Citations

Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of >2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

Discoidin Domain Receptor 2 (DDR2) is a collagen-activated tyrosine kinase required for bone and tooth development as well as regeneration of calvarial and long bones. Although DDR2 is expressed in alveolar bone, its functions in this site have not been previously examined. The present study used global and conditional knockout approaches and lineage tracing to examine the functions of DDR2 in alveolar bone formation during tooth socket healing. First molars were extracted from the maxillae of wild-type and globally Ddr2 -deficient ( Ddr2 LacZ/LacZ ) mice, and socket healing was measured after 1, 2, or 4 wk. At all times, Ddr2 inactivation significantly reduced socket healing. These changes were associated with decreased cell proliferation 3 d after extraction without any detectable changes in apoptosis. In addition, collagen fibril orientation, measured using Picrosirius Red staining under polarized light, was disrupted in tooth sockets from Ddr2 -deficient mice. For lineage tracing, 4-wk-old Ddr2 mer-cre-mer ; R26R tdTomato and Gli1 CreERT2 ; R26R tdTomato mice were induced with tamoxifen, first molars were extracted, and socket healing was examined after 1, 3, or 7 d. In both cases, tdTomato+ cells migrated into sockets, where they sequentially co-localized with preosteoblast and osteoblast markers. Thus, both DDR2 + and GLI1 + cells contribute to socket healing. The considerable overlap observed between DDR2 + and GLI1+ cells suggested that DDR2 functioned in GLI1 + cells, which are known to have skeletal progenitor properties. Consistent with localization data, conditional knockout ( Gli1 CreERT2 ; Ddr2 fl/fl ) mice exhibited reductions in socket healing 1 wk postextraction, although the inhibition of socket repair was less than that seen in global Ddr2 knockouts. In summary, this work demonstrates a role for DDR2 in alveolar bone repair, a finding that may have therapeutic implications for the treatment of alveolar bone loss associated with periodontal disease and other disorders.

Abstract Recent work on double descent has challenged classical bias–variance tradeoffs, showing that test error can decrease, increase sharply near the interpolation threshold, and then decrease again as model capacity grows. This phenomenon has been documented in regression and classification, but its relevance to survival analysis remains unclear. Survival data are subject to censoring, which obscures true event times, and widely used models such as the Cox proportional hazards model are optimized via partial likelihoods that emphasize ranking rather than calibrated risk estimation. It is therefore unknown whether double descent occurs in this setting, how censoring influences its manifestation, or how it interacts with standard performance metrics.We investigate these questions using synthetic survival data generated from Weibull hazards with controlled censoring, allowing systematic variation of model capacity from under to over parameterized regimes. While we verified double descent occurs in survival models, calibration plateaus and decouples from discrimination, even under strong $\ell_2$ regularization. This decoupling arises because the Cox partial likelihood optimizes rankings rather than magnitudes, producing extreme risk scores that break the Breslow estimator used to estimate survival probabilities. These results highlight limitations of discrimination-based model selection in survival analysis and underscore the need for calibration-aware evaluation in high-capacity prognostic models.

Abstract Background Ceftriaxone-resistant Escherichia coli infections are increasingly common, partially because of the emergence of E. coli sequence type 131 (ST131), including its subclade C2/H30Rx, which produce extended-spectrum β-lactamases. Methods A prospective cohort including 14 US sites, which enrolled monomicrobial ceftriaxone-resistant and susceptible E. coli bloodstream infection (BSI) cases in a 1:1 ratio, was used to compare ST131 versus non-ST131 E. coli BSI, with specific attention to E. coli ST131 C2/H30Rx. Desirability of outcome ranking was determined at 30 days after infection onset. Results This analysis included 282 patients with E. coli BSI; 43% (121/282) were E. coli ST131 and 23% (66/282) belonged to the C2/H30Rx subclade. Resistance to ceftriaxone was present in 79% (96/121) ST131, 86% (57/66) E. coli ST131 C2/H30Rx, and 27% (43/161) E. coli non-ST131. Compared to patients with non-ST131 E. coli BSI, patients with ST131 BSI were older (median 70 years, [Q1 62, Q3 76] years vs 65 years, [51, 74]; P = .005) and more often admitted from long-term care facilities (21/121 [17%] vs 7/161 [4%], P < .001). Overall and empiric carbapenem use was more frequent in the treatment of patients with ST131 BSI compared with non-ST131 BSI (overall 89/121 [74%] vs 50/161 [31%]; empiric: 58/121 [48%] vs 31/161 [19%], P < .001). Desirability of outcome ranking outcomes were similar between groups. Conclusions Most ceftriaxone-resistant E. coli from US patients with E. coli BSI belong to ST131, particularly E. coli ST131 C2/H30Rx, serving as an important driver of carbapenem use.

Background Breast cancer-related lymphedema (BCRL) is a common and life-long adverse event affecting ~20% of breast cancer survivors. As existing non-pharmacologic management is burdensome, expensive, and variably effective, this systematic scoping review aims to identify pharmacologic and herbal agents for prevention and treatment for BCRL. Methods PubMED, Embase, Web of Science Core collection, and the Cumulative Index to Nursing and Allied Health Literature were searched for studies published in English between 1993 and 2025 that investigated the preventative or therapeutic effect of pharmacologic or herbal agents on BCRL among adult stage I-III breast cancer patients. Studies describing interventions with systemically absorbed anti-inflammatories, anti-thrombotics, anti-coagulants, and blood product components were included. Systematic reviews, protocols for ongoing clinical trials, preclinical and non-human studies, editorials, and studies not exclusive to BCRL were excluded. Three reviewers screened and extracted data between June and August 2025. The primary outcomes of interest were reduction in BCRL incidence or severity. Results Of the 217 articles screened, 37 were included in the final review. After full text review, 13 were excluded for repetitive data, non-English language, or irrelevant outcomes. The 24 studies included in the analysis investigated anti-diabetic, herbal, anti-inflammatory, anti-hypertensive, immunomodulatory, and microbiome modifying agents, and venoactive flavinoid derivates. Three studies explored the role of pharmacologic/herbal agents in BCRL prevention. While thiazolidinediones, anti-hypertensives, and non-steroidal anti-inflammatory drugs (NSAIDs) had no effect on BCRL incidence, glucagon-like peptide-1 receptor agonists (GLP-1 RA) were associated with BCRL prevention. In the 21 studies that assessed the effect of pharmacologic/herbal agents in BCRL treatment, NSAIDs/steroids, anti-hypertensives, microbiome/synbiotic supplements, and doxycycline showed no benefit and data for flavonoid-derived venoactive agents and herbal products were inconsistent. Immune-modulating therapies were associated with improved BCRL signs/symptoms in three studies. Conclusion This systematic scoping review found limited evidence suggesting that GLP-1 RAs may reduce the risk of BCRL and that immunomodulatory agents may improve signs/symptoms of BCRL. Rigorous prospective trials using standardized limb volume/edema, quality-of-life (QoL), and symptom measures and longer follow-up are needed to inform clinical practice aimed at preventing and treating BCRL. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420251055134.

Abstract Background Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms associated with prolonged survival and substantial symptom burden. However, patient-reported outcomes across NET subtypes remain poorly characterized, particularly in real-world settings. This study describes baseline health-related quality of life (HRQoL) and care experiences among patients with gastroenteropancreatic and lung NETs, examining differences by tumor site and time since diagnosis. Methods The Neuroendocrine Tumors–Patient Reported Outcomes study is a prospective, multi-institutional US cohort of adults (aged 18 years and older) with incident small intestinal, pancreatic, gastroenteropancreatic, or lung NETs diagnosed from January 2018 through September 2024, identified via a validated electronic medical record–based computable phenotype. Baseline surveys assessed HRQoL, symptoms, care experiences, and clinical characteristics using validated instruments. Descriptive statistics and standardized mean differences compared responses by NET site and time since diagnosis. Results Among 2367 participants (mean age = 57.8 years; 57.3% female), 1974 had gastroenteropancreatic NETs (659 small intestinal NET, 555 pancreatic NET) and 393 had lung NETs. Fatigue (mean = 33.0), insomnia (mean = 32.5), and diarrhea (mean = 25.7) were the most burdensome symptoms. Lung NET patients reported worse dyspnea (standardized mean difference = 0.58, P < .001) and lower physical, role, and global QoL scores than those with gastroenteropancreatic NETs, while pancreatic NET patients reported better functioning. Diarrhea worsened over time, especially in small intestinal NETs. Most rated care highly (75.3%) but cited concerns about treatment side effects (80.4%), costs (60.7%), and travel burden (58.8%). Conclusions This large US cohort reveals persistent symptom burden and HRQoL variation by tumor site and disease duration, underscoring the need for longitudinal HRQoL assessment in NET care.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

PURPOSE BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian ). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2 , a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer–related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.