy, 4, and movement disorders, 2. Inflammatory MRI abnormalities were identified in 5/16 patients (31%) with CNS disorders: T2 signal change (2), LETM (2), leptomeningeal enhancement (1). Seven of 8 (88%) had inflammatory CSF (pleocytosis, 5 [median 25.5 cells, range 7–294]; elevated IgG index/synthesis rate, 4; CSF‐exclusive oligoclonal bands, 4). Six had paraneoplastic causation (lung cancer, 2; other, 4); 3 were postinfectious (1 each of COVID‐19, HSV‐1, and post‐Group A streptococcal infection). Of 9 immunotherapy‐treated patients, 5 improved. Interpretation UNAs are partly accounted for by a repertoire of diverse mostly intracellular synaptic antigens. Their characterization is expedited by protein arrays and PhIPSeq. Further individual studies are needed to assess them as disease biomarkers.