Citations

Abstract Background The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research has shown that the deleterious effects and the subsequent molecular consequence of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantified on an exome-wide scale if the existence of pathogenic variants in paralogous genes at a conserved position could serve as evidence for the pathogenicity of a new variant. For the gene family of voltage-gated sodium channels where variants and expert-curated clinical phenotypes were available, we also assessed whether phenotype patterns of multiple disorders for each gene were also conserved across variant positions within the gene family. Methods We developed a framework that assesses the presence of pathogenic missense variants located in conserved residues across paralogous genes. We systematically mapped 2.5 million pathogenic and general population variants from the ClinVar, HGMD, and gnomAD databases onto a total of 9,990 genes and aligned them by gene families. We evaluated the quantity of classifiable amino acids by utilizing pathogenic variants identified in databases alone and then compared this assessment to the inclusion of paralogous pathogenic variants. We validated and quantified the evidence of conserved pathogenic paralogous variants in variant pathogenicity classification. Results Considering conserved pathogenic variants in paralogous genes, increased the number of classifiable variants 2.8-fold across the exome, compared to pathogenic variants in the gene of interest alone. The presence of a pathogenic variant in a paralogous gene is associated with a positive likelihood ratio of 8.32 for variant pathogenicity. The likelihood ratio was gene family-specific. Across ten genes encoding voltage-gated sodium channels and 22 expert-curated disorders, we identified cross-paralog correlated phenotypes based on 3D structure spatial position. For example, the established loss-of-function disorders SCN1A-associated Dravet syndrome, SCN2A-associated autism, SCN5A-associated Brugarda Syndrome, and SCN8A-associated neurodevelopmental disorder without seizures were correlated in their spatial variant position on structure. Finally, we show that phenotype integration in paralog variant selection improves variant classification. Conclusion Our results show that paralogous variants, in particular with phenotype information can enhance our understanding of variant effects.

Introduction: Metabolic pharmacotherapies [Glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i)] have shown benefit in patients with heart failure and preserved ejection fraction (HFpEF). It remains unclear whether the two classes would have additive effects. Methods: We performed a retrospective study using a de-identified federated database with 89 contributing health care organizations (HCO), including over 126 million patients (TriNetX Research Network, Cambridge, MA; date of data access: May 23, 2024). TriNetX regularly aggregates clinical data directly from participating HCOs, and performs extensive data quality and accuracy assessment. While TriNetX obfuscates institutional information relating to participating HCOs, a typical HCO includes a large academic health center with inpatient, outpatient, and specialty care services. We identified all patients with a diagnosis of Heart failure with preserved ejection fraction (HFpEF, ICD-10: I50.3), and SGLT2i usage. We then categorized this patient population into two cohorts, including patients with concomitant GLP1RA use, and patients without GLP1RA use. For both cohorts, we collected data on patient demographics, and the outcomes of all-cause mortality, and all-cause hospitalization, occurring up to 10-years after the index diagnosis. We evaluated differences in outcome risk using hazards ratios and 95% confidence intervals. Results: Prior to propensity score matching, we identified 114,329 patients, with 7931 patients receiving SGLT2i +GLP1RA vs 106398 receiving SGLT2i-alone. Majority (55.7%) identified as white and 24.4% as African Americans and >90% of the patients had a diagnosis of type 2 diabetes mellitus. After propensity matching, the rate of all-cause hospitalization within the combination group was lower than SGLT2i group (29.6% vs 32.4%, HR 0.76 [0.73- 0.79], P<0.001). All-cause mortality for the combination group was 6.8% versus 10.6% within the SGLT2i-alone group (HR 0.52 [0.47-0.56], P<0.001)). Conclusion: In this propensity-matched cohort, patients with HFpEF receiving GLP1RA and SGLT2i had lower rates of hospitalizations and all-cause mortality compared with those receiving SGLT2i alone. Large randomized controlled trials are warranted to corroborate these findings.

Introduction/Background: Patients with heart failure and those waiting for a heart transplant often experience a significant decrease in their ability to perform daily activities and exercise, leading to a lower quality of life. Although exercise-based cardiac rehabilitation (EBCR) is a possible treatment option, its effectiveness has not been well measured, resulting in limited adoption. Research Questions/Hypothesis: Could physical rehabilitation before receiving a heart transplant improve functional status and better outcomes? Goals/Aims: Our objective is to evaluate the effect of pre-transplant physical therapy on the standardized improvement of AM-PAC scores, measured from the earliest pre-transplant assessment to the most recent pre-transplant evaluation. Our second objective is to assess the impact of the latest Pre-Transplant AM-PAC Score on the number of hospital-free days following transplantation. Methods: We conducted a retrospective study on 91 heart transplant patients who received Impella support from January 2019 to April 2023, approved by the Mayo Clinic Institutional Review Board. We collected data on demographics, AMPAC scores, and outcomes at three time points. Continuous variables were compared using the T-test or Mann-Whitney test, and categorical variables using the Chi-square or Fisher's exact test. We used a linear regression model to investigate the relationship between rehabilitation duration and AMPAC scores. Quantile regression was preferred due to the non-normal distribution of the outcome, hospital-free days. Results: We conducted a linear regression analysis and found a statistically significant association between increased hours spent in PT and greater improvement. After one hour of physical therapy, there was an average increase of 1.07 (95% CI 0.1, 2; p=0.03) in AMPAC scoore. We also compared the change in the AMPAC score with hospital-free days, and it was statistically significant in quantile regression analysis, indicating an increase of 0.28 (95% CI 0.2, 0.55; P=0.03) points in the AMPAC Score, corresponding to an additional hospital-free day. Conclusion: Increased hours spent in physical therapy show a significant positive association with greater improvement in standardized AM-PAC Mobility scores and hospital-free days. These findings encourage increasing uptake and support of cardiac rehabilitation programs.

Abstract The field of infectious diseases (ID) offers a rewarding career path and is widely viewed as an essential subspecialty in medicine. However, in recent years, these positive aspects have been overshadowed by concerns surrounding low fellowship match rates, undercompensation, and burnout. The Infectious Diseases Society of America Fellowship Training Program Directors Committee met in 2023, discussed the future of ID as a specialty, and sought to develop strategies to highlight the value and opportunities of ID for future generations, as well as underscore the importance of and provide tools for positive messaging to trainees about the subspecialty. This paper presents ideas generated at this meeting and is meant to serve as a reference for ID training program directors, as well as the wider ID community, in uplifting and shaping the future of the field.

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

Study Design. Literature review. Objective. The goal of this study was to provide a comprehensive outline of spinal injuries that may transpire over the course of military service from traumatic to repetitive stress injuries and chronic sequelae. We considered studies that assessed spinal injuries in combat and non-combat settings as reported in the literature over the last 15 to 20 years. Background. Military service places servicemembers under substantial physical demands, while also exposing them to dangerous, unpredictable environments. As a result, servicemembers are at an increased risk of spinal injuries from combat-related trauma and other causes. They may have different care needs and recovery profiles when compared with civilians with spinal disorders. Materials and Methods. We performed a review of the available literature on spinal injuries and spinal care in the Military Health System from 2001 to the present. Results. The studies discussed in this review were primarily focused on the conflicts in both Iraq and Afghanistan from over 10 years ago and do not fully capture the present-day advancements in military technology that may have an impact on the potential for spinal injuries. The long-term effects of sustained military service and the relative influence of high demand versus sedentary military occupations on the development of spinal disorders remain poorly understood. Given the changing nature of military service, both with respect to the demographic in uniform and the ever-evolving nature of modern combat, we believe that only a long-term prospective observational study dedicated to the surveillance of spinal problems could effectively answer these questions. Conclusion. Further research into the present-day characterization of spinal injuries is warranted given the advancements in both military technology and spine care that have occurred over the last 10 years.

Background: Cardiometabolic disease (CMD) disproportionately affects African American/Black (AA) and Latino communities. CMD disparities are exacerbated by their underrepresentation in clinical trials for CMD treatments including nutritional interventions. The study aimed to (1) form a precision nutrition community consultant panel (PNCCP) representative of Latino and AA communities in Los Angeles to identify barriers and facilitators to recruitment and retention of diverse communities into nutrition clinical trials and (2) develop culturally informed strategies to improve trial diversity. Methods: A deliberative community engagement approach was used to form a PNCCP for the Nutrition for Precision Health (NPH) trial, part of the of the All of Us research initiative. The PNCCP included individuals that provide services for Latino and AA communities who met during 11 virtual sessions over 1 year. Discussion topics included enhancing recruitment and cultural acceptance of the NPH trial. We summarized CCP recommendations by theme using an inductive qualitative approach. Results: The PNCCP included 17 adults (35% AA, 47% Latino). Four thematic recommendations emerged: reducing structural barriers to recruitment, the need for recruitment materials to be culturally tailored and participant-centered, community-engaged trial recruitment, and making nutrition trial procedures inclusive and acceptable. We outlined the study response to feedback, including the constraints that limited implementation of suggestions. Conclusion: This study centers community voices regarding the recruitment and retention of AA and Latino communities into a nutrition clinical trial. It highlights the importance of community engagement early on in protocol development and maintaining flexibility to enhance inclusion of diverse communities in nutrition clinical trials.