Knee Osteoarthritis and the Efficacy of Kinesthesia, Balance & Agility Exercise Training: A Pilot Study

Kinesthesia, balance and agility (KBA) neuromuscular exercises are commonly used for rehabilitation of lower extremity injuries. KBA combined with strength training (ST) reportedly improves function among persons with knee osteoarthritis (OA), but independent effects of KBA are unknown. The purpose of this study was to determine the efficacy of KBA exercises, independent of ST, to improve function among persons with knee OA. Twenty participants (69.3, SD 11.4 y) were randomized to 8 weeks, 3-days per week, instructor-lead KBA or ST groups. Self-reported physical function (difficulty with daily living activities such as walking, bending, stair climbing, etc.) was measured at baseline and every two weeks. Community physical activity level, negative and positive outcome expectancies for exercise, self-reported knee stability, and timed 10-stair climb, 10-stair descent, and ‘get up and go’ 15 m walk were measured at baseline and follow-up. Physical function improved 59% (p = 0.02) with KBA and 40% (p = 0.02) with ST at 8 weeks. Community physical activity level improved only in KBA (p = 0.04); knee stability improved in both KBA (p = 0.04) and ST (p = 0.01). There were no significant between-group differences (p \u3e 0.05). In conclusion, both interventions appear to improve function and knee stability among persons with symptomatic knee OA. As KBA has never been studied as an independent treatment program, our results indicate it is a promising stand-alone intervention worthy of further study

Emerging Roles of Primary Cilia in Glioma

Primary cilia are microtubule-based organelles that are typically present on cells during the G0 or G1-S/G2 phases of the cell cycle. Recent studies of glioblastoma (GBM) biopsies, a brain tumor that is notorious for its aggressive growth and resistance to treatment, show that many cells in the tumor lack cilia. At this point, it remains unclear whether primary cilia promote or suppress glioma tumorigenesis. In this review, we will discuss the different roles that have been proposed for primary cilia in glioma and how cilia may contribute to the resistance of these tumors to current therapies

IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders

Diagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multiple Phenotype Resources Optimizes Variant Evaluation in Developmental Disorders (IMPROVE-DD) by incorporating additional classes of data commonly available to clinicians and recorded in health records. In doing so, we quantify the distinct contributions of sex, growth, and development in addition to Human Phenotype Ontology (HPO) terms and demonstrate added value from these readily available information sources. We use likelihood ratios for nominal and quantitative data and propose a classifier for HPO terms in this framework. This Bayesian framework results in more robust diagnoses. Using data systematically collected in the Deciphering Developmental Disorders study, we considered 77 genes with pathogenic/likely pathogenic variants in ≥10 individuals. All genes showed at least a satisfactory prediction by receiver operating characteristic when testing on training data (AUC ≥ 0.6), and HPO terms were the best predictor for the majority of genes, though a minority (13/77) of genes were better predicted by other phenotypic data types. Overall, classifiers based upon multiple integrated phenotypic data sources performed better than those based upon any individual source, and importantly, integrated models produced notably fewer false positives. Finally, we show that IMPROVE-DD models with good predictive performance on cross-validation can be constructed from relatively few individuals. This suggests new strategies for candidate gene prioritization and highlights the value of systematic clinical data collection to support diagnostic programs

Primary Paediatric Bronchial Airway Epithelial Cell in Vitro Responses to Environmental Exposures

Acknowledgments: The authors are grateful to the children who participated in this study and their parents. The authors would like to thank the following colleagues in the department of Ear Nose and Throat Surgery at NHS Grampian for allowing us to recruit their patients: Nicola Kryle, Derek Veitch, Kim Ah-See, Bhaskar Ram, Sangeeta Maini and Clive Brewis. We are also grateful to Tenovus Scotland whose funds enabled analysis of the samples (Grant reference G13_17) but did not include open access publishing fees.Peer reviewedPublisher PD

T granules in human platelets function in TLR9 organization and signaling

Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tubular system-related compartment we have named the T granule. TLR9 colocalizes with protein disulfide isomerase and is associated with either VAMP 7 or VAMP 8, which regulates its distribution in PLTs on contact activation (spreading). Preincubation of PLTs with type IV collagen specifically increased TLR9 and CD62P surface expression and augmented oligodeoxynucleotide (ODN) sequestration and PLT clumping upon addition of bacterial/viral ODNs. Collectively, this paper (a) tracks TLR9 to a new intracellular compartment in PLTs and (b) describes a novel mechanism of TLR9 organization and signaling in human PLTs

Multimodal imaging and spatial analysis of Ebola retinal lesions in 14 survivors of Ebola virus disease

Importance: Differentiation between Ebola retinal lesions and other retinal pathologies in West Africa is important, and the pathogenesis of Ebola retinal disease remains poorly understood. Objective: To describe the appearance of Ebola virus disease (EVD) retinal lesions using multimodal imaging to enable inferences on potential pathogenesis. Design, Setting, and Participants: This prospective case series study was carried out at 34 Military Hospital in Freetown, Sierra Leone. Ophthalmological images were analyzed from 14 consecutively identified survivors of EVD of Sierra Leonean origin who had identified Ebola retinal lesions. Main Outcomes and Measures: Multimodal imaging findings including ultra-widefield scanning laser ophthalmoscopy, fundus autofluorescence, swept-source optical coherence tomography (OCT), Humphrey visual field analysis, and spatial analysis. Results: The 14 study participants had a mean (SD) age of 37.1 (8.8) years; 6 (43%) were women. A total of 141 Ebola retinal lesions were observed in 22 of 27 eyes (81%) of these 14 survivors on ultra-widefield imaging. Of these, 41 lesions (29.1%) were accessible to OCT imaging. Retinal lesions were predominantly nonpigmented with a pale-gray appearance. Peripapillary lesions exhibited variable curvatures in keeping with the retinal nerve fiber layer projections. All lesions respected the horizontal raphe and spared the fovea. The OCT imaging demonstrated a V-shaped hyperreflectivity of the outer nuclear layer overlying discontinuities of the ellipsoid zone and interdigitation zone in the smaller lesions. Larger lesions caused a collapse of the retinal layers and loss of retinal thickness. Lesion shapes were variable, but sharp angulations were characteristic. Perilesional areas of dark without pressure (thinned ellipsoid zone hyporeflectivity) accompanied 125 of the 141 lesions (88.7%) to varying extents. Conclusions and Relevance: We demonstrate OCT evidence of localized pathological changes at the level of the photoreceptors in small lesions among survivors of EVD with retinal lesions. The relevance of associated areas of dark without pressure remains undetermined

Hepatic and adipose phenotype in Alström syndrome

BACKGROUND AND AIMS: Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. METHODS: Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. RESULTS: Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. CONCLUSIONS: NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS.Alström UKThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/liv.1316

Delayed mucosal antiviral responses despite robust peripheral inflammation in fatal COVID-19

Background: While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. Methods: We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0–5 days after symptom onset) or late (6–20 days after symptom onset) phase. Results: Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions: Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19