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AbstractBackgroundOver the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi‐organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day‐to‐day activities and are directly associated with poor quality of life.MethodsMice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late‐effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post‐necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7‐positive nuclei per myofibre), post‐sepsis whole muscle metabolomics and MuSC isolation and high‐content transcriptional profiling.ResultsWe report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post‐sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post‐sepsis muscle recovery (maintenance of 5–8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post‐sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis‐recovered mice exhibited evidence of impaired muscle regeneration compared with non‐septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post‐sepsis mice and found clear transcriptional differences in all post‐sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001).ConclusionsOur data show that MuSCs and muscle regeneration are required for effective post‐sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post‐sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.

Introduction: Esthesioneuroblastoma (ENB) is a rare malignant neoplasm arising from the olfactory epithelium of the cribriform plate. Although survival is excellent with a reported 5-year overall survival (OS) of 82%, recurrence is frequent and occurs in 40–50% of cases. This study investigates the characteristics of ENB recurrence and the subsequent prognosis of patients with recurrence. Methods: The clinical records of all patients diagnosed as having ENB with subsequent recurrence at a tertiary hospital from 1 January 1960 to 1 January 2020 were retrospectively reviewed. Overall survival (OS) and progression-free survival (PFS) were reported. Results: A total of 64 out of 143 ENB patients had recurrences. In total, 45 out of 64 recurrences met the inclusion criteria and were included in this study. From these, 10 (22%) had a sinonasal recurrence, 14 (31%) had an intracranial recurrence, 15 (33%) had a regional recurrence, and 6 (13%) had a distal recurrence. The average interval from initial treatment to recurrence was 4.74 years. There were no differences in rates of recurrence with respect to age, sex, or types of surgery (endoscopic, transcranial, lateral rhinotomy, and combined). The time to recurrence was shorter for Hyams grades 3 and 4 compared to Hyams grades 1 and 2 (3.75 years vs. 5.70 years, p < 0.05). Patients with recurrence limited to the sinonasal region had a lower overall primary Kadish stage compared to recurrences beyond the sinonasal region (2.60 vs. 3.03, p < 0.05). A total of 9 (20%) out of 45 patients developed secondary recurrence. Following recurrence, the subsequent 5-year OS and PFS were 63 and 56%, respectively. The mean time to secondary recurrence after treatment of the primary recurrence was 32 months, which was significantly shorter than the time to primary recurrence (32 months vs. 57 months, p = 0.048). The mean age of the secondary recurrence group is significantly older than the primary recurrence group (59.78 years vs. 50.31 years, p = 0.02). No statistically significant differences were observed between the secondary recurrence group and the recurrence group in terms of their overall Kadish stages or Hyams grades. Conclusions: Following an ENB recurrence, salvage therapy appears to be an effective therapeutic option with a subsequent 5-year OS of 63%. However, subsequent recurrences are not infrequent and may require additional therapy.

Although the precise mechanisms for neurodegeneration in Parkinson’s disease (PD) are unknown, evidence suggests that neuroinflammation is a critical factor in the pathogenic process. Here, we sought to determine whether the voltage-gated proton channel, Hv1 (HVCN1), which is expressed in microglia and regulates NADPH oxidase, is associated with dopaminergic neurodegeneration. We utilized data mining to evaluate the mRNA expression of HVCN1 in the brains of PD patients and controls and uncovered increased expression of the gene encoding Hv1, HVCN1, in the brains of PD patients compared to controls, specifically in male PD patients. In an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 16 mg/kg) mouse model of PD, Hvcn1 gene expression was increased 2-fold in the striatum. MPTP administration to wild-type (WT) mice resulted in a ~65% loss of tyrosine hydroxylase positive neurons (TH+) in the substantia nigra (SN), while a ~39% loss was observed in Hv1 knockout (KO) mice. Comparable neuroprotective effects of Hv1 deficiency were found in a repeated-dose LPS model. Neuroprotection was associated with decreased pro-inflammatory cytokine levels and pro-oxidant factors in both neurotoxicant animal models. These in vivo results were confirmed in primary microglial cultures, with LPS treatment increasing Hvcn1 mRNA levels and Hv1 KO microglia failing to exhibit the LPS-mediated inflammatory response. Conditioned media from Hv1 KO microglia treated with LPS resulted in an attenuated loss of cultured dopamine neuron cell viability compared to WT microglia. Taken together, these data suggest that Hv1 is upregulated and mediates microglial pro-inflammatory cytokine production in parkinsonian models and therefore represents a novel target for neuroprotection.

Purpose To (1) report the long‐term outcomes associated with both operative and nonoperative management of capitellar osteochondritis dissecans (OCD), (2) identify factors associated with failure of nonoperative management, and (3) determine whether delay in surgery affects final outcomes. Methods All patients who received a diagnosis of capitellar OCD from 1995‐2020 within a geographic cohort were included. Medical records, imaging studies, and operative reports were manually reviewed to record demographic data, treatment strategies, and outcomes. The cohort was divided into 3 groups: (1) nonoperative management, (2) early surgery, and (3) delayed surgery. Delayed surgery (surgery ≥6 months after symptom onset) was considered failure of nonoperative management. Results Fifty elbows with a mean follow‐up period of 10.5 years (median, 10.3 years; range, 1‐25 years) were studied. Of these, 7 (14%) were definitively treated nonoperatively, 16 (32%) underwent delayed surgery after at least 6 months of failed nonoperative treatment, and 27 (54%) underwent early surgical intervention. When compared with nonoperative management, surgical management resulted in superior Mayo Elbow Performance Index pain scores (40.1 vs 33, P = .04), fewer mechanical symptoms (9% vs 50%, P < .01), and better elbow flexion (141° vs 131°, P = .01) at long‐term follow‐up. Older patients trended toward increased failure of nonoperative management ( P = .06). The presence of an intra‐articular loose body predicted failure of nonoperative management ( P = .01; odds ratio, 13). Plain radiography and magnetic resonance imaging had poor sensitivities for identifying loose bodies (27% and 40%, respectively). Differences in outcomes after early versus delayed surgical management were not observed. Conclusions Nonoperative management of capitellar OCD failed 70% of the time. Elbows that did not undergo surgery had slightly more symptoms and decreased functional outcomes compared with those treated surgically. The greatest predictors of failure of nonoperative treatment were older age and presence of a loose body; however, an initial trial of nonoperative treatment did not adversely impact the success of future surgery. Level of Evidence Level III, retrospective cohort study.

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon’s minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery–magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues–Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor β (PDGFRβ) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.

Background: Long-QT syndrome (LQTS) is characterized by QT prolongation and increased risk for syncope, seizures, and sudden cardiac death. The majority of LQTS stems from pathogenic mutations in KCNQ1 , KCNH2 , or SCN5A . However, ≈10% of patients with LQTS remain genetically elusive. We utilized genome sequencing to identify a novel LQTS genetic substrate in a multigenerational genotype-negative LQTS pedigree. Methods: Genome sequencing was performed on 5 affected family members. Only rare nonsynonymous variants present in all affected family members were considered. The candidate variant was characterized functionally in patient-derived induced pluripotent stem cell and gene-edited, variant corrected, isogenic control induced pluripotent stem cell–derived cardiomyocytes. Results: A missense variant (p.G6S) was identified in ALG10B -encoded α-1,2-glucosyltransferase B protein. ALG10B (alpha-1,2-glucosyltransferase B protein) is a known interacting protein of KCNH2 -encoded K v 11.1 (HERG [human Ether-à-go-go–related gene]). Compared with isogenic control, ALG10B-p.G6S induced pluripotent stem cell–derived cardiomyocytes showed (1) decreased protein expression of ALG10B (p.G6S, 0.7±0.18, n=8 versus control, 1.25±0.16, n=9; P <0.05), (2) significant retention of HERG in the endoplasmic reticulum ( P <0.0005), and (3) a significantly prolonged action potential duration confirmed by both patch clamp (p.G6S, 531.1±38.3 ms, n=15 versus control, 324.1±21.8 ms, n=13; P <0.001) and multielectrode assay ( P <0.0001). Lumacaftor—a compound known to rescue HERG trafficking—shortened the pathologically prolonged action potential duration of ALG10B-p.G6S induced pluripotent stem cell–derived cardiomyocytes by 10.6% (n=31 electrodes; P <0.001). Conclusions: Here, we demonstrate that ALG10B-p.G6S downregulates ALG10B, resulting in defective HERG trafficking and action potential duration prolongation. Therefore, ALG10B is a novel LQTS-susceptibility gene underlying the LQTS phenotype observed in a multigenerational pedigree. ALG10B mutation analysis may be warranted, especially in genotype-negative patients with an LQT2-like phenotype.

Menopausal hormone therapy (HT) was widely used in the past, but with the publication of seminal primary and secondary prevention trials that reported an excess cardiovascular risk with combined estrogen-progestin, HT use declined significantly. However, over the past 20 years, much has been learned about the relationship between the timing of HT use with respect to age and time since menopause, HT route of administration, and cardiovascular disease risk. Four leading medical societies recommend HT for the treatment of menopausal women with bothersome menopausal symptoms. In this context, this review, led by the American College of Cardiology Cardiolovascular Disease in Women Committee, along with leading gynecologists, women’s health internists, and endocrinologists, aims to provide guidance on HT use, including the selection of patients and HT formulation with a focus on caring for symptomatic women with cardiovascular disease risk.