Personalized transcriptome signatures in a cardiomyopathy stem cell biobank.

BACKGROUND: There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines. METHODS: We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility. RESULTS: We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line . ADCY5 was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment. CONCLUSIONS: We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for ADCY5 in cardiomyopathy.

Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation?

Defining mechanisms of cardiomyocyte proliferation should guide the understanding of endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In the neonatal heart, energy metabolic reprogramming (phenotypic alteration of glucose, fatty acid, and amino acid metabolism) parallels cell cycle arrest of cardiomyocytes. The metabolic reprogramming occurring shortly after birth is associated with alterations in blood oxygen levels, metabolic substrate availability, hemodynamic stress, and hormone release. In the adult heart, myocardial infarction causes metabolic reprogramming but these changes cannot stimulate sufficient cardiomyocyte proliferation to replace those lost by the ischemic injury. Some putative pro-proliferative interventions can induce the metabolic reprogramming. Recent data show that altering the metabolic enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 [pyruvate dehydrogenase kinase 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] is sufficient to partially reverse metabolic reprogramming and promotes adult cardiomyocyte proliferation. How metabolic reprogramming regulates cardiomyocyte proliferation is not clearly defined. The possible mechanisms involve biosynthetic pathways from the glycolysis shunts and the epigenetic regulation induced by metabolic intermediates. Metabolic manipulation could represent a new approach to stimulate cardiac regeneration; however, the efficacy of these manipulations requires optimization, and novel molecular targets need to be defined. In this review, we summarize the features, triggers, and molecular regulatory networks responsible for metabolic reprogramming and discuss the current understanding of metabolic reprogramming as a critical determinant of cardiomyocyte proliferation.

Low absolute risk of thrombotic and cardiovascular events in outpatient pregnant women with COVID-19.

INTRODUCTION: Pregnancy may contribute to an excess risk of thrombotic or cardiovascular events. COVID-19 increases the risk of these events, although the risk is relatively limited among outpatients. We sought to determine whether outpatient pregnant women with COVID-19 are at a high risk for cardiovascular or thrombotic events. MATERIALS & METHODS: We analyzed pregnant outpatients with COVID-19 from the multicenter CORONA-VTE-Network registry. The main study outcomes were a composite of adjudicated venous or arterial thrombotic events, and a composite of adjudicated cardiovascular events. Events were assessed 90 days after the COVID-19 diagnosis and reported for non-pregnant women ≤45 years, and for men ≤45 years, as points of reference. RESULTS: Among 6585 outpatients, 169 were pregnant at diagnosis. By 90-day follow-up, two pregnant women during the third trimester had lower extremity venous thrombosis, one deep and one superficial vein thrombosis. The cumulative incidence of thrombotic events was 1.20 % (95 % confidence interval [CI]: 0.0 to 2.84 %). Respective rates were 0.47 % (95 % CI: 0.14 % to 0.79 %) among non-pregnant women, and 0.49 % (95 % CI: 0.06 % to 0.91 %) among men ≤45 years. No non-thrombotic cardiovascular events occurred in pregnant women. The rates of cardiovascular events were 0.53 % (95 % CI: 0.18 to 0.87) among non-pregnant women, and 0.68 % (95 % CI: 0.18 to 1.18) in men aged ≤45 years. CONCLUSIONS: Thrombotic and cardiovascular events are rare among outpatients with COVID-19. Although a higher event rate among outpatient pregnant women cannot be excluded, the absolute event rates are low and do not warrant population-wide cardiovascular interventions to optimize outcomes.

Healthcare Utilization Among Adults With Vestibular Vertigo in the United States.

OBJECTIVES: Vestibular vertigo has been shown to have a high lifetime prevalence. Previous studies have described the increased morbidities associated with vestibular vertigo. DESIGN: In this cross-sectional study of the 2016 National Health Interview Study, we sought to explore whether individuals with vestibular vertigo were more likely to utilize healthcare resources compared with those without vestibular vertigo. We characterized utilization of specific healthcare resources including general doctors, specialist doctors, emergency departments, mental health professionals, and others among individuals with vestibular vertigo to better understand how individuals with vertigo interact with the US healthcare system. RESULTS: In multivariable analyses, participants with vestibular vertigo had an increased number of nights in the hospital in the last 12 months (mean difference = 0.67 days, 95% confidence interval [CI] = 0.37 to 0.97), increased odds of receiving healthcare 10 or more times in the last 12 months (odds ratio = 2.22, 95% CI = 1.99 to 2.48) and increased number of visits to a healthcare professional in the last 2 weeks (mean difference = 0.17 visits, 95% CI = 0.14 to 0.21). In addition, participants with vestibular vertigo had increased odds of visiting both general doctors, specialist doctors, and other healthcare professionals. CONCLUSIONS: These findings characterize how individuals with vestibular vertigo utilize and interact with healthcare resources compared with those without vestibular vertigo.

Rhinoplasty Outcomes in Patients with Symptoms of Body Dysmorphia.

BACKGROUND: Patients with symptoms of body dysmorphia often seek consultation for aesthetic rhinoplasty. While body dysmorphic disorder is a formal psychiatric diagnosis, recent evidence indicates that patients with symptoms of this condition who seek rhinoplasty may experience increased satisfaction with their appearance following surgery. OBJECTIVES: To determine the psychological impact of rhinoplasty in patients screened pre-/postoperatively with a body dysmorphia screening questionnaire. METHODS: Retrospective chart review of patients who underwent aesthetic and/or functional rhinoplasty by a single surgeon (S.P.M.) from 6/2021- 4/2023. Adult patients with a complete pre- and postoperative body dysmorphic disorder-aesthetic surgery questionnaire (BDDQ-AS), Standardized Cosmesis and Health Nasal Outcomes Survey-Obstruction and Cosmesis (SCHNOS), and Visual Analog Scale (VAS) were included. Patient characteristics and outcomes were analyzed stratifying by BDDQ-AS screen. RESULTS: One-hundred fifteen patients (88% female) met criteria for inclusion. There was an 83% resolution rate in BDDQ-AS positive screening following rhinoplasty. Positive BDDQ-AS screening status pre- and postoperatively correlated with worse aesthetic satisfaction (all p<0.002). No patient reported outcome measures were indicative of which patients with a BDDQ-AS positive screen preoperatively would experience 'resolution' postoperatively. CONCLUSIONS: Body dysmorphia screening resolution following surgical intervention correlated with improved patient aesthetic satisfaction, pointing to a potential positive psychological impact of undergoing rhinoplasty.

Telehealth Usage in Otolaryngology: A Comparative Study Pre- and Post-COVID-19.

The COVID-19 pandemic led to increased telehealth utilization in outpatient otolaryngology settings. While other studies on telehealth usage in otolaryngology settings have focused on demographic disparities during the pandemic, none have yet assessed how these demographic disparities have evolved from before versus after the pandemic. This study examines 4 recent consecutive years of demographic and clinical data from a large hospital system to investigate how the COVID-19 pandemic has changed demographic patterns in telehealth utilization. We demonstrate substantial increases in the number of otolaryngology patients participating in telehealth since the beginning of the COVID-19 pandemic but with no differences in patient distributions by race or ethnicity over time. We also found that telehealth patients, on average, were younger, more likely to be English-speaking, and more likely to be female. While these disparities widened slightly after the start of the pandemic, they were also present prior to the pandemic.

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

Environmental Risk Factors for Pediatric Epistaxis vary by Climate Zone.

INTRODUCTION AND OBJECTIVE: Prior studies have provided variable results regarding environmental risk factors for epistaxis. These studies were conducted in varying climate zones, which may explain discrepancies in results. The objective of this study is to investigate correlations between season, temperature, and humidity on frequency of pediatric epistaxis across climate zones. METHODS: Children seen in the outpatient setting for epistaxis were identified from the 2007-2010 IBM MarketScan database. Climate zones were assigned according to International Energy Conservation Code (IECC) classification, where temperature zones in the United States and territories were assigned on an ordinal scale from 1 (tropical) to 8 (subarctic), and humidity zones were categorized as moist, dry, or marine. The control population was a sample of all well-child visits matched by age and county. RESULTS: We identified 184,846 unique children seen for epistaxis and 1,897,012 matched controls. Moderate temperature zones were associated with lower odds of epistaxis compared with the hottest and coldest zones. Humidity was associated inversely with epistaxis rates in moderate temperature zones but was not a significant predictor of epistaxis in climates with extreme heat. Additionally, summer was associated with lower odds of epistaxis compared to winter. Interestingly, however, there were significantly higher rates of cautery procedures during summer months, driven largely by increased procedures performed in clinic, as opposed to the operating room or emergency room. CONCLUSIONS: Environmental risk factors for epistaxis vary by climate zone. The model presented reconciles prior reports and may allow for more personalized clinical management based on regional climate. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1450-1456, 2024.

Nonopioid Versus Opioid Analgesics After Thyroid and Parathyroid Surgery: A Systematic Review.

OBJECTIVE: To determine whether nonopioid analgesic regimens, taken after discharge for thyroid and parathyroid surgery have noninferior pain outcomes in comparison to opioid analgesic regimens. Secondarily, we sought to determine if nonopioid analgesic regimens decrease the number of opioid medications taken after thyroid and parathyroid surgery, and to assess adverse events associated with opioid versus nonopioid regimens. DATA SOURCES: PubMed, Embase, Cochrane. REVIEW METHODS: A comprehensive search of the literature was performed according to the PRISMA guidelines, and identified 1299 nonduplicate articles for initial review of which 2 randomized controlled trials (RCTs) were identified as meeting all eligibility criteria. Meta-analysis was not conducted due to heterogeneity in the data and statistical analyses. RESULTS: Both RCTs included in this systematic review found no significant differences in postoperative pain scores between individuals discharged with a nonopioid only analgesic regimen compared to analgesic regimen that included oral opioid medications. One study reported significantly increased number of postoperative calls related specifically to pain in the nonopioid arm compared to the opioid arm (15.6% vs. 3.2%, P = .045). CONCLUSION: This systematic review of RCTs revealed a limited number of studies examining nonopioid versus opioid postoperative pain medications among adults who undergo thyroid and parathyroid surgery. Among the 2 RCTs on this topic, there is a shared finding that nonopioid analgesic regimens are noninferior to opioid analgesic regimens in managing postoperative pain after thyroid and parathyroid surgery, supporting the use of nonopioid pain regimens given the risk of opioid dependence associated with prescription opioid medications.

Choosing Wisely and Promoting High-Value Care and Staff Safety During the COVID-19 Pandemic in a Large Safety Net System.

BACKGROUND AND OBJECTIVES: As the COVID-19 pandemic brought surges of hospitalized patients, it was important to focus on reducing overuse of tests and procedures to not only reduce potential harm to patients but also reduce unnecessary exposure to staff. The objective of this study was to create a Choosing Wisely in COVID-19 list to guide clinicians in practicing high-value care at our health system. METHODS: A Choosing Wisely in COVID-19 list was developed in October 2020 by an interdisciplinary High Value Care Council at New York City Health + Hospitals, the largest public health system in the United States. The first phase involved gathering areas of overuse from interdisciplinary staff across the system. The second phase used a modified Delphi scoring process asking participants to rate recommendations on a 5-point Likert scale based on criteria of degree of evidence, potential to prevent patient harm, and potential to prevent staff harm. RESULTS: The top 5 recommendations included avoiding tracheal intubation without trial of noninvasive ventilation (4.4); not placing routine central venous catheters (4.33); avoiding routine daily laboratory tests and batching laboratory draws (4.19); not ordering daily chest radiographs (4.17); and not using bronchodilators in the absence of reactive airway disease (4.13). CONCLUSION: We successfully developed Choosing Wisely in COVID-19 recommendations that focus on evidence and preventing patient and staff harm in a large safety net system to reduce overuse.

Foreign Body Reaction Requiring Re-Exploration After Tympanoplasty With Porcine Small Intestinal Submucosa Reconstruction.

OBJECTIVE: We present the first published case of large foreign body reaction to Biodesign (Cook Medical, Bloomington, IN), an acellular otologic graft matrix derived from porcine small intestinal submucosa, after use in tympanoplasty surgery in a patient without previous exposure to meat products. METHODS: A single case report of a 39-year-old female who developed tinnitus, ear drainage, and large fibrotic mass in external auditory canal and extending into middle ear after Type I medial graft tympanoplasty with Biodesign Graft. Left endoscopic microdissection and resection of the tympanic membrane and middle ear fibrotic mass were performed. MAIN FINDINGS: Surgical excision of the fibrous mass required extensive microdissection to ensure preservation of the ossicles and chorda tympani. Postoperatively, hearing improved and otalgia and otorrhea resolved. CONCLUSIONS: We report the first case of post-tympanoplasty reaction with the use of Biodesign acellular porcine graft in a patient with no previous known exposure to meat products. Although this presentation appears to be rare, it reinforces the need for careful patient selection and counseling around the use of porcine or other foreign grafts.

The novel antibody fusion protein rhNRG1-HER3i promotes heart regeneration by enhancing NRG1-ERBB4 signaling pathway.

Stimulating cardiomyocyte proliferation in the adult heart has emerged as a promising strategy for cardiac regeneration following myocardial infarction (MI). The NRG1-ERBB4 signaling pathway has been implicated in the regulation of cardiomyocyte proliferation. However, the therapeutic potential of recombinant human NRG1 (rhNRG1) has been limited due to the low expression of ERBB4 in adult cardiomyocytes. Here, we investigated whether a fusion protein of rhNRG1 and an ERBB3 inhibitor (rhNRG1-HER3i) could enhance the affinity of NRG1 for ERBB4 and promote adult cardiomyocyte proliferation. In vitro and in vivo experiments were conducted using postnatal day 1 (P1), P7, and adult cardiomyocytes. Western blot analysis was performed to assess the expression and activity of ERBB4. Cardiomyocyte proliferation was evaluated using Ki67 and pH 3 immunostaining, while fibrosis was assessed using Masson staining. Our results indicate that rhNRG1-HER3i, but not rhNRG1, promoted P7 and adult cardiomyocyte proliferation. Furthermore, rhNRG1-HER3i improved cardiac function and reduced cardiac fibrosis in post-MI hearts. Administration of rhNRG1-HER3i inhibited ERBB3 phosphorylation while increasing ERBB4 phosphorylation in adult mouse hearts. Additionally, rhNRG1-HER3i enhanced angiogenesis following MI compared to rhNRG1. In conclusion, our findings suggest that rhNRG1-HER3i is a viable therapeutic approach for promoting adult cardiomyocyte proliferation and treating MI by enhancing NRG1-ERBB4 signaling pathway.

Parosteal Lipoma Overlying an Osteochondroma of the Hyoid Bone: A Case Report and Literature Review.

Parosteal lipomas and osteochondromas of the head and neck are uncommon benign tumors, constituting a small fraction of lipoma and bone tumor cases. We present a unique case of a 66-year-old male with a parosteal lipoma overlying an osteochondroma in the anterior midline neck, causing dysphagia. Surgical excision confirmed the diagnosis, and a literature review revealed similar cases predominantly adjacent to the mandible or calvaria. This case emphasizes the need to have parosteal lipoma and osteochondroma on the differential diagnosis for patients presenting with a firm mass of the central neck, especially with a history of trauma. Laryngoscope, 2023.

Prevalence and Characteristics Associated with Positive Body Dysmorphic Disorder Screening Among Patients Presenting for Cosmetic Facial Plastic Surgery.

Background: Many patients with body dysmorphic disorder (BDD) seek out cosmetic surgery to alleviate their symptoms of distress related to a perceived defect in their appearance; however, the prevalence and risk factors for BDD among patients with cosmetic concerns have not been well characterized. Methods: We screened adult patients presenting to the clinic from June 2021 through September 2022 for BDD using the BDD Questionnaire-Aesthetic Surgery (BDDQ-AS) who were seen in consultation for rhinoplasty, aging face, and injectables. Results: Among 488 patients, the prevalence of screening positive for BDD was 41.0%. The prevalence of a positive BDD screen was highest among patients who were younger (p = 0.02), and those who had a positive self-reported psychiatric history (p = 0.02). Among rhinoplasty patients, those with aesthetic/cosmetic motivations, and those seeking revision rhinoplasty had higher rates of positive BDD screen. Higher scores on the Standardized Cosmesis and Health Nasal Outcomes Survey-Nasal Obstruction Score (SCHNOS-O) (p = 0.01) and Standardized Cosmesis and Health Nasal Outcomes Survey-Nasal Obstruction Score-Nasal Cosmesis Score (SCHNOS-C) (p < 0.0001) were predictive of a positive BDD screen, while question 5 of the SCHNOS was highly predictive of positive BDD screening (p < 0.0001). Conclusions: Our study characterizes relationships between positive BDD screening and age, gender, self-reported psychiatric history, and motivations for consultation, among patients seen for cosmetic surgery evaluation in a facial plastic and reconstructive surgery setting.

The characteristics of proliferative cardiomyocytes in mammals.

Better understanding of the mechanisms regulating the proliferation of pre-existing cardiomyocyte (CM) should lead to better options for regenerating injured myocardium. The absence of a perfect research model to definitively identify newly formed mammalian CMs is lacking. However, methodologies are being developed to identify and enrich proliferative CMs. These methods take advantages of the different proliferative states of CMs during postnatal development, before and after injury in the neonatal heart. New approaches use CMs labeled in lineage tracing animals or single cell technique-based CM clusters. This review aims to provide a timely update on the characteristics of the proliferative CMs, including their structural, functional, genetic, epigenetic and metabolic characteristics versus non-proliferative CMs. A better understanding of the characteristics of proliferative CMs should lead to the mechanisms for inducing endogenous CMs to self-renew, which is a promising therapeutic strategy to treat cardiac diseases that cause CM death in humans.

Choosing Wisely interventions to reduce antibiotic overuse in the safety net.

OBJECTIVES: Physician pay-for-performance (P4P) programs frequently target inappropriate antibiotics. Yet little is known about P4P programs' effects on antibiotic prescribing among safety-net populations at risk for unintended harms from reducing care. We evaluated effects of P4P-motivated interventions to reduce antibiotic prescriptions for safety-net patients with acute respiratory tract infections (ARTIs). STUDY DESIGN: Interrupted time series. METHODS: A nonrandomized intervention (5/28/2015-2/1/2018) was conducted at 2 large academic safety-net hospitals: Los Angeles County+University of Southern California (LAC+USC) and Olive View-UCLA (OV-UCLA). In response to California's 2016 P4P program to reduce antibiotics for acute bronchitis, 5 staggered Choosing Wisely-based interventions were launched in combination: audit and feedback, clinician education, suggested alternatives, procalcitonin, and public commitment. We also assessed 5 unintended effects: reductions in Healthcare Effectiveness Data and Information Set (HEDIS)-appropriate prescribing, diagnosis shifting, substituting antibiotics with steroids, increasing antibiotics for ARTIs not penalized by the P4P program, and inappropriate withholding of antibiotics. RESULTS: Among 3583 consecutive patients with ARTIs, mean antibiotic prescribing rates for ARTIs decreased from 35.9% to 22.9% (odds ratio [OR], 0.60; 95% CI, 0.39-0.93) at LAC+USC and from 48.7% to 27.3% (OR, 0.81; 95% CI, 0.70-0.93) at OV-UCLA after the intervention. HEDIS-inappropriate prescribing rates decreased from 28.9% to 19.7% (OR, 0.69; 95% CI, 0.39-1.21) at LAC+USC and from 40.9% to 12.5% (OR, 0.72; 95% CI, 0.59-0.88) at OV-UCLA. There was no evidence of unintended consequences. CONCLUSIONS: These real-world multicomponent interventions responding to P4P incentives were associated with substantial reductions in antibiotic prescriptions for ARTIs in 2 safety-net health systems without unintended harms.