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This article systematically reviews the evidence base for couple and family interventions for depressive and bipolar disorders published from 2010 to 2019. Included in the review were intervention studies on depression for couples (n = 6), depression for families (n = 13), and bipolar for families (n = 5); zero studies on couple interventions for bipolar were located. Well-established interventions include cognitive and/or behavioral couple and family interventions for depression and psychoeducational family interventions for bipolar. Attachment-based couple and family interventions for depression are probably efficacious. Finally, family psychoeducation for depression is possibly efficacious, and integrative couple interventions and family play-based interventions for depression are experimental. Couple and family interventions also improved relationship dynamics, which is noteworthy since poor relationships are associated with non-remission, relapse, and recurrence of depressive and bipolar symptoms. Future research is needed on couple interventions for bipolar disorders and interventions for minoritized populations.

Objective Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are two debilitating, moderately comorbid illnesses in which chronic musculoskeletal pain symptoms are prevalent. These individuals can experience post-exertional malaise (PEM), a phenomenon in which symptom severity is worsened for 24 hours or longer after physical stress, but the pain-related component of PEM is not well characterized. Design Systematic review and meta-analysis. Methods Case–control studies involving adults with ME/CFS or FM and measuring pain symptoms before and after exposure to a standardized aerobic exercise test were included. Hedges’ d effect sizes were aggregated with random-effects models, and potential moderators were explored with meta-regression analysis. Results were adjusted for nesting effects with three-level modeling. Results Forty-five effects were extracted from 15 studies involving 306 patients and 292 healthy controls. After adjusting for nesting effects, we observed a small to moderate effect indicating higher post-exercise pain in patients than in controls (Hedges’ d = 0.42; 95% confidence interval [CI]: 0.16–0.67). The mean effect was significantly moderated by pain measurement time point (b = –0.19, z = –2.57, P = 0.01), such that studies measuring pain 8–72 hours after exercise showed larger effects (d = 0.71, 95% CI = 0.28–1.14) than did those measuring pain 0–2 hours after exercise (d = 0.32, 95% CI = 0.10–0.53). Conclusions People with ME/CFS and FM experience small to moderate increases in pain severity after exercise, which confirms pain as a component of PEM and emphasizes its debilitating impact in ME/CFS and FM. Future directions include determining mechanisms of pain-related PEM and developing exercise prescriptions that minimize symptom exacerbation in these illnesses.

Objective To evaluate the prognostic significance of detectable circulating cell-free DNA (cfDNA) BRAF V600E/K mutations in patients with advanced melanoma enrolled in a clinical trial without BRAF-targeted therapy. Patients and Methods BRAF V600E/K mutation status was determined on archived tissue and pretreatment stored plasma from 149 patients with unresectable stage IV melanoma who were enrolled between May 5, 2010 and May 2, 2014 in the North Central Cancer Treatment Group/Alliance N0879 randomized phase 2 clinical trial. Results were reported as presence or absence of cfDNA BRAF V600E/K detection of assay vs tissue. Progression-free survival (PFS) and overall survival (OS) were assessed for patients with and without detectable BRAF mutation. Results In total, 63 of 149 (42.3%) patients had BRAF V600E/K results for tissue and blood, and 20 of 63 (31.7%) patients had tissue-diagnosed mutant BRAF. Of these, 11 of 20 (55.0%) patients had detectable plasma cfDNA BRAF. Among patients with tissue-mutant BRAF V600E/K, PFS and OS were shorter for those with corresponding cfDNA mutations (PFS, 5.8 vs 12.0 months; P=.051; OS, 9.2 vs 27.1 months; P=.054). Our assay demonstrated sensitivity of 55% (95% CI, 0.322 to 0.768), specificity of 97.7% (95% CI, 0.932 to 1.000), positive predictive value of 91.7% (95% CI, 0.760 to 1.000), and negative predictive value of 82.4% (95% CI, 0.719 to 0.928). Conclusion In advanced melanoma, detectable cfDNA BRAF V600E/K mutation is present in about half the patients with stage IV with BRAF-mutant melanoma tumor tissue and appears to confer a poorer prognosis when detectable. Given the poorer prognosis, cfDNA can be used to risk-stratify patients with metastatic melanoma in practice or clinical trials.Trial Registration: clinicaltrials.gov Identifier: NCT00976573

OBJECTIVE Active treatment of small- or medium-sized vestibular schwannoma during wait-and-scan management is currently recommended at most centers globally once growth is detected. The primary aim of the current study was to characterize the natural history of growing sporadic vestibular schwannoma during observation. STUDY DESIGN Cohort study. SETTING Four tertiary referral centers across the United States and Denmark. PATIENTS Patients with two prior MRI scans demonstrating ≥2 mm of linear growth who continued observational management. INTERVENTION Observation with serial imaging. MAIN OUTCOME MEASURE Subsequent linear growth-free survival (i.e., an additional ≥2 mm of growth) following initial growth of ≥2 mm from tumor size at diagnosis. RESULTS Among 3,402 patients undergoing observation, 592 met inclusion criteria. Median age at initial growth was 66 years (IQR 59-73) for intracanalicular tumors (N = 65) and 62 years (IQR 54-70) for tumors with cerebellopontine angle extension (N = 527). The median duration of MRI surveillance following initial detection of tumor growth was 5.2 years (IQR 2.4-6.9) for intracanalicular tumors and 1.0 year (IQR 1.0-3.3) for cerebellopontine angle tumors. For intracanalicular tumors, subsequent growth-free survival rates (95% CI; number still at risk) at 1, 2, 3, 4, and 5 years following the initial MRI that demonstrated growth were 77% (67-88; 49), 53% (42-67; 31), 46% (35-60; 23), 34% (24-49; 17), and 32% (22-47; 13), respectively. For cerebellopontine angle tumors, subsequent growth-free survival rates were 72% (68-76; 450), 47% (42-52; 258), 32% (28-38; 139), 26% (21-31; 82), and 22% (18-28; 57), respectively. For every 1 mm increase in magnitude of growth from diagnosis to tumor size at detection of initial growth, the HRs associated with subsequent growth were 1.64 (95% CI 1.25-2.15; p

Background Capsular contracture causes pain, poor cosmesis, and reoperations. This study analyzes its incidence and risk factors in a more modern treatment era. Methods Patients undergoing mastectomy with implant reconstruction from 2010 to 18 were reviewed. Univariate and multivariate analysis evaluated rates and risk factors for capsular contracture. Results Among 451 patients, the majority underwent nipple-sparing mastectomy (262, 58.1%) with one-stage reconstruction (283, 62.7%) utilizing subpectoral implants (353, 77.4%) and acellular dermal matrix (354, 78.5%). Overall capsular contracture incidence was 9.8%; the rate after post-mastectomy radiation therapy (PMRT) was 18.7%, and 7.5% for patients without PMRT. Significant factors included neoadjuvant chemotherapy (P = 0.006), hematoma (P = 0.047), and PMRT (P = 0.001). Multivariate analysis showed that PMRT increased risk of capsular contracture (OR = 3.12, 95% CI 1.55–6.26, P = 0.001), and adjuvant chemotherapy was protective (OR = 0.289, 95% CI 0.114–0.731, P = 0.01). Conclusions Incidence of capsular contracture is lower than previously reported. Advancing therapeutic techniques may reduce the risk of this complication.

Study conducted to determine frequency and timing of unplanned breast implant removal after mastectomy, reconstruction, and postmastectomy radiation (PMRT). From 2010-2017, 52 patients underwent mastectomy, reconstruction, and PMRT. With median follow-up of 3.1 years, 23 patients (44%) experienced implant removal. Implant removal occurred in 9 (17%) patients before starting PMRT and 14 (27%) patients after starting PMRT. Implant removal rates were similar for hypofractionated PMRT compared with standard fractionation and for proton compared with photon PMRT. Implant removal is common for women undergoing mastectomy and reconstruction followed by PMRT. The risk is clinically significant even before starting radiation.

Pyoderma gangrenosum (PG) is a diagnosis of exclusion worsened by surgical debridement. This report presents two atypical manifestations of PG in the reconstructed breast, whereby the disease is only confined to the irradiated chest wall tissue bed, sparing the abdominal donor sites and the contralateral reconstructed breast.

Objective The aim of this study is to determine if pretreatment growth of sporadic vestibular schwannomas (VS) predicts postradiosurgery response. Methods This study was a retrospective chart review at a tertiary referral center of patients with VS that had at least two pretreatment magnetic resonance imaging (MRI) studies at least 6 months apart and underwent Gamma Knife radiosurgery with a minimum of 14 months postradiosurgery imaging surveillance. Tumor linear measurements and volumetric segmentation were assessed before and after radiosurgery. The main outcome measure was persistent enlargement following radiosurgery, defined as 2 mm enlargement in greatest axial diameter or 20% enlargement in volume without size regression. Results Thirty-five patients met the inclusion criteria. Patients were observed for median pre- and posttreatment intervals of 29.5 and 40.6 months, respectively. Median dose to the tumor margin was 13 Gy. Postradiosurgery enlargement occurred in six (17.1%) and nine (25.7%) patients based on linear and volumetric enlargement definitions, respectively. Pseudoprogression—defined as tumor enlargement—followed by linear or volumetric regression that occurred in 34.3% of tumors, reaching a maximum size at a median time of 6.3 months (3.3–8.4) postradiosurgery. When controlling for age, gender, and radiation dose, preradiosurgery tumor volume less than 0.3 cm3 (odds ratio [OR]: 59.7, p = 0.012) and preradiosurgery tumor diameter growth rate greater than or equal to 2.5 mm/year (OR: 19.3, p = 0.045) were associated with persistent postradiosurgery tumor enlargement. Conclusion Smaller pretreatment tumor volume and greater linear tumor growth rates were associated with postradiosurgery tumor enlargement when controlling for age, gender, and radiation dose. Level of Evidence This study indicates that the level of evidence is V.

Three-dimensional (3D) nipple–areolar tattoo is a novel approach to nipple–areolar complex reconstruction for which little data exist. Our aim was to evaluate 3D nipple–areolar tattoo outcomes and investigate if patient factors, payer status, surgeries, or therapies affect tattoo utilization. Patients pursuing skin-sparing (SSM) or attempted nipple-sparing mastectomy (NSM) with breast reconstruction from 2008 to 2019 were reviewed. Outcomes included frequency of 3D tattoo, post-procedure complications (infections, or other local adverse sequelae), and rates, indications, and timing of revisions. Patient factors, payer status, surgeries, and adjuvant therapies underwent univariate analysis comparing rates of 3D tattoo and revisions. A total of 191 patients were identified; median follow-up was 4 years. The majority of patients were white (165, 86%), married (146, 76%), and post-menopausal (97, 51%), with private insurance (156, 81%). Surgeries included SSM (172, 90%) or attempted NSM (19, 10%) with implant (154, 81%) or autologous reconstruction (37, 19%). Sixty-two patients (32%) underwent 3D nipple–areolar tattooing. No post-procedure complications occurred. After tattooing, 20 patients (32%) pursued revisions, the majority due to color fading (12, 60%). Average time from tattoo to completion of revisions was 5.6 months. Patients undergoing autologous reconstruction had a higher rate of 3D tattooing (p

Parvalbumin-expressing interneurons (PV-INs) are highly vulnerable to stressors and have been implicated in many neuro-psychiatric diseases such as schizophrenia, Alzheimer’s disease, autism spectrum disorder, and bipolar disorder. We examined the literature about the current knowledge of the physiological properties of PV-INs and gathered results from diverse research areas to provide insight into their vulnerability to stressors. Among the factors that confer heightened vulnerability are the substantial energy requirements, a strong excitatory drive, and a unique developmental trajectory. Understanding these stressors and elaborating on their impact on PV-IN health is a step toward developing therapies to protect these neurons in various disease states and to retain critical brain functions.

PURPOSE Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are two debilitating illnesses primarily characterized by chronic symptoms of fatigue and musculoskeletal pain, respectively. Some investigators have observed an elevated sense of effort in these patient groups; however, this effect has not been substantiated via quantitative review. As such, we conducted a meta-analysis of RPE responses to aerobic exercise in ME/CFS and FM compared with healthy adults. METHODS Case-control studies involving adults with ME/CFS or FM that measured RPE and heart rate responses to acute aerobic exercise were included. Data sources included PubMed, Scopus/Embase, CINAHL, CENTRAL, and Google Scholar. Risk of bias was assessed by evaluating each study's description of participant characteristics, matching procedures, and administration of RPE scales. Hedges' d effect sizes for RPE were calculated and aggregated using random-effects models, and potential moderators were explored with meta-regression analysis. RESULTS Forty-one effects were extracted from 37 studies involving 1016 patients and 686 healthy controls. We observed a large (Hedges' d = 0.85, 95% confidence interval = 0.62-1.08) effect indicating higher RPE in patients than controls. The mean effect size was significantly moderated (P < 0.001, R = 0.38) by whether RPE data were analyzed at a peak or submaximal intensity (b = 0.60, z = 4.6, P < 0.001) and the type of patient group that was studied (b = 0.25, z = 2.08, P = 0.04). CONCLUSIONS People with ME/CFS and FM perceive aerobic exercise as more effortful than healthy adults, but the exact causes are unclear. The large magnitude of this effect merits further exploration of underlying mechanisms that could provide insight into the pathophysiology of ME/CFS and FM or the broader debate about the nature of central and/or peripheral signals that influence RPE.

Stapes surgery is challenging yet rewarding hearing restoration procedure. Endoscopic ear surgery is a relatively new technique for managing otologic pathology. Stapes surgery presents a unique challenge when performed via a transcanal endoscopic approach because the surgeon is confined to using one hand for management of the footplate and placing the prosthesis. Outcomes have been published for endoscopic stapes surgery, with several studies comparing endoscopic with the traditional microscopic approach. Several authors noted the need for less bone removal and less pain after endoscopic stapes surgery. Complication rates following stapes surgery did not seem to differ whether the endoscope or the microscope was used. Nonetheless, the overall audiometric results appear to be equivalent. Endoscopic stapes surgery has several potential benefits including visualizing unique anatomic variants, improved visualization of the anterior crus, the need for less bone removal in the setting of malleus fixation, and to date equivalent hearing outcomes.

Purpose: The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. Patients and Methods: Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. Results: Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3–4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or >1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. Conclusions: MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

Background/Objectives Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. Methods Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. Results Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2–7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. Conclusions Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.

Despite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

The Eating Disorder Examination Questionnaire (EDE-Q) is a gold standard questionnaire to identify eating disorder symptoms but has not yet been validated in Danish. The scale consists of four theoretical constructs of disordered eating: Restraint eating, Eating concerns, Shape concerns and Weight concerns. However, the four-factor structure has been difficult to replicate across cultures. This study aimed to examine the factor structure and psychometric properties of the EDE-Q in Danish. The study consisted of four samples (aged 15–70): Patients with anorexia, bulimia and unspecified eating disorders (n = 101), patients with symptoms of binge-eating disorder (n = 300), recreational athletes (n = 404), and elite athletes (n = 526). Depending on the analysis performed, participants had to complete the EDE-Q, the SCOFF questionnaire for eating disorders or the Binge Eating Disorders Questionnaire. In accordance with international research, we found no evidence for a four-factor structure in the EDE-Q among patients or among athletes. But our results showed significant, positive associations between EDE-Q and SCOFF, BED-Q and MDI in all samples. We conclude that the internal structure of EDE-Q is low, while construct validity is high, making EDE-Q useful as an instrument to identify individuals with eating disorder symptoms, including recreational, and elite athletes.

Aims The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. Methods and results In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P, Graphical Abstract Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. SARC+: sarcomere positive; SARC−: sarcomere negative.

Autism is a spectrum disorder with wide variation in type and severity of symptoms. Understanding gene–phenotype associations is vital to unravel the disease mechanisms and advance its diagnosis and treatment. To date, several databases have stored a large portion of gene–phenotype associations which are mainly obtained from genetic experiments. However, a large proportion of gene–phenotype associations are still buried in the autism-related literature and there are limited resources to investigate autism-associated gene–phenotype associations. Given the abundance of the autism-related literature, we were thus motivated to develop Autism_genepheno, a text mining pipeline to identify sentence-level mentions of autism-associated genes and phenotypes in literature through natural language processing methods. We have generated a comprehensive database of gene–phenotype associations in the last five years’ autism-related literature that can be easily updated as new literature becomes available. We have evaluated our pipeline through several different approaches, and we are able to rank and select top autism-associated genes through their unique and wide spectrum of phenotypic profiles, which could provide a unique resource for the diagnosis and treatment of autism. The data resources and the Autism_genpheno pipeline are available at: https://github.com/maiziezhoulab/Autism_genepheno.

The aim of this study is to report the case of a 25-year-old male with a history of schizophrenia who presented involuntarily to the psychiatric emergency department (ED) due to worsening agitation, paranoia, and disorganized behavior concerning a psychotic episode. During medical clearance to rule out acute organic causes of altered mental status prior to admission, the patient was found to have agenesis of the corpus callosum (ACC) on CT of the brain. ACC is a rare congenital disorder characterized by the partial or complete absence of the commissural pathway that connects the two cerebral hemispheres. This case presents a thought-provoking incidental anatomical finding in a patient with an acute exacerbation of chronic schizophrenia and allows for further discussion about the prevalence of undiagnosed malformations and possible underlying genetic contributions in patients with chronic mental illness.

Cardiac memory is a common cause of deep T-wave inversions (TWI) in the anterior precordial leads and can be difficult to distinguish from alternative causes of TWI such as myocardial ischemia. Cardiac memory is generally a benign condition except in the setting of prolonged QT when it can contribute to the precipitation of torsades de pointes. Herein, we describe the presentation and clinical course of a case of cardiac memory due to intermittent left bundle branch block (LBBB) that presented asymptomatically to our outpatient cardiology clinic with deep anterior TWI. We discuss common causes of and mechanisms underlying cardiac memory and how to distinguish it from alternative causes of TWI based on 12-lead electrocardiogram. In conclusion, intermittent LBBB is an under-recognized cause of cardiac memory that can present as deep anterior TWI mimicking cardiac ischemia, and awareness of this clinical entity may help prevent unnecessary invasive and expensive testing on otherwise healthy patients.

Chronic rotator cuff tears are a common source of shoulder pain and disability. Patients with rotator cuff tears often have substantial weakness, fibrosis, and fat accumulation, which limit successful surgical repair and postoperative rehabilitation. The Murphy Roths Large (MRL) strain of mice have demonstrated superior healing and protection against pathological changes in several disease and injury conditions. We tested the hypothesis that, compared with the commonly used C57Bl/6 (B6) strain, MRL mice would have less muscle fiber atrophy and fat accumulation, and be protected against the loss in force production that occurs after cuff tear. Adult male B6 and MRL mice were subjected to a rotator cuff tear, and changes in muscle fiber contractility and histology were measured. RNA sequencing and shotgun metabolomics and lipidomics were also performed. The muscles were harvested one month after tear. B6 and MRL mice had a 40% reduction in relative muscle force production after rotator cuff tear. RNA sequencing identified an increase in fibrosis-associated genes and a reduction in mitochondrial metabolism genes. The markers of glycolytic metabolism increased in B6 mice, while MRL mice appeared to increase amino acid metabolism after tear. There was an accumulation of lipid after injury, although there was a divergent response between B6 and MRL mice in the types of lipid species that accrued. There were strain-specific differences between the transcriptome, metabolome, and lipidome of B6 and MRL mice, but these differences did not protect MRL mice from weakness and pathological changes after rotator cuff tear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:811-822, 2020.

OBJECTIVE Identify features on computed tomography (CT) that predict mastoidectomy conversion (MC) during transcanal endoscopic ear surgery (TEES). STUDY DESIGN Retrospective case-control. SETTING University otology practice. PATIENTS Consecutive patients with cholesteatoma. INTERVENTION TEES cholesteatoma dissection versus those requiring MC. MAIN OUTCOME MEASURES Antrum opacification, depth of scutum involvement, and erosion of the mastoid trabeculae, ossicular chain, and tegmen were evaluated. Univariable and multivariable regression analysis was performed. The Antrum-Malleus-Tegmen (AMT) score was created using receiver operating characteristic curves to assess feasibility of performing TEES for cholesteatoma dissection. RESULTS There were 39 TEES and 19 MC cases. Groups had similar age (median 28.5 yr), gender, laterality, and revision surgery status. Median surgical time for MC cases was longer than TEES (231 min vs. 171 min, p

Knowledge of intelligence is essential for interpreting cognitive performance following traumatic brain injury (TBI). The Test of Premorbid Functioning (ToPF), a word reading test co-normed with the Wechsler Adult Intelligence Scale 4(th) Edition (WAIS-IV), was examined as a tool for estimating premorbid intelligence in persons with a history of TBI. Fifty-two participants with mild, moderate, or severe TBI were administered the ToPF and WAIS-IV between two weeks and 19 months post-injury. The independent ability of the ToPF/demographic score and the Verbal Comprehension Index (VCI) to predict WAIS-IV Full Scale IQ (FSIQ) was examined, as were discrepancies between ToPF and WAIS-IV scores within and between participants. The ToPF/demographic predicted FSIQ accounted for a significant proportion of variability in actual FSIQ, above and beyond that accounted for by education or time since injury. ToPF and WAIS-IV scores did not differ by injury severity. In our sample, the ToPF/demographic predicted FSIQ underestimated intelligence in a substantial portion of our participants (31%), particularly in those with high average to superior intelligence. Finally, VCI scores were more predictive of actual FSIQ than the ToPF/demographic predicted FSIQ. The ToPF frequently underestimated post-injury intelligence and is therefore not accurately measuring premorbid intelligence in our sample, particularly in those with above average to superior intelligence. Clinicians are encouraged to administer the entire WAIS-IV, or at minimum the VCI subtests, for a more accurate measure of intelligence in those with above average intelligence and history of TBI.

Hypoglycemia is a common safety event when attempting to optimize glycemic control in diabetes (DM). While electronic medical records provide a natural ground for detecting and analyzing hypoglycemia, ICD codes used in the databases may be invalid, insensitive or non-specific in detecting new hypoglycemic events. We developed text preprocessing methods to improve automatic detection of hypoglycemia from analysis of clinical encounter text notes.We set out to improve hypoglycemia detection from clinical notes by introducing three preprocessing methods: stop word filtering, medication signaling, and ICD narrative enrichment. To test the proposed methods, we selected clinical notes from VA Maryland Healthcare System, based on various combinations of three criteria that are suggestive of hypoglycemia, including ICD-9 code of diabetes and hypoglycemia, laboratory glucose values70 md/dL, and text reference to a proximate hypoglycemia event. In addition, we constructed one dataset of 395 clinical notes from year 2009 and another of 460 notes from year 2014 to test the generality of the proposed methods. For each of the datasets, two physician judges manually reviewed individual clinical notes to determine whether hypoglycemia was present or absent. A third physician judge served as a final adjudicator for disagreements.Each of the proposed preprocessing methods contributed to the performance of hypoglycemia detection by significantly increasing the F1 score in the range of 5.3∼7.4% on one dataset (p .01). Among the methods, stop word filtering contributed most to the performance improvement (7.4%). Combining all the preprocessing methods led to greater performance gain (p .001) compared with using each method individually. Similar patterns were observed for the other dataset with the F1 score being increased in the range of 7.7%∼9.4% by individual methods (p .001). Nevertheless, combining the three methods did not yield additional performance gain.The proposed text preprocessing methods improved the performance of hypoglycemia detection from clinical text notes. Stop word filtering achieved the most performance improvement. ICD narrative enrichment boosted the recall of detection. Combining the three preprocessing methods led to additional performance gains.

Background: The live attenuated non-pathogenic Edmonston MV vaccine strain has advantages as an oncolytic platform given its tumor specificity, potent bystander effect, and ability to be engineered and retargeted. MV-NIS expresses the human thyroidal sodium-iodide symporter (NIS) and is selectively oncolytic, entering tumor cells through CD46 (overexpressed on many cancers, including breast cancer of all subtypes) and Nectin-4. NIS expression in MV-NIS infected cells permits noninvasive monitoring of virus spread by SPECT-CT imaging of Tc-99m pertechnetate or I-123 uptake. Methods: NCT01846091 is a standard 3+3 phase I trial of a single IT administration of MV-NIS in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) or metastatic breast cancer (MBC). Primary objectives are (a) safety and tolerability and (b) maximally tolerated single dose. The secondary clinical objective is to preliminarily assess antitumor efficacy at and away from the MV injection site. Key eligibility criteria were: absence of standard therapy with life prolonging intent; at least one lesion >1 cm amenable to percutaneous injection; and no impending visceral crisis. MV-NIS was administered on D1 with mandatory SPECT-CT at baseline (BL) and on D3&D8; repeat SPECT-CT on D15&D21 if the prior result was positive; mandatory tumor biopsies on D3&D21; optional tumor biopsies on D8&D15; assessments for viremia and viral shedding at BL and on D3,D8,D15,D21; and standard imaging for restaging at BL,D21,W6,W12. Results: Accrual completed with 12 evaluable pts (6 SCCHN and 6 MBC) at 3 dose levels (108, 3x108, 109 TCID50). The MBC group included 5 HR+/HER2- pts and 1 pt with mixed HR+/HER2- and HR+/HER2+ disease. 5 pts had evidence of disease progression prior to study participation. No dose limiting toxicities were observed among the MBC pts; AEs possibly related to MV-NIS in this group were gr2 fatigue, gr1 flu-like illness, gr2 lymphopenia (all n=1). No SCCHN responses were observed. Best response for the MBC pts was: stable disease (SD) >6 wks, n=4; clinical response, n=1; progression, n=1. One MBC pt with SD for 12 wks had positive SPECT/CT imaging at and away from the injection site on D3&D8 and was the only pt seronegative for measles IgG antibodies prior to MV-NIS exposure. The MBC pt who responded after initial MV-NIS exposure was the only pt with low viral RNA in blood (D3); she received additional doses at W9&W13 without toxicity through an expanded access protocol exemption and had disease progression by W19. No viral shedding was detected from mouth rinse or urine in any pt. MV was detected in tumor samples from all pts treated at the highest dose level. Additional blood and tissue analyses are in progress. Conclusion: These results demonstrate the safety of IT MV-NIS administration, provide early evidence of biologic activity in MBC, and support the possibility of viral replication in tumors remote from the IT injection site. A MV strain encoding the immunomodulatory neutrophil activating protein transgene has been constructed (MV-s-NAP) with preclinical evidence of improved antitumor activity and immunogenicity. The phase I MV-s-NAP trial will start recruitment in Fall 2018. Citation Format: Liu MC, Peng K-W, Federspiel MJ, Russell SJ, Brunton BA, Zhou Y, Packiriswamy N, Hubbard JM, Loprinzi CL, Peethambaram PP, Ruddy KJ, Allred JB, Galanis E, Okuno SH. Phase I trial of intratumoral (IT) administration of a NIS-expressing derivative manufactured from a genetically engineered strain of measles virus (MV) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-03.

Previous studies assessing healthcare provider compliance to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines indicate a significant underuse of statin therapy at appropriate intensity. However, data are limited in primary prevention patients. Our study aimed to evaluate the impact of the 2013 ACC/AHA guidelines through a retrospective analysis of primary prevention patients presenting with first time acute coronary syndrome (ACS). We retrospectively calculated the 10-year predicted Atherosclerotic Cardiovascular Disease (10yASCVD) risk in 1,265 patients ages 40 to 75 who presented with ACS and no previous ASCVD. In patients without known ambulatory systolic blood pressure, a multivariable linear regression model was used to predict outpatient systolic blood pressure. Outcomes analyzed in each 10yASCVD category included statin status and statin intensity (high/medium/low) with further categorization by type of ACS event and date of left heart catheterization. In both primary analysis and sensitivity analysis (patients with predicted systolic blood pressure), statistical significance was shown with respect to overall statin status, ST Elevation Myocardial Infarction, and date of left heart catheterization. In summary, retrospective calculation of 10yASCVD in patients with a first ACS event showed a significant number of ACS patients would have qualified for statin therapy per 2013 ACC/AHA guidelines before their event but had not been initiated on one.

Introduction Bevacizumab offers a medical treatment that may slow the growth of vestibular schwannomas (VS) and possibly preserve hearing in patients with neurofibromatosis type 2 (NF2). This study aims to investigate the effect of long-term bevacizumab treatment on VS progression. Methods Demographic, clinical, audiometric, and radiographic data were collected from the medical records of NF2 patients treated with bevacizumab at a tertiary medical center. Results Eleven tumors from seven NF2 patients treated with bevacizumab were analyzed. The median age was 17 years (range: 12–47 years). Median bevacizumab treatment time was 33 months (range: 12–74 months). Of five patients with serviceable hearing pretreatment, one (20%) maintained serviceable hearing during bevacizumab therapy. Significantly slower growth rates for both tumor diameters and tumor volumes were identified during active bevacizumab treatment. Median tumor diameters and volumes during active bevacizumab treatment were 0 cm/year (range: –0.13–0.17 cm/year) and 0.1 cm3/year (range: –0.92–0.41), compared with 0.37 cm/year (range: 0–1.5 cm/year, p = 0.0011) and 1.38 cm3/year (range: 0.013–3.74), respectively, without bevacizumab treatment (p = 0.0263). Reduced tumor progression was noted with bevacizumab treatment utilizing both linear greatest diameter (hazard ratio 0.16, p = 0.006) and segmentation volumes (hazard ratio 0.15, p = 0.023). Complications of bevacizumab treatment included fatigue (43%), nausea/vomiting (43%), hypertension (43%), epistaxis (29%), and proteinuria (29%). One subject had a cerebrovascular accident detected on screening magnetic resonance imaging without symptoms or neurological sequelae. Discussion Bevacizumab may reduce tumor growth rate and the risk of progression based on both volumetric and linear measurements.

Femoroacetabular impingement (FAI) and labral pathology are associated with pain, decreased function, and hip strength deficits. Existing data are in conflict regarding when hip strength normalizes following arthroscopic treatment of FAI. The objective of this study was to identify preoperative hip strength relative to the contralateral hip not undergoing surgery as well as when postoperative strength in 4 functional muscle groups normalizes following arthroscopic treatment of FAI. Ninety-eight individuals with radiographic evidence of FAI and labral pathology underwent arthroscopic labral repair. Pre-surgical hip strength testing was performed in the symptomatic “surgical hip” and the contralateral “non–surgical hip.” Hip strength measurements were repeated at 8 and 16 weeks postoperatively. Significant preoperative hip strength deficits were noted in the surgical hip compared with the non–surgical hip in flexion, extension, and adduction. At 8 weeks postoperatively, hip strength in the surgical hip improved to being equivalent to that in the non–surgical hip in adduction and extension, remained equivalent to that of the non–surgical hip in abduction, and decreased in flexion relative to the non–surgical hip. At 16 weeks, hip strength remained equivalent in the surgical hip and the non–surgical hip in abduction and adduction, but the surgical hip exceeded the non–surgical hip in extension. While flexion strength improved between 8 and 16 weeks postoperatively for the surgical hip, it had not fully recovered to that of the non–surgical hip. Using a structured postoperative rehabilitation protocol, abduction strength was maintained at 8 weeks postoperatively, while adduction and extension strength had improved to those of the non–surgical hip. At 16 weeks postoperatively, hip abduction and adduction had strength equivalent to those of the non–surgical hip. Despite preoperative improvement, flexion of the surgical hip lagged behind that of the non–surgical hip 16 weeks postoperatively. [ Orthopedics . 2021;44(3):148–153.]

Nutritional strategies that optimize immunity of feedlot cattle are warranted due to increasing regulations with the use of feed-grade antimicrobials. This study evaluated physiological, health, and performance responses of cattle receiving a synbiotic supplement (yeast-derived prebiotic + Bacillus subtilis probiotic), which replaced feed-grade antimicrobials or were fed in conjunction with monensin during the initial 45 days in the feedlot. Angus-influenced steers (n = 256) were acquired from an auction facility on day −2, and transported (800 km) to the feedlot. Shrunk BW was recorded upon arrival (day −1). Steers were allocated to 1 of 18 pens (day 0), and pens were assigned to receive (n = 6/treatment) a free-choice diet containing: (1) monensin and tylosin (RT; 360 mg/steer daily from Rumensin and 90 mg/steer daily from Tylan; Elanco Animal Health, Greenfield, IN, USA), (2) yeast-derived ingredient and B. subtilis probiotic (CC; 18 g/steer daily of Celmanax and 28 g/steer daily of Certillus; Church and Dwight Co., Inc., Princeton, NJ, USA), or (3) monensin in addition to yeast-derived and B. subtilis ingredients (RCC) as in RT and CC. Steers were assessed for bovine respiratory disease (BRD) and DMI daily. Steer BW was recorded on days 45 and 46, and averaged for final BW. Blood samples were collected on days 0, 7, 17, 31, and 45. Feed intake was greater (P ≤ 0.05) in CC vs. RCC and RT during the initial 3 weeks upon feedlot arrival. No treatment differences were noted (P ≥ 0.41) for average daily gain, BW, and feed efficiency. Incidence of BRD did not differ (P = 0.77) between treatments (average 80.1%). A greater proportion (P ≤ 0.03) of RT steers diagnosed with BRD required a second antimicrobial treatment compared with CC and RCC (57.3, 37.3, and 38.6%, respectively). Removal of steers from the trial due to severe morbidity + mortality was greater (P = 0.02) in RT vs. CC (22.4 and 7.0%), and did not differ (P ≥ 0.16) among RCC (12.9%) vs. RT and CC. Plasma glucose concentrations were greater (P ≤ 0.02) in CC vs. RCC and RT on day 7. Plasma concentrations of nonesterified fatty acids were greater (P ≤ 0.02) in RT and RCC vs. CC on day 7, and in RT vs. CC on day 17. Steers receiving the synbiotic supplement had improved response to BRD treatment, suggesting heightened immunocompetence from partially enhanced metabolism and the nutraceutical effects of B. subtilis and yeast compounds.

Iatrogenic splenic injury is a rare complication of all abdominal surgeries. Despite the procedure’s overall safety, colonoscopy is now the procedure most frequently associated with iatrogenic splenic injury. A 58-year-old male with a past medical history of hypertension, lung cancer in remission, colon polyps, and severe scoliosis presented for grade three splenic laceration two days following a routine colonoscopy. He had no recent history of injury or other inciting events that could have led to traumatic injury. Non-operative management included splenic artery embolization and transfusion of one unit of packed red blood cells, after which he improved in the hospital and was discharged home in stable condition. This case postulates the possible influence of his severe scoliosis, and thus altered abdominal viscera anatomy, on his iatrogenic splenic injury, as well as the potential importance of investigating scoliosis as a risk factor for difficult colonoscopy or even iatrogenic splenic injury during colonoscopy.

Autism is a spectrum disorder with wide variation in type and severity of symptoms. Understanding gene–phenotype associations is vital to unravel the disease mechanisms and advance its diagnosis and treatment. To date, several databases have stored a large portion of gene–phenotype associations which are mainly obtained from genetic experiments. However, a large proportion of gene–phenotype associations are still buried in the autism-related literature and there are limited resources to investigate autism-associated gene-phenotype associations. Given the abundance of the autism-related literature, we were thus motivated to develop Autism_genepheno, a text mining pipeline to identify sentence-level mentions of autism-associated genes and phenotypes in literature through natural language processing methods. We have generated a comprehensive database of gene-phenotype associations in the last five years’ autism-related literature that can be easily updated as new literature becomes available. We have evaluated our pipeline through several different approaches, and we are able to rank and select top autism-associated genes through their unique and wide spectrum of phenotypic profiles, which could provide a unique resource for the diagnosis and treatment of autism. The data resources and the Autism_genpheno pipeline are available at: https://github.com/maiziezhoulab/Autism_genepheno.

Angiotensin II (Ang II) presents a critical mediator in various pathological conditions such as non-genetic cardiomyopathy. Osmotic pump infusion in rodents is a commonly used approach to model cardiomyopathy associated with Ang II. However, profound differences in electrophysiology and pharmacokinetics between rodent and human cardiomyocytes may limit predictability of animal-based experiments. This study investigates the application of an Organ-on-a-chip (OOC) system in modeling Ang II-induced progressive cardiomyopathy. The disease model is constructed to recapitulate myocardial response to Ang II in a temporal manner. The long-term tissue cultivation and non-invasive functional readouts enable monitoring of both acute and chronic cardiac responses to Ang II stimulation. Along with mapping of cytokine secretion and proteomic profiles, this model presents an opportunity to quantitatively measure the dynamic pathological changes that could not be otherwise identified in animals. Further, we present this model as a testbed to evaluate compounds that target Ang II-induced cardiac remodeling. Through assessing the effects of losartan, relaxin, and saracatinib, the drug screening data implicated multifaceted cardioprotective effects of relaxin in restoring contractile function and reducing fibrotic remodeling. Overall, this study provides a controllable platform where cardiac activities can be explicitly observed and tested over the pathological process. The facile and high-content screening can facilitate the evaluation of potential drug candidates in the pre-clinical stage.

BackgroundAttentional bias to threat has been implicated as a cognitive mechanism in anxiety disorders for youth. Yet, prior studies documenting this bias have largely relied on a method with questionable reliability (i.e. dot-probe task) and small samples, few of which included adolescents. The current study sought to address such limitations by examining relations between anxiety – both clinically diagnosed and dimensionally rated – and attentional bias to threat.MethodsThe study included a community sample of adolescents and employed eye-tracking methodology intended to capture possible biases across the full range of both automatic (i.e. vigilance bias) and controlled attentional processes (i.e. avoidance bias, maintenance bias). We examined both dimensional anxiety (across the full sample; n = 215) and categorical anxiety in a subset case-control analysis (n = 100) as predictors of biases.ResultsFindings indicated that participants with an anxiety disorder oriented more slowly to angry faces than matched controls. Results did not suggest a greater likelihood of initial orienting to angry faces among our participants with anxiety disorders or those with higher dimensional ratings of anxiety. Greater anxiety severity was associated with greater dwell time to neutral faces.ConclusionsThis is the largest study to date examining eye-tracking metrics of attention to threat among healthy and anxious youth. Findings did not support the notion that anxiety is characterized by heightened vigilance or avoidance/maintenance of attention to threat. All effects detected were extremely small. Links between attention to threat and anxiety among adolescents may be subtle and highly dependent on experimental task dimensions.

Supplemental Digital Content is available in the text., Uveal melanoma is a rare form of melanoma with particularly poor outcomes in the metastatic setting. In contrast with cutaneous melanoma, uveal melanoma lacks BRAF mutations and demonstrates very low response rates to immune-checkpoint blockade. Our objectives were to study the transcriptomics of metastatic uveal melanoma with the intent of assessing gene pathways and potential molecular characteristics that might be nominated for further exploration as therapeutic targets. We initially analyzed transcriptional data from The Cancer Genome Atlas suggesting PI3K/mTOR and glycolysis as well as IL6 associating with poor survival. From tumor samples collected in a prospective phase II trial (A091201), we performed a transcriptional analysis of human metastatic uveal melanoma observing a novel role for epithelial-mesenchymal transition associating with survival. Specifically, we nominate and describe initial functional validation of neuropillin-1 from uveal melanoma cells as associated with poor survival and as a mediator of proliferation and migration for uveal melanoma in vitro. These results immediately nominate potential next steps in clinical research for patients with metastatic uveal melanoma.

A patient with heart failure due to nonischemic cardiomyopathy presented as a transfer to our institution following peripheral (femoral) venoarterial (VA) extracorporeal membrane oxygenation (ECMO) placement. With peripheral VA ECMO cannulation, the patient continued to have unstable ventricular tachyarrhythmias. Echocardiography demonstrated left ventricular (LV) dilation and severe mitral regurgitation (MR) with clinical and chest X-ray evidence of pulmonary edema. To provide venous drainage and simultaneous decompression of the left atrium (LA) and thereby indirect LV venting, a single multistage venous cannula was placed across the inter-atrial septum (IAS) using the previously described left atrial venoarterial (LA-VA) ECMO cannulation technique. Two- and three-dimensional (3D) transesophageal echocardiography (TEE) demonstrated utility in guiding cannula placement into the appropriate position and providing real time assessment of ventricular decompression and MR severity. There was subsequent improvement in pulmonary edema. This case is thought to be the first demonstration of real time resolution of pulmonary venous flow reversal in a patient undergoing LA-VA ECMO cannulation. This demonstration offers important mechanistic insight into some of the potential benefits of such an approach.

OBJECTIVES/HYPOTHESIS To determine if commonly used radiomics features have an association with histological findings in vestibular schwannomas (VS). STUDY DESIGN Retrospective case-series. METHODS Patients were selected from an internal database of those who had a gadolinium-enhanced T1-weighted MRI scan captured prior to surgical resection of VS. Texture features from the presurgical magnetic resonance image (MRI) were extracted, and pathologists examined the resected tumors to assess for the presence of mucin, lymphocytes, necrosis, and hemosiderin and used a validated computational tool to determine cellularity. Sensitivity, specificity, and positive likelihood ratios were also computed for selected features using the Youden index to determine the optimal cut-off value. RESULTS A total of 45 patients were included. We found significant associations between multiple MRI texture features and the presence of mucin, lymphocytes, hemosiderin, and cellularity. No significant associations between MRI texture features and necrosis were identified. We were able to identify significant positive likelihood ratios using Youden index cut-off values for mucin (2.3; 95% CI 1.2-4.3), hemosiderin (1.5; 95% CI 1.04-2.1), lymphocytes (3.8; 95% CI 1.2-11.7), and necrosis (1.5; 95% CI 1.1-2.2). CONCLUSIONS MRI texture features are associated with underlying histology in VS. LEVEL OF EVIDENCE 3 Laryngoscope, 131:E2000-E2006, 2021.

Introduction The endpoint of resuscitative interventions after traumatic injury resulting in cardiopulmonary arrest varies across institutions and even among providers. The purpose of this study was to examine survival characteristics in patients suffering torso trauma with no recorded vital signs (VS) in the emergency department (ED). Methods The National Trauma Data Bank was analyzed from 2007 to 2015. Inclusion criteria were patients with blunt and penetrating torso trauma without VS in the ED. Patients with head injuries, transfers from other hospitals, or those with missing values were excluded. The characteristics of survivors were evaluated, and statistical analyses performed. Results A total of 24,191 torso trauma patients without VS were evaluated in the ED and 96.6% were declared dead upon arrival. There were 246 survivors (1%), and 73 (0.3%) were eventually discharged home. Of patients who responded to resuscitation (812), the survival rate was 30.3%. Injury severity score (ISS), penetrating mechanism (odds ratio [OR] 1.99), definitive chest (OR 1.59) and abdominal surgery (OR 1.49) were associated with improved survival. Discharge to home (or police custody) was associated with lower ISS (OR 0.975) and shorter ED time (OR 0.99). Conclusion Over a recent nine-year period in the United States, nearly 25,000 trauma patients were treated at trauma centers despite lack of VS. Of these patients, only 73 were discharged home. A trauma center would have to attempt over one hundred resuscitations of traumatic arrests to save one patient, confirming previous reports that highlight a grave prognosis. This creates a dilemma in treatment for front line workers and physicians with resource utilization and consideration of safety of exposure, particularly in the face of COVID-19.

Introduction: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can cause myocardial injury, heart failure, and death. MicroRNAs (miRNAs) have emerged as important regulators of viral pathogenesis, but the impact of host miRNAs on SARS-CoV-2 infectivity remains unknown. Hypothesis: Bioinformatic analysis of host miRNAs targeting the SARS-CoV-2 genome, viral entry proteins ACE2 and TMPRSS2, and their upstream regulators the interferons (IFNs) will reveal high-probability miRNAs that may regulate myocardial injury during SARS-CoV-2 infection. Methods: Using validated bioinformatic prediction algorithms, we generated a prioritized atlas of host miRNAs predicted to bind to SARS-CoV-2 genome, ACE2, TMPRSS2, and IFNs. We validated the biologic plausibility of these binding interactions by investigating their expression in established miRNA profiling datasets from cell lines susceptible or resistant to SARS-CoV-2 infection and in human tissue samples. Results: Phylogenetic analysis of 820 SARS-CoV-2 genomes revealed high homology and, after iterative filtering, 288 predicted binding miRNAs. Overlay of these miRNAs in susceptible and resistant cell lines identified miRNA binders to ORFs (miR-23a (1ab), miR-29a, -29c (1ab, N), miR-151a, -151b (S spike), miR-4707-3p (S spike), miR-298 (5’-UTR), miR-7851-3p (5’-UTR), miR-8075 (5’-UTR)) that may be important for viral infectivity. We also highlight miRNAs predicted to regulate critical host factors during infection including the receptor ACE2 3’-UTR (miR-9-5p, miR-218-5p), the serine protease TMPRSS2 3’-UTR (let-7d-5p, -7e-5p, miR-494-3p, miR-382-3p, miR-181c-5p), and the IFNs such as IFN-α 3’-UTR (miR-361-5p, miR-410-3p). Given the known roles for several of these miRNAs in cardiovascular injury (e.g. miR-23a, -29a, -29c, -494, and let-7), we discuss a framework for further interrogation of these miRNAs in patients and disease-based models. Conclusions: Overall, this study provides insight into potential novel regulatory mechanisms of SARS-CoV-2 by host miRNAs and lays the foundation for future investigation of these miRNAs as potential therapeutic targets or biomarkers for myocardial injury.

This experiment compared physiological, health, and performance responses of beef heifers assigned to different commingling schemes (one, two, or four sources per pen) during a 56-d feedlot receiving period. Ninety-six recently weaned Angus-influenced heifers were obtained from an auction facility. Heifers originated from four cow-calf ranches, and were reared in the same herd within each ranch since birth. Heifers were loaded into two livestock trailers at the auction yard (two sources per trailer; d −2), arranged in two sections of each trailer according to source, and transported for 10 h to stimulate the stress of a long-haul. Heifers were not mixed with cohorts from other sources prior to and at the auction yard. Upon arrival (d −2), shrunk body weight (BW) was recorded and heifers were maintained in four paddocks by source with ad libitum access to a complete starter feed and water for 36 h. On d 0, heifers were ranked by source and shrunk BW and allocated to 1 of 24 drylot pens (four heifers per pen) containing: 1) heifers from a single source (1SRC, n = 8), 2) heifers from two sources (2SRC, n = 8), or 3) heifers from four sources (4SRC, n = 8). From d 0 to d 55, heifers had free-choice access to the complete starter feed and water. Heifers were assessed daily for symptoms of bovine respiratory disease (BRD), and feed intake was recorded from each pen daily. Blood samples were collected on d 0, d 6, d 13, d 27, d 41, and d 55, and shrunk BW (after 16 h of water and feed withdrawal) was recorded on d 56 for average daily gain (ADG). No treatment differences were noted (P ≥ 0.56) for heifer ADG (mean ± SE = 0.853 ± 0.043 kg/d), final shrunk BW, feed intake, and feed efficiency. No treatment differences were noted (P ≥ 0.27) for plasma concentrations of cortisol and haptoglobin, and serum concentrations of antibodies against BRD viruses and Mannheimia haemolytica. No treatment differences were noted (P ≥ 0.17) for incidence of BRD (mean ± SE = 59.3 ± 5.0%) or mortality. The proportion of heifers diagnosed with BRD that required three antimicrobial treatments to regain health increased linearly (P = 0.03) according to the number of sources (0.0, 12.3, and 20.8% of 1SRC, 2SRC, and 4SRC heifers, respectively; SEM = 7.0). Hence, commingling heifers from different sources did not impact performance, physiological responses, and BRD incidence during a 56-d receiving period, although recurrence of BRD after the second antimicrobial treatment increased according to commingling level.

This experiment evaluated the impacts of administering a bovine appeasing substance (BAS) at feedlot entry to receiving cattle. Angus-influenced steers (n = 342) from 16 sources were purchased from an auction yard on day –1, and transported (12 hr; 4 trucks) to the feedlot. Upon arrival on day 0, shrunk body weight (BW; 240 ± 1 kg) was recorded and steers were ranked by load, shrunk BW, and source and assigned to receive BAS (IRSEA Group, Quartier Salignan, France; n = 171) or placebo (diethylene glycol monoethyl ether; CON; n = 171). The BAS is a mixture of fatty acids that replicate the composition of the bovine appeasing pheromone. Treatments (5 mL) were topically applied to each individual steer on their nuchal skin area. Steers were allocated to 1 of 24 drylot pens (12 pens/treatment) and received a free-choice diet until day 46. Steers were assessed daily for bovine respiratory disease (BRD) signs, and feed intake was recorded from each pen daily. Steer unshrunk BW was recorded on days 7, 17, 31, 45, and 46. Shrunk BW on day 0 was added an 8% shrink to represent initial BW, and final BW was calculated by averaging BW from days 45 and 46. Blood samples were collected from 5 steers/pen on days 0, 7, 11, 31, and 45. Pen was considered the experimental unit. Steer BW gain was greater (P = 0.04) in BAS vs. CON (1.01 vs. 0.86 kg/d, SEM = 0.05). Feed intake did not differ (P = 0.95) between treatments, resulting in greater (P = 0.05) feed efficiency in BAS vs. CON (171 vs. 142 g/kg, SEM = 10). Plasma cortisol concentration was greater (P = 0.05) and plasma glucose concentration was less in CON vs. BAS on day 7 (treatment × day; P = 0.07 and

The aim of this study is to investigate facial nerve outcomes after microsurgical resection in neurofibromatosis type 2 (NF2) compared to sporadic tumors.Single institutional retrospective chart review.Tertiary referral center.All adult patients with NF2 vestibular schwannoma (VS) or sporadic VS who underwent microsurgical resection from 2008 to 2019 with preoperative magnetic resonance imaging (MRI) and 1 year of postsurgical follow-up were included. The primary outcome measure was postoperative House-Brackmann (HB) facial nerve score measured at first postoperative visit and after at least 10 months.In total, 161 sporadic VSs and 14 NF2 VSs met inclusion criteria. Both median tumor diameter (NF2, 33.5 mm vs sporadic, 24 mm,Tumor volume3 cm

Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (2‐day CPET protocol) are increasingly used to evaluate post‐exertional malaise (PEM) and related disability among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This protocol may extend to other fatiguing illnesses with similar characteristics to ME/CFS; however, 2‐day CPET protocol reliability and minimum change required to be considered clinically meaningful (i.e., exceeding the standard error of the measure) are not well characterized. To address this gap, we evaluated the 2‐day CPET protocol in Gulf War Illness (GWI) by quantifying repeatability of seven CPET parameters, establishing their thresholds of clinically significant change, and determining whether changes differed between veterans with GWI and controls. Excluding those not attaining peak effort criteria (n = 15), we calculated intraclass correlation coefficients (ICCs), the smallest real difference (SRD%), and repeated measures analysis of variance (RM‐ANOVA) at the ventilatory anaerobic threshold (VAT) and peak exercise in 15 veterans with GWI and eight controls. ICC values at peak ranged from moderate to excellent for veterans with GWI (mean [range]; 0.84 [0.65 – 0.92]) and were reduced at the VAT (0.68 [0.37 – 0.78]). Across CPET variables, the SRD% at peak exercise for veterans with GWI (18.8 [8.8 – 28.8]) was generally lower than at the VAT (28.1 [9.5 – 34.8]). RM‐ANOVAs did not detect any significant group‐by‐time interactions (all p > .05). The methods and findings reported here provide a framework for evaluating 2‐day CPET reliability, and reinforce the importance of carefully considering measurement error in the population of interest when interpreting findings., Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (referred to as 2‐day CPET protocol) are increasingly promoted as an important clinical tool for illness diagnosis and measurement of disability in conditions with idiopathic fatigue; however, reliability and minimum values necessary to be considered clinically meaningful are not well characterized. With an emphasis on taking standard error of the measure into account, this study introduces a framework for evaluating repeatability and establishing reference values in the 2‐day CPET.

Environmental enrichment (EE) attenuates traumatic brain injury (TBI)-induced loss of medial septal (MS) choline acetyltransferase (ChAT)-cells and enhances spatial learning and memory vs. standard (STD) housing. Whether basal forebrain cholinergic neurons (BFCNs) are important mediators of EE-induced benefits after TBI requires further investigation. Anesthetized female rats were randomly assigned to intraseptal infusions of the immunotoxin 192-IgG-saporin (SAP; 0.22 μg in 1.0 μL) or vehicle (VEH; 1.0 μL IgG) followed immediately by a cortical impact (2.8 mm deformation depth at 4m/s) or sham injury and divided into EE and STD housing. Spatial learning and memory retention were assessed on post-operative days 14–19. MS ChAT(+) cells were quantified at 3 weeks. SAP significantly reduced ChAT(+) cells in both the EE and STD groups. Cognitive performance was improved in the EE groups, regardless of VEH or SAP infusion, vs. the STD-housed groups (p’s < 0.05). No cognitive differences were revealed between the TBI + EE + SAP and TBI + EE + VEH groups (p > 0.05) or between the TBI + STD + SAP and TBI + STD + VEH groups (p > 0.05). These data show that despite significant MS ChAT(+) cell loss, the EE-mediated benefit in cognitive recovery is not compromised.

Aim: We tested the safety and immunogenicity of a novel vaccine in patients with resected high-risk melanoma. Patients & methods: HLA-A2-positive patients with resected Stage II–IV melanoma were randomized to receive up to three vaccinations of melanoma-associated peptide (MART-1a) combined with a stable oil-in-water emulsion (SE) either with the Toll-like receptor 4 agonist glucopyranosyl lipid A (GLA-SE–Schedule 1) or alone (SE–Schedule 2). Safety and immunogenicity of the vaccines were monitored. Results: A total of 23 patients were registered. No treatment-related grade 3 or higher adverse events were observed. Increases in MART-1a-specific T cells were seen in 70 and 63% of Schedule 1 and Schedule 2 patients, respectively. Conclusion: Both vaccine schedules were well-tolerated and resulted in an increase in MART-1a-specific T cells. Clinical Trial registration: NCT02320305 ( ClinicalTrials.gov ).

Concentrations of different circulating microparticles (MPs) may have clinical and physiological relevance to cardiovascular disease pathologies. Purpose To quantify plasma concentrations of CD31+/CD42b−, CD62E+, and CD34+ MPs across healthy individuals and those with coronary artery disease (CAD) or acute cardiovascular events (non‐ST elevation myocardial infarction (NSTEMI)). Fasted blood was obtained from CAD patients (n = 10), NSTEMI patients (n = 13), and healthy older men (n = 15) 60–75 years old. Methods CD31+/CD42b−, CD62E+, and CD34+ MPs were isolated from plasma and quantified using flow cytometry. Relationships between MP subtypes, fasting blood lipids, blood glucose, blood pressure, body mass index, and total number of medications were assessed. Results Concentrations of CD31+/CD42b− MPs were significantly lower in CAD and NSTEMI subjects compared with healthy individuals (p = .02 and .003, respectively). No differences between groups were found for CD62E+ or CD34+ MPs (p > .05 for both). Surprisingly, among all variables assessed, only CD62E+ MP concentrations were positively correlated with triglyceride levels (p = .012) and inversely correlated with SBP (p = .03). Conclusions Our findings provide support for the use of different MP subtypes, specifically CD31+/CD42b− MPs, as a potential biomarker of cardiovascular disease. Importantly, results from this study should be looked at in adjunct to previous MP work in CVD conditions as a way of highlighting the complex interactions of variables such as comorbid conditions and medications on MP concentrations., In contrast to CD62E+ and CD34+ MPs, CD31+/CD42b− MPs were significantly lower in CAD and NSTEMI patients versus healthy older adults. These findings suggest CD31+/CD42b− MP concentration as a potential biomarker of cardiovascular disease and highlight the need for a better understanding of comorbidities and medications on MP concentrations.

Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.

To assess whether medication use, specifically statin, metformin, and aspirin, affects the growth of vestibular schwannomas (VSs).Retrospective case series.Single tertiary care academic hospital.Patients were enrolled if they were diagnosed with sporadic VS and had at least 2 magnetic resonance imaging (MRI) studies at a minimum of 6 months apart prior to any intervention. Electronic medical records were reviewed for demographic and medication data. Tumor volumes on MRI studies were assessed via BrainLab iPlan. The primary endpoint was VS tumor growth, defined as a 20% increase in tumor volume, between consecutive MRI studies or between the first and last available MRI study. Predictors of volumetric growth, specifically statin, aspirin, or metformin use, were analyzed withA total of 387 patients met inclusion criteria, 53.5% of whom were women. For all patients, the mean age was 60.6 years (range, 18.2-89.2 years); the mean axial tumor diameter, 11.9 mm (range, 1.7-32.0 mm); and the mean tumor volume, 0.85 cmMetformin use is associated with reduced volumetric VS growth.