Citations

BACKGROUND: Cardiac computed tomography (CT) acquired during the acute stroke imaging protocol is an emerging modality to detect cardiac thrombi. We determined its yield in patients with acute ischemic stroke. METHODS: We performed a 1-stage individual patient data meta-analysis of 4 prospective observational cohorts (AIS of HEARTS [Acute Ischemic Stroke of Heart-Related Embolic Sources Detected on Acute Cardiac CT Scans]), including patients with acute ischemic stroke who underwent ECG-gated or non–ECG-gated cardiac CT between May 2018 and June 2024. We excluded patients with transient ischemic attack or stroke mimics. The primary outcome was the proportion of patients with a thrombus on cardiac CT. Secondary outcomes were additional scan time, radiation dose, comparison with echocardiography, and 90-day outcomes. We performed logistic regression analyses to compare 90-day outcomes between patients with and without thrombus, adjusting for age, sex, history of atrial fibrillation, ischemic heart disease, chronic heart failure, stroke or transient ischemic attack, anticoagulant use, prestroke modified Rankin Scale score, National Institutes of Health Stroke Scale score, large vessel occlusions, and intravenous thrombolysis, as appropriate for each outcome. RESULTS: We included 3919 patients (median age, 74 [interquartile range (IQR), 63–82], 58% male, median National Institutes of Health Stroke Scale score 6 [IQR, 3–12]). Cardiac CT detected a thrombus in 243 (6.2%) patients. Among 1323 patients that underwent both cardiac CT and transthoracic echocardiography, cardiac CT had a higher yield than transthoracic echocardiography (odds ratio, 7.4 [95% CI, 4.0–15.1]; P <0.001). Median additional scan time was 6 minutes (IQR, 5–7) for ECG-gated and 13 seconds (IQR, 12–61) for non–ECG-gated cardiac CT. Median additional radiation dose was 2.9 mSv (IQR, 1.6–4.1). Patients with thrombi had higher 90-day mortality (33% versus 15%, adjusted odds ratio, 1.6 [95% CI, 1.1–2.3]) and worse modified Rankin Scale scores (median modified Rankin Scale score 3 versus 2, adjusted odds ratio, 1.6 [95% CI, 1.2–2.0]), but similar recurrent stroke rates (5% versus 4%, adjusted odds ratio, 1.4 [95% CI, 0.7–2.5]). CONCLUSIONS: Implementing cardiac CT into the acute stroke imaging protocol is feasible, detects thrombi in ≈6% of patients, and has a higher yield than transthoracic echocardiography. Cardiac thrombi were associated with higher mortality, but not higher stroke recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT07165093.

Introduction Historic series have demonstrated the importance of construct rigidity in the treatment of pelvic discontinuities, but there remains limited data comparing different constructs, especially contemporary cup-cages and custom triflange components. The aim of this study was to evaluate reconstructive constructs with emphasis on implant survivorship, radiographic results, complications, and clinical outcomes. Methods We reviewed 184 revision THAs with unilateral pelvic discontinuity at a single institution between 1998–2022. Mean age was 66 years, 83% were female, and mean BMI was 29 kg/m2. Constructs included uncemented cup and plating (n=66, 36%), cup-cages (n=59, 32%), jumbo uncemented acetabular components (n=30, 16%), conventional antiprotrusio cages (n=16, 9%), and custom triflanges (n=13, 7%). Since 2013, 73% of cases were treated with either a cup-cage or custom triflange. Acetabular distraction (n=36, 20%) and porous augments (n=33, 18%) were used as adjuncts. Mean follow-up was 8 years. Results The 5-year survivorships free of revision for aseptic loosening, any revision, and any reoperation were 92%, 79%, and 75%. Of 43 revisions, the most common indications were aseptic loosening (n=15) and dislocation (n=15). For each construct, the 5-year survivorships free of revision for aseptic loosening were 100% (triflange), 94% (cup-cage), 92% (uncemented jumbo acetabular component), 90% (plating), and 86% (conventional anti-protrusio cage). Radiographic analysis demonstrated discontinuity healing in 85% of unrevised patients. Of the 15 re-revisions for aseptic loosening, 92% involved loss of fixation from inferior hemipelvis. There were 63 complications with dislocation (n=32), nerve palsy (n=10), and wound problems (n=9) most common. Mean Harris hip scores improved from 51 to 70 at 5 years. Conclusion In this series, the 5-year survivorship free from aseptic loosening was very good (92%), especially with contemporary techniques like custom triflange (100%) and cup-cage constructs (94%). Survivorship free from any revision (79%) and reoperation (75%) remain lower due to dislocation and infection.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P &amp;lt; .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P &amp;lt; .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P &amp;lt; .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P &amp;lt; .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Abstract Introduction Daily fluctuations in sleep disturbances have been shown to shape pain experiences among individuals with chronic pain. Additional biobehavioral factors, such as abuse history, depression, current and long-term anxiety, opioid use, physical functioning, and fatigue, may also affect daily pain outcomes. Yet the extent to which these factors collectively contribute to daily pain intensity and unpleasantness remains insufficiently understood. Methods Using baseline data from the SPINII randomized controlled trial (R01NR017168; McCrae, PI), women with insomnia and fibromyalgia (N = 294, x- age = 40) completed 14 days of sleep diaries assessing sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and pain intensity and unpleasantness (0–100). Additional predictors included abuse history, Beck Depression Inventory (BDI), State–Trait Anxiety Inventory (STAI), and PROMIS-57 physical functioning and social functioning. Linear mixed models examined the effects of sleep and related factors on daily pain. Results Significant predictors of pain intensity included higher between-person SOL (b = 0.08, p &lt; .001) and WASO (b = 0.08, p &lt; .001), lower between-person TST (b = -0.10, p &lt; .001), lower within-person TST (b = −0.03, p &lt; .001), opioid use (b = 2.84, p = .029), poorer physical functioning (b = −0.35, p = .008), and higher depression scores (b = 0.20, p = .046). Pain unpleasantness showed nearly identical patterns, with only physical functioning becoming non-significant. Random intercepts and residual variance values were significant in both models (p &lt; .001), indicating within- and between-person variation in pain. ICCs of .80-.85 revealed that the majority of variance was between-person, while non-significant autocorrelations (p &gt; .05) indicated minimal day-to-day carryover effects beyond stable individual differences. Conclusion Overall sleep quality and emotional health shape pain experience more strongly than daily fluctuations. Although TST offers some next-day relief, chronic contributors are more relevant to daily pain. Effects were largely consistent; between- and within-person TST showed strong effects, and depression had a slightly larger effect on pain unpleasantness than pain sensitivity, reinforcing a multidimensional biopsychosocial pain process. These findings highlight the need for integrated interventions that strengthen sleep, emotional well-being, and physical functioning. Support (if any) NIDA

Abstract Introduction Chronic and episodic headaches have a strong bidirectional relationship with insomnia and poor sleep outcomes. AM (morning) headaches are common among chronic pain populations, but additional research is needed to understand their pain experiences and potentially inform targeted interventions. Herein, we investigated whether presence of AM headaches is associated with differences in diary-based sleep parameters and pain ratings in women with pain and sleep complaints. We hypothesize individuals with AM headaches will have more sleep disturbances and fatigue as well as greater pain intensity and unpleasantness. Methods Women (N=293, Mage=39.59, SD 12.65, 65% with morning headaches) reporting insomnia and pain complaints (65% also reporting morning headaches) were recruited in mid-Missouri for an RCT (R01NR017168, ClinicalTrials.gov Identifier: NCT03744156). During baseline assessment, participants completed 2 weeks of daily electronic diaries and reported AM headache presence (Y/N). Independent samples t-tests (SPSS) evaluated differences in sleep parameters and pain ratings in those with and without AM headaches. Participants reporting diagnosed sleep apnea were excluded. Results Morning fatigue was higher among individuals with AM headaches (M=54.72+/-18.25) than those without (M=50.02+/-19.12), t(291)=-2.07, p=.04. Pain intensity was greater in the AM headache group in the morning (M=47.65+/-19.73 vs. M=42.52+/-21.91), t(291)=-2.04, p=.042, and evening, (M=49.62+/-19.10 vs. M=44.23+/-20.66), t(283)=-2.21, p=.028. Evening pain unpleasantness was also rated as higher among those with AM headaches (M=45.90+/-19.55) compared to those without (M=40.82+/-22.52), t(283)=-1.99, p=.048, but morning pain unpleasantness ratings only trended towards significance. Conclusion AM headaches can present as a chronic condition or as a symptom of other sleep disorders. Individuals with AM headaches had minimal sleep differences overall, but morning fatigue, pain intensity (AM and PM), and evening pain unpleasantness ratings were all significantly greater in those with AM headaches. Undiagnosed sleep disorders other than insomnia (i.e., obstructive sleep apnea) or other health concerns, like increased intracranial pressure, may have contributed to pain-related findings. Considering the high prevalence of COMISA in chronic pain populations, further investigation should examine its impact on sleep and headache severity. Support (if any) National Institute of Nursing Research (NR017168; Clinical trial: NCT03744156; PI: McCrae).

Abstract Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of &lt;30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.

ABSTRACT In 2018, the International Niemann‐Pick Disease Alliance (INPDA) and the International Niemann‐Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann‐Pick disease type C (NPC)—an ultra‐rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease‐modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high‐quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re‐evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up‐to‐date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital‐based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Abstract Background The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine–specific recommendations in the United States for the gender-diverse population. Content This document outlines pathology- and laboratory medicine–specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following 5 topics: (a) reference intervals and interpretation of laboratory tests impacted by use of GAHT (testosterone for transgender men; estradiol with or without antiandrogens for transgender women), focusing on those stably on GAHT for 6 months or longer; (b) transfusion medicine considerations for the gender-diverse patient population, (c) consideration of gender diversity in autopsy and death investigation, (d) interpretation of histology from tissues that are impacted by GAHT and surgical procedures; and (e) pathology and laboratory medicine informatics challenges and opportunities. Summary A relatively small group of laboratory tests is significantly impacted by GAHT. The histology of some tissues shows changes attributable to GAHT or to nonhormonal medical procedures. Autopsy and transfusion medicine practices for the gender-diverse population currently lack standardization, although this is evolving. The landscape of pathology informatics related to gender diversity is complicated by varying electronic health record and laboratory informatics systems functionality.

Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger’s MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] &lt; 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p&lt;5×10-8; MAF&gt;0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p&lt;2.4×10-6) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2), BRCA2 (OR=2.0, 95% CI=1.7-2.3), CHEK2 (OR=1.6, 95% CI=1.5-1.8), ATM (OR=1.6, 95% CI=1.4-1.9), FAM111A (OR=1.4, 95% CI=1.3-1.5), BIK (OR=1.4, 95% CI=1.2-1.6), SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB390.

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.