Citations

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Anti-retroviral therapy (ART) has greatly improved the quality and length of life for people living with HIV, but immune activation does not normalize during ART, and persistent immune activation has been linked to increased morbidity and mortality. We report a comparison of assays of two potential sources of immune activation during ART: rare cells producing HIV and the virus’ major viral protein, p24, benchmarked on a cell model of active and latent infections and a method to visualize HIV-producing cells.

Background: Black adults experience a disproportionately higher burden of cardiovascular risk factors and disease in comparison with White adults in the United States. Less is known about how sex-based disparities in cardiovascular mortality between these groups have changed on a national scale over the past 20 years, particularly across geographic determinants of health and residential racial segregation. Methods: We used CDC WONDER (Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research) to identify Black and White adults age ≥25 years in the United States from 1999 to 2019. We calculated annual age-adjusted cardiovascular mortality rates (per 100 000) for Black and White women and men, as well as absolute rate differences and rate ratios to compare the mortality gap between these groups. We also examined patterns by US census region, rural versus urban residence, and degree of neighborhood segregation. Results: From 1999 to 2019, age-adjusted mortality rates declined overall for both Black and White adults. There was a decline in age-adjusted cardiovascular mortality among Black (602.1 to 351.8 per 100 000 population) and White women (447.0 to 267.5), and the absolute rate difference (ARD) between these groups decreased over time (1999: ARD, 155.1 [95% CI, 149.9–160.3]; 2019: ARD, 84.3 [95% CI, 81.2–87.4]). These patterns were similar for Black (824.1 to 526.3 per 100 000) and White men (637.5 to 396.0; 1999: ARD, 186.6 [95% CI, 178.6–194.6]; 2019: ARD, 130.3 [95% CI, 125.6–135.0]). Despite this progress, cardiovascular mortality in 2019 was higher for Black women (rate ratio, 1.32 [95% CI, 1.30–1.33])— especially in the younger (age <65 years) subgroup (rate ratio, 2.28 [95% CI, 2.23–2.32])—as well as for Black men (rate ratio, 1.33 [95% CI, 1.32–1.34]), compared with their respective White counterparts. There was regional variation in cardiovascular mortality patterns, and the Black-White gap differed across rural and urban areas. Cardiovascular mortality rates among Black women and men were consistently higher in communities with high levels of racial segregation compared with those with low to moderate levels. Conclusions: During the past 2 decades, age-adjusted cardiovascular mortality declined significantly for Black and White adults in the United States, as did the absolute difference in death rates between these groups. Despite this progress, Black women and men continue to experience higher cardiovascular mortality rates than their White counterparts.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

Abstract Using exome sequencing for biomarker discovery and precision medicine requires connecting nucleotide-level variation with functional changes in encoded proteins. However, for functionally annotating the thousands of cancer-associated missense mutations, or variants of uncertain significance (VUS), purifying variant proteins for biochemical and functional analysis is cost-prohibitive and inefficient. We describe parallel functional annotation (PFA) of large numbers of VUS using small cultures and crude extracts in 96-well plates. Using members of a histone methyltransferase family, we demonstrate high-throughput structural and functional annotation of cancer-associated mutations. By combining functional annotation of paralogs, we discovered two phylogenetic and clustering parameters that improve the accuracy of sequence-based functional predictions to over 90%. Our results demonstrate the value of PFA for defining oncogenic/tumor suppressor functions of histone methyltransferases as well as enhancing the accuracy of sequence-based algorithms in predicting the effects of cancer-associated mutations.

Objectives To assess the association between emergency medicine physician supervision and 3-day mortality for patients receiving care from non-physician clinicians in a task-sharing model of emergency care in rural Uganda. Design Retrospective cohort analysis with multivariable logistic regression. Setting Single rural Ugandan emergency unit. Participants All patients presenting for care from 2009 to 2019. Interventions Three cohorts of patients receiving care from non-physician clinicians had three different levels of physician supervision: ‘Direct Supervision’ (2009–2010) emergency medicine physicians directly supervised all care; ‘Indirect Supervision’ (2010–2015) emergency medicine physicians were consulted as needed; ‘Independent Care’ (2015–2019) no emergency medicine physician supervision. Primary outcome measure Three-day mortality. Results 38 033 ED visits met inclusion criteria. Overall mortality decreased significantly across supervision cohorts (‘Direct’ 3.8%, ‘Indirect’ 3.3%, ‘Independent’ 2.6%, p<0.001), but so too did the rates of patients who presented with ≥3 abnormal vitals (‘Direct’ 32%, ‘Indirect’ 19%, ‘Independent’ 13%, p<0.001). After controlling for vital sign abnormalities, ‘Direct’ and ‘Indirect’ supervision were both significantly associated with reduced OR for mortality (‘Direct’: 0.57 (0.37 to 0.90), ‘Indirect’: 0.71 (0.55 to 0.92)) when compared with ‘Independent Care’. Sensitivity analysis showed that this mortality benefit was significant for the minority of patients (17.2%) with ≥3 abnormal vitals (‘Direct’: 0.44 (0.22 to 0.85), ‘Indirect’: 0.60 (0.41 to 0.88)), but not for the majority (82.8%) with two or fewer abnormal vitals (‘Direct’: 0.81 (0.44 to 1.49), ‘Indirect’: 0.82 (0.58 to 1.16)). Conclusions Emergency medicine physician supervision of emergency care non-physician clinicians is independently associated with reduced overall mortality. This benefit appears restricted to the highest risk patients based on abnormal vitals. With over 80% of patients having equivalent mortality outcomes with independent non-physician clinician emergency care, a synergistic model providing variable levels of emergency medicine physician supervision or care based on patient acuity could safely address staffing shortages.

Background: The study of hypertrophic cardiomyopathy (HCM) can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease. Methods: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered short hairpin ribonucleic acids and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell–derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics. Results: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio . Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell–derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil. Conclusions: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

Introduction Coronavirus disease 2019 accelerated the use of virtual visits within health care. We examined the utility of telemedicine for conducting visits in a tertiary head and neck practice. Methods A retrospective study was conducted on patients presenting via video to a tertiary-level head and neck clinic between January 2020 and December 2020. Patient demographics were collected in addition to visit indication, diagnostic imaging/tests at the time of visit, and post-visit plan. Visits were deemed successful if evaluation by video was sufficient in determining a clinical plan and did not require deferment of recommendations for subsequent in-person consult visits and/or work-up (labs, imaging). Logistic regression was performed to identify variables that served as significant predictors of successful video visits. Results A total of 124 video visits were reviewed. Video visits were successful for the initial evaluation 88.7% of the time ( n = 110). Computerized tomographic scans were the most available diagnostic test, available for 54% of patients ( n = 67), followed by biopsy report 30.6% ( n = 38). Visit indication had a statistically significant effect on whether a treatment plan could be made ( p = 0.024). For new patients with parotid masses ( n = 42), definitive treatment plans could be made 97.6% of the time ( n = 41). Patients presenting with an indication of thyroid mass (odds ratio: 0.19 (confidence interval: 0.00072–0.50), p = 0.018) and other neck mass (odds ratio: 0.035 (confidence interval: 0.0014, 0.90), p = 0.043) were at significantly lesser odds than parotid patients to have a successful video visit. Discussion In this study, virtual visits were successful for a high percentage of head and neck visits, particularly among patients seeking evaluation for parotid-related concerns.

TPS8604 Background: Chemoimmunotherapy followed by durvalumab maintenance yields a median overall survival of 12.9 months in patients with extensive stage Small Cell Lung Cancer (ES SCLC), which is an improvement over chemotherapy alone. However, 90% of these patients will have progressive disease. While topotecan and lurbinectedin have established modest activity in the second line, it is unknown whether continuing immunotherapy in this setting confers additional benefit. In preclinical studies lurbinectedin, a DNA minor groove binder, used with immune checkpoint inhibitors has synergistic effects. Methods: This phase 2 trial is enrolling patients with ES SCLC who have progressed on platinum based chemoimmunotherapy, to three treatment groups. Group 1 includes patients with platinum sensitive SCLC who will receive durvalumab (1500 mg given as an intravenous [IV] infusion once every 3 weeks) and topotecan (1.25 mg/m2/day IV for 5 consecutive days every 3 weeks). In Groups 2A and 2B, patients with platinum sensitive and platinum resistant disease respectively, receive durvalumab and lurbinectedin (3.2 mg/m2 IV on Day 1 of every 21-day cycle). Patients with platinum sensitive disease are assigned to Groups 1 or 2A based on the preferences of the treating physician and the patient. Patients with treated/stable CNS metastases are eligible. The primary endpoint is the proportion of patients who are alive at 6 months (6OS) for Group 1 and the proportion of patients who are alive and progression-free at 6 months (6PFS) in Groups 2A and 2B. Secondary endpoints include safety, adverse event profile, response rate, PFS, and OS. The sample size is based on a 2-stage Simon Optimal Design. For Treatment Group 1, with 22 eligible patients there is 80% power to detect a true 6-month OS rate (6OS) of 75%, with 10% alpha under the null hypothesis that the true 6OS is at most 50%. For Treatment Group 2A, with 20 eligible patients this design has 80% power to detect a true 6-month PFS rate (6PFS) of 65%, with 10% alpha under the null hypothesis that the true 6PFS is at most 40%. For Treatment Group 2B, with 22 eligible patients this design has 80% power to detect a true 6-month PFS rate (6PFS) of 40%, with 10% alpha under the null hypothesis that the true 6PFS is at most 19%. To account for possible drop-outs, accrual targets will be 24, 22, and 24 patients to Groups 1, 2A, and 2B respectively. For the safety analyses, 6 patients will be enrolled at the starting dose level for each treatment group (1, 2) and then briefly closed to accrual to assess adverse events. If we observe 2+ DLTs in these 6 treated patients during Cycle 1 within a treatment group (1 vs. 2), we will declare the combination treatment too toxic and lower the starting dose of chemotherapy for the next 6 patients. The study was open for all 3 groups as of January 2022 and has accrued 2 patients. Clinical trial information: NCT04607954.

Abstract Background: The discovery of the driving oncogenic alterations in pediatric low-grade gliomas (pLGGs) has shifted our focus towards management with targeted therapies, especially in relapsing or progressive disease. Limited data is available on the durability of response to targeted therapy in pLGGs once the therapy has ceased. Methods: Multi-institutional retrospective chart review of patients with pLGGs younger than 25 years, between 2010-2021, was undertaken to evaluate the durability of response to targeted therapy and determine risk factors associated with disease progression after cessation of therapy. Results: Current analysis included 18 patients from two centers. Seven (39%) had neurofibromatosis type-1 (NF-1). Diagnoses included: optic pathway glioma (OPG) (6/18, 33%), pilocytic astrocytoma (8/18, 44%), diffuse fibrillary astrocytoma (1/18), ganglioglioma (1/18), glioneural neoplasm (2/18). Sixteen patients received at least one prior line of chemotherapy (range 1-5). Targeted agents included trametinib (50%), selumetinib (5%), binimetinib (22%), vemurafenib (11%) and everolimus (11%). Median time on therapy was 351 days (range 29-979 days). All, but one patient had residual intracranial findings at the end of therapy: eight patients (44%) had stable disease, while ten required additional therapy; 50% were NF-1 patients with OPG. Median time to progression was 203 days (range 29-615 days). Of those who did not require any additional therapies, 50% had suprasellar tumors. Genomic data was available for twelve patients; BRAF-KIAA1549 fusion was the most common genomic alteration. Others included mutations in KRAS, BRAF (V600E), PTPN11, SOX6-RAF1 fusion, NF-1, and a patient with FGFR1, KMT2C, and PTPN11 alterations. Conclusion: Preliminary analysis demonstrates that despite initial response, the majority of patients required additional line of therapy. Patients with NF-1 and OPGs tend to progress after discontinuing therapy, while suprasellar non-NF1 pLGGs tend to develop sustained response to targeted therapies. Additional multi-institutional analysis is underway and will be presented at the meeting.