Citations

Abstract Models that estimate the probability of an adverse clinical outcome require an operational cutoff to translate continuous estimated probabilities into discrete labels that can trigger clinical action. Although statistical methods identify ‘optimal’ cut-offs, threshold selection ultimately reflects value judgments regarding harm tolerance, resource allocation, and workflow feasibility. We describe a governance-informed approach to selecting a deployment threshold for an asthma exacerbation (AE) prediction model integrated into clinical workflows. Using prevalence-adjusted performance metrics and real-world provider capacity modeling, we evaluated multiple candidate thresholds and quantified downstream workload and missed-event trade-offs. We demonstrate that statistically optimal thresholds may produce operationally infeasible alert volumes or unacceptable miss rates. We propose a structured threshold governance framework integrating statistical performance, clinical utility, stakeholder input, and human oversight safeguards. This case illustrates how threshold decisions should be treated as organizational governance processes rather than purely technical optimizations.

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.

ABSTRACT Background Chemotherapy‐induced peripheral neuropathy (CIPN), characterized by loss of sensation and impaired physical function, is a prevalent and debilitating side effect of chemotherapy, affecting 30%–50% of breast cancer survivors (BCS) with effects lasting years after treatment completion. Mindfulness‐based interventions are shown to be efficacious in reducing symptoms in neuropathies. This subgroup analysis examined the effect of Mindfulness‐Based Stress Reduction on Breast Cancer (MBSR(BC)) compared to Breast Cancer Education Support (BCES) or Usual Care (UC) on CIPN among BCS who received chemotherapy or chemotherapy and radiation. Methods BCS ( n = 114) were randomly assigned to the 6‐week MBSR(BC) ( n = 48), BCES ( n = 52), or UC ( n = 14) regimen. Demographic and clinical data were assessed at baseline, and CIPN was assessed using the Chemotherapy‐Induced Peripheral Neuropathy assessment tool (CIPNAT) at baseline, 6, 12, and 26 weeks. Between‐ and within‐group differences were evaluated and change over time was compared between groups. Results BCS (mean age = 52.7 years, range: 28–81 years) were primarily White and non‐Hispanic ( n = 78, 68%). The pattern of effect sizes was similar for CIPNAT symptoms and interference with improvements in CIPN for MBSR(BC) and BCES groups overtime. For both groups, the effects were larger compared to the UC. Differences tended to increase over time with significant effects observed between MBSR(BC) and UC, and between BCES and UC at weeks 12 and 26. Conclusions The findings indicate that MBSR(BC) and BCES may effectively reduce CIPN symptoms among BCS compared to UC. MBSR(BC) and BCES programs are effective non‐pharmacological interventions for CIPN that may translate into practice.

The radiopharmaceutical therapy field is experiencing a surge of novel treatments and expanded uses for existing treatments, broadening the range of patients that can be treated. This expansion presents new challenges for managing patient release due to new patient populations with additional comorbidities, increasing the incidence of patients requiring care shortly after administration. This paper outlines the challenges and potential solutions for managing readmitted radiopharmaceutical therapy patients. It discusses the importance of having radiation protection policies and procedures in place for staff who may be unfamiliar with radiation. The paper also highlights the need for just-in-time training and radiation monitoring equipment for care staff, as well as the development of a notification system within the electronic health record to ensure staff can safely care for these patients. Preparing for these eventualities is essential for implementing a radiopharmaceutical therapy program that is ready for the expansion of existing and novel treatments.

Introduction: The Revised Cardiac Risk Index (RCRI) and the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) are well-recognized tools to predict 30-day postoperative cardiac events in noncardiac surgeries. However, their predictive accuracy is yet to be assessed in minimally invasive transurethral prostate surgery. We compared the RCRI- and NSQIP-predicted postoperative cardiac outcomes with the actual incidence of cardiac events after transurethral prostate surgery. Methods: We conducted a retrospective review of patients who underwent transurethral prostate surgery between July and December of 2022. We assessed for postoperative cardiac events within 30 days, as defined by the seminal cardiac VISION study. The RCRI and NSQIP cardiac event predictions were calculated. Fisher’s exact test was used for analysis. Results: We included 185 patients with an average age of 73 ± 8.4 (standard deviation) years, 86 of whom (46%) had transurethral resection of the prostate, and 99 underwent Holmium Laser Enucleation of the Prostate (54%). Myocardial injury after noncardiac surgery surveillance was needed for 34 patients (18.4%) as per standard practice. No patient had any intraoperative cardiac events. One patient experienced a nonfatal postoperative cardiac event (asystole) within hours of surgery. The 30-day cardiac event prediction by the RCRI was 4.8% of the patient cohort ( n ≈ 9), significantly higher than the observed incidence of 0.5% ( p = 0.0198). NSQIP predicted that 0.54% of the patient cohort ( n = 1) will have a cardiac complication within 30 days, which is not significantly different from the observed cardiac event incidence ( p = 1). Conclusion: The RCRI significantly overestimated the 30-day cardiac risk after transurethral prostate surgery, whereas NSQIP predictions and the observed rate of cardiac events were similar. Utilizing more representative predictive tools helps improve risk stratification and will allow patients and surgeons to make better-informed decisions.

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.