Citations

ABSTRACTBackground and AimsWe aimed to assess the impact of setons on perianal fistula outcomes in patients with perianal fistulising Crohn's disease (PFCD) treated with anti‐TNF therapy.MethodsWe included patients treated with their first anti‐TNF therapy for PFCD after undergoing a pelvic MRI between 2005 and 2022 from 6 North American centres. Our exposure was one or more setons at the time of anti‐TNF therapy. Our primary outcome was major adverse fistula outcome (MAFO), a composite of repeat local surgical intervention, hospitalisation, or faecal diversion for PFCD, and our secondary outcome was fistula remission defined clinically. We used 1:1 cardinality matching and propensity score weighting to control for fistula severity based on centrally read MRIs, luminal characteristics, and concomitant therapies.ResultsOur analysis included 221 patients: 81 with setons and 140 without setons. After cardinality matching, our cohorts were balanced (standardised difference < 0.1 for all covariates). Patients with setons had similar rates of MAFO (HR 1.23; 95% CI, 0.68–2.21) and fistula remission at 6 months (OR, 0.81; 95% CI, 0.41–1.59) and 12 months (OR, 0.63; 95% CI, 0.31–1.27) compared to patients without setons. Our results remained stable when analysed by propensity score weighting and in a sensitivity analysis of patients who underwent an exam under anaesthesia. In patients with abscesses, there were lower rates of MAFO (HR, 0.49; 95% CI, 0.19–1.25) but not statistically significant in patients with setons.ConclusionsIn this multicentre, setons were not associated with improved fistula outcomes. Future prospective controlled studies are warranted.

Background: Patients who experience homelessness manifest poor cancer outcomes, often because of treatment delays. Few studies have used mixed methods to learn what happens at the patient and health care staff level to explain these delays. Methods: This single-institution, multi-site study interrogated the entire medical record system (thousands of patients annually) for homelessness and cancer diagnoses from January 1, 2019, through October 10, 2023. Records were abstracted for relevant quantitative and qualitative data; rigorous methods were used to analyze, integrate, and report findings. Results: Forty-three patients with a median age of 58 years (range: 32, 73 years) and 34 (79%) assigned male sex at birth are the focus of this report. The most common cancers include hematologic (n = 8), gastrointestinal (n = 8), and genitourinary (n = 8). Thirty-five patients (81%) initiated cancer therapy, and 27 (63%) manifested treatment delay (>4 weeks post-diagnosis). The median time to cancer therapy was 9 weeks (95% confidence interval: 4.6, 12 weeks). Qualitative themes that explain delays are as follows: (1) logistical challenges in communication between the patient and health care team (“lack of a cell phone”); (2) patient reluctance to receive care (“patient elected to leave Against Medical Advice”); and (3) medical challenges in providing care (“he was hospitalized after being found down and hypotensive”). Conclusions: This study confirms that initiation of cancer therapy is often delayed in patients who experience homelessness. It sheds light on reasons for delay – for example, lack of phone access, an observation which suggests that perhaps provision of a burner phone might help some patients.

Abstract Context Research and scholarship are core drivers of medicine in the modern era. Evidence-based practice continues to replace expert opinion and long-held practice beliefs. Involvement in the development and writing of these guidelines is critical for Doctors of Osteopathic Medicine (DOs) to maintain a seat at the academic table. According to the American Osteopathic Association (AOA), 11 % of practicing physicians in the US are DOs. This number is growing, as nearly 25 % of current medical students attend an osteopathic medical school. Without involvement in guideline development, DOs risk giving up control of their own practice of medicine. Objectives To quantify the contribution of DOs to the body of literature guiding practice, author information was extracted from all US-based guidelines published in the years 2021, 2022, and 2023 listed in the Emergency Care Research Institute (ECRI) Guidelines Trust database. Methods Authors of US-based guidelines listed in the ECRI Trust database from the years 2021–2023 were counted and categorized into one of three groups based on terminal degree: MD holders, DO holders, and Other-degree holders. Authors whose degrees could not be identified were counted as “Unidentifiable.” Additional data including sponsoring organization, organization type, and specialty were collected. Results A total of 674 guidelines were published by US organizations in 2021, 2022, and 2023, with 604 reporting author information. A total of 9,376 authors were counted. Of that, 7,253 held an MD (77 %), 110 held a DO (1.2 %), and 1,848 held another terminal degree (19.7 %); meanwhile, 1.66 % of counted authors did not have an identifiable degree. A total of 604 guidelines published by US organizations were identified. Of these, 88 (14.6 %) contained at least one DO author in their author list. Sixty-two unique specialties were identified, along with 130 unique sponsoring organizations. Of those specialties, 28 (44.4 %) had at least one DO author of at least one guideline. Of 130 sponsoring organizations, 44 (33.8 %) developed at least one guideline with at least one DO author. No osteopathic sponsoring organizations were identified. Conclusions Based on these results, we conclude that DOs are underrepresented in the development of guidelines.

Abstract The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8 T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the antitumor response which has been weakened by mechanisms of central tolerance. Here, we show that inflammatory Vesicular Stomatitis Virus (VSV) failed to prime an adoptively transferred, or pre-existing, population of tumor-reactive T cells.Combination with αPD1 immune checkpoint blockade therapy improved survival only when VSV expressed tumor associated antigens (TAA). These data show that, in this model, the highly inflammatory OV VSV alone actively outcompetes antitumor immunity. However, we also show that viral expression of a mutant near-self TAA can break central tolerance expanding heteroclitic self-reactive and near-self-reactive T cells, thus overcoming viral immunodominance by promoting tumor-specific T cell proliferation in parallel with expanding antiviral T cells.

ABSTRACT Background Mitral annular disjunction (MAD) carries an increased risk of complex ventricular arrhythmias, which can lead to sudden cardiac death. Many of these patients undergo implantable cardioverter defibrillator (ICD) implantation, but their ICD outcomes are not known. Objective The aim of this study was to assess the outcomes of ICD implantation and the predictors of appropriate ICD therapies in patients with MAD. Methods The study included patients with MAD who underwent ICD implantation. Clinical, electrocardiographic, cardiac imaging, and device therapy data were collected. Results Forty‐nine patients with MAD and ICD were included. Median age was 49 (21) years, and 29 (59%) were female. 13 (27%) patients underwent ICD implantation for primary prevention and 36 (73%) patients for secondary prevention. Over a median follow‐up of 27.3 (35.3) months, 23 (47%) patients received ICD therapies. 18 (37%) patients had appropriate ICD therapies, and 5 (10%) patients had inappropriate ICD shocks. Median time to first appropriate therapy was 22.3 (63.3) months. In patients with a secondary prevention ICD indication, the rate of appropriate ICD therapies was 44%, while in patients with a primary prevention ICD indication, it was 15%. Among patients with appropriate ICD therapies, the first therapies were delivered for monomorphic ventricular tachycardia (VT) in 7 (39%) patients and polymorphic VT or ventricular fibrillation (VF) in 11 (61%) patients. Patients with appropriate ICD therapies were more likely to have a history of SCA ( p = 0.003) and/or low left ventricular ejection fraction (LVEF) ( p = 0.022) before ICD implantation as compared to patients without appropriate ICD therapies. Conclusions In our cohort of patients with MAD and ICD, appropriate ICD therapies were common. Most appropriate ICD therapies were delivered for polymorphic VT or VF. Larger studies are needed to elucidate the mechanisms of VAs and refine risk stratification in MAD.

AbstractAlthough endoscopic submucosal dissection (ESD) is associated with higher en-bloc and R0 resection rates than cap-assisted endoscopic mucosal resection (cEMR), its comparative impact on achieving complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) in BE endoscopic eradication therapy (EET) is not well defined. We aimed to compare the journey of patients from initial endoscopic resection (ER) with ESD and cEMR to achieving CRD and CRIM.Patients undergoing ESD or cEMR followed by ablation for BE neoplasia at two academic institutions in the United States were included. Primary outcomes included CRD and CRIM rates following ER in the two groups. Secondary outcomes included the number of resection/ablative procedures from initial ER to achieving CRD and CRIM. Inverse probability treatment weighting (IPTW) was used to balance confounding variables between groups.A total of 801 patients (606 cEMR, 195 ESD) were included. ESD group patients had higher en-bloc resection rates (ESD 94.4%, cEMR 44.7%). Higher rates of CRD were observed in patients undergoing initial ESD (HR 1.53, P < 0.01). With time-to-event and IPTW analyses, rates of achieving CRD and CRIM were comparable between the groups. There were no significant differences in mean number of endoscopic resection or ablative procedures among patients undergoing initial cEMR resection compared with those treated with initial ESD.Despite larger lesion sizes and more cancers in patients undergoing ESD, the EET journey to achieving CRD and CRIM was comparable to that in patients receiving cEMR. Prospective studies are required to further study differences between these two treatment approaches.

Abstractα-synucleinopathies are a complex group of progressive neurodegenerative disorders with an increasingly recognized long prodromal period, during which sleep dysfunction is a hallmark. Sleep disorders during the prodromal synucleinopathy period, primarily isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and daytime hypersomnolence correlate best with the recently proposed “body-first” Lewy body disease progression. iRBD is the most widely recognized form of prodromal α-synucleinopathy, and patients with iRBD show abnormal α-synuclein in tissues and biofluids even in the absence of cognitive or motor symptoms. More importantly, individuals with iRBD have an elevated risk for near-term development of a clinically diagnosable symptomatic synucleinopathy. Other sleep disorders such as hypersomnia and circadian rhythm dysfunction also occur across the synucleinopathy spectrum, although their prognostic significance is less well understood than iRBD. Finally, isolated REM sleep without atonia may represent an even earlier stage of prodromal synucleinopathy, but further studies are needed.

ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is a non-malignant state characterized by hematopoietic stem cells exhibiting clonality driven by acquired mutations during aging. Using next-generation sequencing, it has been reported that the prevalence of CHIP increases exponentially with age. Thus far, epigenetic mutations including DNMT3A, TET2 and ASXL1 are the most common mutations identified in driving CHIP. CHIP is considered a pre-malignant state, however with reports of its associations with non-malignant disease states, the clinical impact of CHIP has been of great interest, in particular its effect on the renal and cardiac systems. CHIP has been associated with a higher rate of estimated glomerular filtration rate decline and increased risk of acute kidney injury. CHIP and its driver mutations have also been shown to increase cardiovascular disease and atherosclerosis through various inflammatory pathways. In this review, we discuss the pathophysiology of CHIP through aging, its impact on kidney disease and implications on cardiovascular health. We also compare CHIP to another pre-malignant clonal disorder, monoclonal gammopathy of undetermined significance (MGUS).