Citations

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder with a pathogenic mutation identified in approximately 50% of cases. The MYH7 and MYBPC3 genes account for over half of these cases, while dozens of other genes can be pathogenic(1). Genetic test results are not independently used to determine which people with HCM benefit from implanted cardiac defibrillators (ICDs)(2, 3). Little is known about the additive role of genetic testing results to existing indications for ICD insertion. Purpose This study aims to examine the interaction between genetic testing results and existing ICD indications and imaging results on defibrillator discharge rates in HCM. Methods Patients who underwent an ICD for HCM, who underwent a cardiac magnetic resonance (CMR) study and who underwent genetic testing were included across 3 sites. The outcome was the incidence rate of appropriate ICD discharges, calculated using cox regression controlling for current age and primary vs secondary prevention. Interaction analysis between genetic risk factors and existing ICD indications, and with CMR quantification of LGE and septal thickness, was performed, and stratum specific estimates calculated using linear computation. Results 177 patients were included in the study, of whom 70 (39.55%) had a pathogenic mutation, 5 (2.82%) had a variant likely pathogenic (VLP), 44 (24.86%) had a variant of undetermined significance (VUS) and 58 (39.55%) had no identifiable mutation. The event rate was 3.32 {2.28 to 4.84) per 100 person years. There was no association between genetic variables and ICD discharge rate. There was an 80% reduction in ICD discharge rate in people who underwent ICD insertion exclusively for family history of sudden cardiac death or for syncope who had no pathogenic or likely pathogenic mutation, however this change was not statistically significant (table 2). Conclusion There is no strong association between genetic characteristics and ICD discharge rates among people with hypertrophic cardiomyopathy with an existing ICD indication. There is a nonsignificant trend towards fewer ICD discharges among people who underwent ICD insertion for family history alone or for a history of syncope and did not have a pathologic variant.Table 1 Table 2

Abstract Non-tubercular mycobacteria (NTM) present a serious challenge in managing lung transplant candidates and recipients. Pretransplant NTM isolation has been associated with post-transplant NTM infection and significantly increased mortality risk. Strategies for managing pre-transplant NTM isolation vary widely in clinical practice. We present a 35-year-old lung transplant candidate from a tuberculosis-endemic country with severe pulmonary hypertension and Eisenmenger Syndrome due to unrepaired atrial septal defect, who underwent bilateral lung transplantation. Two years prior to transplant, she was successfully treated for pulmonary tuberculosis with six months of an unknown regimen in her home country. After moving to the U.S., she received M. tuberculosis (MTB) clearance from her state tuberculosis board, with three negative sputum samples six months prior to transplant. During her transplant evaluation, multi-drug-resistant M. fortuitum complex was isolated from one mycobacterial sputum culture. There was no clinical or radiographic evidence of active lung infection, and no targeted therapies were added. Standard peri-transplant antibiotics (vancomycin, cefepime, and caspofungin) were given. The patient received basilixamab for induction immunosuppression, and tacrolimus, mycophenolate mofetil, and prednisone for maintenance immunosuppression. Explant pathology showed necrotizing granuloma in the right upper lobe with acid-fast bacilli (AFB). The differential diagnosis included non-viable MTB, viable MTB despite prior clearance, or M. fortuitum. Three bronchoscopy washings were obtained in the first week post-transplant and returned negative for MTB by PCR, AFB stain, and culture. In collaboration with the Mycobacteriology laboratory, broad-range PCR testing was performed on the formalin-fixed paraffin-embedded samples from the explanted right lung, which was positive for MTB complex DNA. In total, the patient completed six sputum samples within the year pre-transplant and six respiratory samples within a month post-transplant, all of which returned negative for MTB by PCR, AFB stain, and culture. Blood flow cytometric (FC) immunoprofiling with mycobacterial antigens and controls was conducted (Escalante et al. 2015). The patient's FC antigen-specific activated T-cell profiling was consistent with a reduced risk of latent TB infection (FC CD4+ CD25+CD134+ T-cells (RD1-peptides-nil) = 0.19%). T-cell reactivity to MTB300 and PPD antigens suggested prior MTB, NTM, and/or BCG vaccination exposures. She progressed well without any preventive therapy for LTBI. FC immunoprofiling one year after transplantation showed similar results. She continues to have good pulmonary function and quality of life in her second-year post-transplant without evidence of NTM or MTB infection. Escalante P, et al. Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Am J Respir Crit Care Med. 2015;192(5):605-17. PMCID: PMC4595688.

Importance Use of modern neoadjuvant chemotherapy (NAC) regimens has markedly increased rates of pathologic complete response (pCR) in breast cancer, raising the question of whether surgical removal of the primary tumor is required for patients with pCR. For surgery to be omitted, one must be able to accurately predict pCR before surgery. Objective To investigate if adding post-NAC core needle biopsy of the tumor bed to trimodality imaging in patients who have clinical complete response (cCR) will predict pCR (resolution of both invasive disease and ductal carcinoma in situ) in 90% or more cases. Design, Setting, and Participants This was a phase 2, prospective, nonrandomized clinical trial. Patients were enrolled from August 2017 to June 2019. This is the final analysis, which was completed in December 2023. The setting included academic and community hospital center members of NRG (ie, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) in the US and Canada. Patients with operable (T1-T3, stage I-III) invasive ductal carcinoma who completed NAC and achieved cCR and radiological complete response (rCR) or near rCR by mammography (mass ≤1 cm and no malignant microcalcifications), ultrasound (mass ≤2 cm), and magnetic resonance imaging (no mass with rapid rise or washout kinetics). Interventions Patients underwent marker-directed stereotactic multiple-core needle biopsy of the tumor bed with marker placement before breast-conservation surgery. Main Outcomes and Measures End points were negative predictive value (NPV) and sensitivity of the biopsy. Results A total of 105 patients were enrolled with 101 evaluable (mean [SD] age, 52.8 [10.5] years); 77 patients (76.2%) were younger than 60 years, and all breast cancer subtypes were represented with 32 (31.7%) triple-negative breast cancer, 21 (20.8%) hormone receptor–positive/epidermal growth factor receptor 2 ( ERBB2 ; formerly HER2 )–negative ( ERBB2 −) breast cancer, and 46 (45.5%) ERBB2 -positive ( ERBB2 +) breast cancer. In 101 evaluable patients, 36 had residual disease at surgery (pCR = 64%). With imaging criteria, NPV of the biopsy was 78.3% (95% CI, 67.9%-86.6%), and the sensitivity of the biopsy was 50% (95% CI, 32.9%-67.1%). In an exploratory subset analysis, the NPV in patients with ERBB2 + breast cancer was 90% (95% CI, 76.3%-97.2%). On retrospective central review, 62 of 101 enrolled patients met imaging eligibility criteria. In this exploratory post hoc analysis, NPV in these patients was 86.8% (95% CI, 74.7%-94.5%). Conclusions and Relevance These findings do not support breast conservation treatment without surgery based on the study criteria for cCR and rCR/near rCR by trimodality imaging and negative tumor-bed biopsy. Strict adherence to imaging criteria may be required to achieve acceptable predictive values. TRIAL Registration ClinicalTrials.gov Identifier: NCT03188393

Cardiac cachexia (CC) is a severe complication of advanced heart failure (HF), characterized by involuntary weight loss and muscle wasting, leading to poor outcomes and higher mortality. Despite its severity, CC remains under-recognized and undertreated, lacking targeted therapies specifically addressing its pathophysiology. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), though beneficial in reducing cardiovascular risk in patients with HF, may exacerbate muscle wasting in cachectic patients, necessitating further investigation. Non-pharmacological strategies, including tailored nutritional support and exercise programs, have shown positive effects on body composition and quality of life in patients with CC. However, there remains a gap in recommendations tailored to preventive strategies and pharmacologic therapies for patients with CC and concomitant GLP-1RA use. This review highlights the multifactorial mechanisms underlying CC and current and emerging therapeutic approaches for mitigating HF-related sarcopenia while on GLP-1RAs.

ABSTRACT Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5’ RNA ligase-mediated rapid amplification of cDNA ends (5’ Repeat-RLM-RACE), we identified novel C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, novel intronic template transcripts – even those with short (32 nucleotide) leaders – exhibited robust expression compared to exon-intron and repeat-containing lariat reporters. To assess endogenous lariat repeat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intronic-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development. SIGNIFICANCE STATEMENT An intronic GGGGCC repeat expansion in C9orf72 supports an unusual translational initiation process known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat (DPR) proteins that contribute to neurodegeneration in ALS and FTD. How an intronic repeat RNA engages with ribosomes to support such translation is unclear. Here we identify a series of novel mRNA transcripts that initiate within the repeat-containing intron to create linear m 7 G-capped templates for RAN translation from GGGGCC repeats. These cryptic mRNAs are present in patient iNeurons, engage with ribosomes, and robustly support RAN translation. This finding has important implications for both our understanding of the mechanism by which RAN translation occurs and on therapeutic development in this currently untreatable class of neurodegenerative disorders.

AbstractChronic pelvic pain (CPP), a debilitating condition affecting an estimated 25% of women worldwide, represents a significant yet understudied global health crisis. Existing research is limited and likely fails to capture the true impact of CPP on global health. What is known is that CPP results in a profound health, societal, and economic burden on women. Our inability to fully understand this burden is a critical gap in women's healthcare. To address this urgent need, the International Federation of Gynecology and Obstetrics (FIGO) and the International Pelvic Pain Society (IPPS) have partnered to develop this consensus statement where we examine the key challenges to accessing CPP care and propose a framework for overcoming these barriers. We emphasize that effective global strategies for addressing the negative health consequences of living with CPP must prioritize the lived experiences of patients, empower healthcare professionals with the necessary tools and training, and drive meaningful policy change. This call to action is grounded in a comprehensive vision of women's health and rights to address the full spectrum of conditions women experience throughout their lives. Given its high prevalence, CPP must be a central focus of this expanded vision.

Objectives/Goals: Undergraduate Medical Education (UME) may apply Just-in-Time training (JITT) to provide medical students with learning experiences closely aligned with real-time clinical needs. The purpose of this scoping review is to offer an overview of the implementation of JITT training in UME. Methods/Study Population: Following the five-stage framework by Arksey and O’Malley to methodically collect and analyze studies on JITT in UME, five electronic databases were searched, and a supplemental search for grey literature was conducted. Studies exploring the integration of JITT principles into UME clinical training and their time to follow-up after training were included. Bloom’s Taxonomy was used to assess educational goals of JITT interventions. Results/Anticipated Results: The review yielded 21 studies across 4 countries. The majority were cohort studies (13) and randomized control trials (5). Assessment definitions and use of JITT varied widely. Most studies focused on short-term outcomes, defined by being measured immediately after JITT session (15) or at the end of JITT-based rotation or clerkship (3). Three studies evaluated outcomes at a period longer than 2 weeks after completion of session or clerkship. Attitudes (9), followed by skills (8) were the most common educational goals of intervention. The efficacy and utility of JITT in improving educational goal acquisition was demonstrated in 90% (17/19) of the studies with reported outcomes. Discussion/Significance of Impact: The introduction of JITT in UME has been shown to meet the immediate needs of healthcare environments; however, evidence is limited in the evaluation of longer-term outcomes. Further research to determine the impact of JITT on long-term learning retention and education goal acquisition in UME is merited.

Objective: To address whether kidney transplant (KTx) candidates, ages 60+, should accept a high Kidney Donor Profile Index (KDPI) kidney and differences when considering a high (>85%) versus low (<85%) KDPI KTx. Background: To date, there is limited survival data to guide decision-making for patients aged ≥60 years who are faced with the choice of accepting a high KDPI kidney or remaining on the waitlist. Methods: Propensity-matched cohort study using data from United Network on Organ Sharing (2014–2021). Cox proportional hazard models and competing risk models allowed comparison of (1) patient survival on the waitlist or after KTx and (2) patient and graft survival after KTx for the second comparison between matched groups, stratified by age groups: 60 to 65, 66 to 70, and 71+. Results: Receiving a >85% KDPI kidney versus remaining on the waitlist was associated with reduced mortality [Hazard Ratio (HR): 0.68, 95% CI: 0.59–0.80, P < 0.001] overall and across the 2 oldest age groups: 66 to 70 (HR: 0.57, 95% CI: 0.44–0.73, P < 0.001) and 71+ (HR: 0.59, 95% CI: 0.44–0.83, P < 0.001). Those aged 60 to 65 did not experience a survival benefit (HR: 0.86, 95% CI: 0.67–1.11, P = 0.259). Patients ages 60+ receiving a >85% or ≤85% KDPI kidney experience comparable survival rates. Conclusions: Our study revealed a survival advantage linked to receiving a lower-quality KTx than remaining on the waitlist in the overall sample and for those 66+. Graft failure and survival were independent of the organ quality.