Citations

Introduction: Atrial fibrillation (AF) is the most prevalent arrhythmia, placing a substantial burden on the healthcare system. Patients with AF are cared for in a variety of settings including primary care and cardiology clinics, while some require cardiac electrophysiology (EP) clinics offering specialized drugs or procedures. Appropriate triage of AF referrals to these specific clinics will lead to timely and appropriate care and reduce inefficiency in the health system. Goal: To develop a machine learning (ML) model to triage AF referrals to a large Cardiology center to either the Cardiology or EP clinic based on likelihood of requiring an invasive EP procedure or initiation of antiarrhythmic drug. Methods: We retrospectively analyzed 6,755 patients who were referred to CV with referral diagnosis of AF (mean age 70 ± 11 years, 66% male). We employed multiple input variables to predict the suitability for EP clinic defined as need for initiating an antiarrhythmic drug or an invasive EP procedure. These encompassed patient demographics, relevant comorbidities, medications, prior procedures, medical notes analyzed using natural language processing (NLP), and Holter monitoring data. Results: For internal referrals, XG boost model performed the best with AUC at 79%, accuracy at 72%, and F1 score at 68%. This model produces true positive (TP) at 68% and true negative (TN) at 74%, which was better in comparison with triaging using NLP only (AUC = 69%, TP = 58%, TN = 61%), Holter only (AUC = 52%, TP = 51%, TN = 77%), and NLP/Holter (AUC = 67%, TP = 60%, TN = 60%). When supplementing ML model with Holter readings on average HR ≥ 100 and maximum HR ≥ 150, the results can be improved to TP at 70% and TN at 73%. Conclusions: Our model effectively identifies patients who are more likely to require specialized EP care, enabling the automation and increased efficiency of the AF referral triage process. Prospective validation studies are paramount in determining the true value of this tool.

Purpose To develop a culturally-tailored American Indian/Alaska Native (AI/AN) women’s Facebook group supporting opioid recovery as an adjunct to medication. Design Community-based, qualitative approach. Setting Minnesota, U.S. Participants AI/AN women in opioid recovery, interested parties, and a Community Advisory Committee (CAC) of AI/AN women with lived experience, health care providers, and community members. Intervention We developed evidence-based content focusing on stress/trauma and substance use, mindfulness, responding to triggers, and supportive community resources. Additional content centered on AI/AN culture was also selected. Method Interviews were conducted by two women, then transcribed and coded using content analysis with NVivo software. Results were presented to CAC for further content refinement. Results CAC members (n = 10) guided study methods, intervention development, and dissemination activities. 14 AI/AN women (mean age 36.4 years; mean 6.7 months opioid abstinence) and 12 interested parties (7 men, 5 women) were receptive to an AI/AN gender-specific Facebook group, preferring content with AI/AN people and/or text resonating with AI/AN culture (e.g., Native traditions, family, personal stories, historical trauma). Recommendations included (1) protect confidentiality, (2) retain positivity, (3) incorporate resources and exercises to build coping skills, and (4) moderators should be authentic and relatable to build trust. Conclusions Our approach provides a model for developing culturally tailored, appealing and effective social media interventions to support AI/AN women in recovery from opioid use disorder.

Introduction: Genome-wide association studies (GWAS) have discovered >300 associations for CAD. Few loci are functionally characterized and may represent new mechanisms of disease. Hypothesis: Can an unbiased transcriptional screen for the >2000 candidate GWAS genes in endothelial cells (ECs) identify causal genes and disease-relevant pathways at CAD GWAS loci. Methods: We applied CRISPRi-Perturb-seq to knock down expression of genes within 500 Kb of coronary artery disease GWAS loci (2,300 genes in total) and measure their transcriptomic effects using single-cell RNA-seq. Validation of candidate causal genes was conducted in primary human ECs and zebrafish. Results: We identified 50 programs of co-expressed genes, which represent core cellular pathways (i.e. ribosome biogenesis) and 13 EC-specific pathways such as flow response and angiogenesis. The EC-specific programs show the greatest contribution to CAD heritability. 5 EC-specific programs have the greatest number of GWAS candidate genes. We find that 43 of 306 CAD GWAS signals converge onto these 5 gene programs, and all are regulated by genes in the cerebral cavernous malformations (CCM) pathway—which coordinates KLF2/4 transcriptional responses in endothelial cells, but has not been linked to CAD risk. The strongest regulator of these programs is TLNRD1 , which we show is a new CAD gene and novel regulator of the CCM pathway. TLNRD1 loss-of-function alters actin organization and barrier function in endothelial cells in vitro , and heart development in zebrafish in vivo . Conclusions: High-throughput functional analysis of 2,300 genes proximal to CAD GWAS loci prioritized pathways—such as angiogenesis and EC migration—that are regulated by multiple risk SNPs. Our study identifies new genes that likely influence risk for CAD, identifies convergence of CAD genes into certain pathways in endothelial cells, and prioritizes study of genes in the CCM-signaling pathway for contribution to CAD risk.

AbstractIntroductionThe humerus is a common site of metastases and primary tumors. For some patients with a segmental defect and/or diaphyseal cortical destruction a cemented intercalary device may provide a more reliable construct, however data on their use is limited.MethodsWe reviewed 43 (28 male and 15 female) patients treated with an intercalary humeral spacer at a single tertiary referral center between 1989 and 2022. Humeral lesions were most commonly secondary to metastatic disease (n = 29, 68%), with 25 (58%) patients presenting with a pathologic fracture. Mean age and body mass index were 66 years and 27.9 kg/m2. First generation taper joint device were used in 22 patients and second‐generation lap device in 21 patients.ResultsFollowing reconstruction the 2‐year overall survival was 30%. Mechanical complications occurred in 11 patients, most commonly aseptic loosening (n = 6, 14%). With death as a competing risk, the cumulative incidence of mechanical failure was 28% at 2‐years postoperative. Following the procedure, mean Musculoskeletal Tumor Society scores was 70% and mean shoulder elevation was 87°.ConclusionReconstruction of the humeral diaphysis with an intercalary endoprosthesis provides restoration of function of the upper extremity, however, is associated with one in four patients having mechanical failure.

Importance Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress. Objective To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing. Design, Setting, and Participants Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023. Intervention Participants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits. Main Outcomes and Measures The primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret. Results A total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling. Conclusions and Relevance In the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment. Trial Registration ClinicalTrials.gov Identifier: NCT02993068

ImportanceTesting new medical devices or procedures in terms of safety, effectiveness, and durability should follow the strictest methodological rigor before implementation.ObjectivesTo review and analyze studies investigating devices and procedures used in intracranial aneurysm (IA) treatment for methods and completeness of reporting and to compare the results of studies with positive, uncertain, and negative conclusions.Data SourcesEmbase, MEDLINE, Web of Science, and The Cochrane Central Register of Clinical Trials were searched for studies on IA treatment published between January 1, 1995, and the October 1, 2022. Grey literature was retrieved from Google Scholar.Study SelectionAll studies making any kind of claims of safety, effectiveness, or durability in the field of IA treatment were included.Data Extraction and SynthesisUsing a predefined data dictionary and analysis plan, variables ranging from patient and aneurysm characteristics to the results of treatment were extracted, as were details pertaining to study methods and completeness of reporting. Extraction was performed by 10 independent reviewers. A blinded academic neuro-linguist without involvement in IA research evaluated the conclusion of each study as either positive, uncertain, or negative. The study followed Preferring Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Main Outcomes and MeasuresThe incidence of domain-specific outcomes between studies with positive, uncertain, or negative conclusions regarding safety, effectiveness, or durability were compared. The number of studies that provided a definition of safety, effectiveness, or durability and the incidence of incomplete reporting of domain-specific outcomes were evaluated.ResultsOverall, 12 954 studies were screened, and 1356 studies were included, comprising a total of 410 993 treated patients. There was no difference in the proportion of patients with poor outcome or in-hospital mortality between studies claiming a technique was safe, uncertain, or not safe. Similarly, there was no difference in the proportion of IAs completely occluded at last follow-up between studies claiming a technique was effective, uncertain, or noneffective. Less than 2% of studies provided any definition of safety, effectiveness, or durability, and only 1 of the 1356 studies provided a threshold under which the technique would be considered unsafe. Incomplete reporting was found in 546 reports (40%).Conclusions and RelevanceIn this systematic review and meta-analysis of IA treatment literature, studies claiming safety, effectiveness, or durability of IA treatment had methodological flaws and incomplete reporting of relevant outcomes supporting these claims.

OBJECTIVE Ulnar neuropathy at the elbow (UNE) is common, affecting 1%–6% of the population. Despite this, there remains a lack of consensus regarding optimal treatment. This is primarily due to the difficulty one encounters when trying to assess the literature. Outcomes are inconsistently reported, which makes comparing studies or developing meta-analyses difficult or even impossible. Thus, there is a need for a core outcome set (COS) for UNE (COS-UNE) to help address this problem. The objective of this study was to utilize a modified Delphi method to develop COS-UNE. METHODS A 5-stage approach was utilized to develop COS-UNE: stage 1, consortium development; 2, literature review to identify potential outcome measures; 3, Delphi survey to develop consensus on outcomes for inclusion; 4, Delphi survey to develop definitions; and 5, consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 21 participants, all neurological surgeons representing 11 countries. The final COS-UNE consisted of 22 data points/outcomes covering the domains of demographic characteristics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 6 months, with the consensus optimal timepoints for assessment identified as preoperatively and 3, 6, and 12 months postoperatively. CONCLUSIONS The authors identified consensus data points/outcomes and also provided definitions and specific scales to be utilized to help ensure that clinicians are consistent in their reporting across studies on UNE. This COS should serve as a minimum set of data to be collected in all future neurosurgical studies on UNE. The authors hope that clinicians evaluating ulnar neuropathy will incorporate this COS into routine practice and that future studies will consider this COS in the design phase.

Abstract Background Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. Methods This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. Results Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node–only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. Conclusions Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Abstract Cellular senescence has emerged as a fundamental biological mechanism underpinning the ageing process and has been implicated in the pathogenesis of an increasing number of age-related conditions. Cellular senescence is a cell fate originally defined as an irreversible loss of replicative potential although it is now clear that it can be induced by a variety of mechanisms independent of replication and telomere attrition. The drivers include a persistent DNA damage response causing multiple alterations in cellular function. Senescent cells secrete a range of mediators that drive chronic inflammation and can convert other cells to the senescent state—the senescence-associated secretory phenotype. Much research to date has been conducted in animal models, but it is now clear that senescent cells accompany ageing in humans and their presence is an important driver of disease across systems. Proof-of-concept work suggests that preventing or reversing senescence may be a viable strategy to counteract human ageing and age-related disease. Possible interventions include exercise, nutrition and senolytics/senostatic drugs although there are a number of potential limitations to the use of senotherapeutics. These interventions are generally tested for single-organ conditions, but the real power of this approach is the potential to tackle multiple age-related conditions. The litmus test for this exciting new class of therapies, however, will be whether they can improve healthy life expectancy rather than merely extending lifespan. The outcomes measured in clinical studies need to reflect these aims if senotherapeutics are to gain the trust of clinicians, patients and the public.