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Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1β and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100-family members and epithelial-myeloid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb.

Clustering molecular data into informative groups is a primary step in extracting robust conclusions from big data. However, due to foundational issues in how they are defined and detected, such clusters are not always reliable, leading to unstable conclusions. We compare popular clustering algorithms across thousands of synthetic and real biological datasets, including a new consensus clustering algorithm—SpeakEasy2: Champagne. These tests identify trends in performance, show no single method is universally optimal, and allow us to examine factors behind variation in performance. Multiple metrics indicate SpeakEasy2 generally provides robust, scalable, and informative clusters for a range of applications.

BackgroundEndobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as an important tool for the diagnosis and staging of lung cancer but its role in the diagnosis of tuberculous intrathoracic lymphadenopathy has not been established. The aim of this study was to describe the diagnostic utility of EBUS-TBNA in patients with intrathoracic lymphadenopathy due to tuberculosis (TB).Methods156 consecutive patients with isolated intrathoracic TB lymphadenitis were studied across four centres over a 2-year period. Only patients with a confirmed diagnosis or unequivocal clinical and radiological response to antituberculous treatment during follow-up for a minimum of 6 months were included. All patients underwent routine clinical assessment and a CT scan prior to EBUS-TBNA. Demographic data, HIV status, pathological findings and microbiological results were recorded.ResultsEBUS-TBNA was diagnostic of TB in 146 patients (94%; 95% CI 88% to 97%). Pathological findings were consistent with TB in 134 patients (86%). Microbiological investigations yielded a positive culture of TB in 74 patients (47%) with a median time to positive culture of 16 days (range 3–84) and identified eight drug-resistant cases (5%). Ten patients (6%) did not have a specific diagnosis following EBUS; four underwent mediastinoscopy which confirmed the diagnosis of TB while six responded to empirical antituberculous therapy. There was one complication requiring an inpatient admission.ConclusionsEBUS-TBNA is a safe and effective first-line investigation in patients with tuberculous intrathoracic lymphadenopathy.

Background Few clinical trials have investigated the safety and efficacy of mesenchymal stem cells for the management of post-traumatic osteoarthritis. The objectives of this pilot study were to determine the safety and tolerability and to explore the efficacy of a single intra-articular injection of allogeneic human mesenchymal precursor cells (MPCs) to improve clinical symptoms and retard joint structural deterioration over 24 months in patients following anterior cruciate ligament (ACL) reconstruction. Methods In this phase Ib/IIa, double-blind, active comparator clinical study, 17 patients aged 18–40 years with unilateral ACL reconstruction were randomized (2:1) to receive either a single intra-articular injection of 75 million allogeneic MPCs suspended in hyaluronan (HA) (MPC + HA group) ( n = 11) or HA alone ( n = 6). Patients were monitored for adverse events. Immunogenicity was evaluated by anti-HLA panel reactive antibodies (PRA) against class I and II HLAs determined by flow cytometry. Pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. Joint space width was measured from radiographs, and tibial cartilage volume and bone area assessed from magnetic resonance imaging (MRI). Results Moderate arthralgia and swelling within 24 h following injection that subsided were observed in 4 out of 11 in the MPC + HA group and 0 out of 6 HA controls. No cell-related serious adverse effects were observed. Increases in class I PRA >10% were observed at week 4 in the MPC + HA group that decreased to baseline levels by week 104. Compared with the HA group, MPC + HA-treated patients showed greater improvements in KOOS pain, symptom, activities of daily living, and SF-36 bodily pain scores ( p < 0.05). The MPC + HA group had reduced medial and lateral tibiofemoral joint space narrowing ( p < 0.05), less tibial bone expansion (0.5% vs 4.0% over 26 weeks, p = 0.02), and a trend towards reduced tibial cartilage volume loss (0.7% vs –4.0% over 26 weeks, p = 0.10) than the HA controls. Conclusions Intra-articular administration of a single allogeneic MPC injection following ACL reconstruction was safe, well tolerated, and may improve symptoms and structural outcomes. These findings suggest that MPCs warrant further investigations as they may modulate some of the pathological processes responsible for the development of post-traumatic osteoarthritis following ACL reconstruction. Trial registration ClinicalTrials.gov ( NCT01088191 ) registration date: March 11, 2010

Coronavirus disease 2019 (COVID-19) has been reported to cause cardiovascular complications such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Multiple mechanisms—some overlapping, notably the role of inflammation and IL-6—potentially underlie these complications. The reported cardiac injury may be a result of direct viral invasion of cardiomyocytes with consequent unopposed effects of angiotensin II, increased metabolic demand, immune activation, or microvascular dysfunction. Thromboembolic events have been widely reported in both the venous and arterial systems that have attracted intense interest in the underlying mechanisms. These could potentially be due to endothelial dysfunction secondary to direct viral invasion or inflammation. Additionally, thromboembolic events may also be a consequence of an attempt by the immune system to contain the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been reported with a wide range of implicated contributory factors, ranging from direct viral myocardial injury, as well as other factors, including at-risk individuals with underlying inherited arrhythmia syndromes. Heart failure may also occur as a progression from cardiac injury, precipitation secondary to the initiation or withdrawal of certain drugs, or the accumulation of des-Arg9-bradykinin (DABK) with excessive induction of pro-inflammatory G protein coupled receptor B1 (BK1). The presenting cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently intense interest in vaccine-induced thrombosis and in the treatment of Long COVID since many patients who have survived COVID-19 describe persisting health problems. This review will summarise the proposed physiological mechanisms of COVID-19-associated cardiovascular complications.

The classification of non-specific chronic low back pain (CLBP) according to multidimensional data could guide clinical management; yet recent systematic reviews show this has not been attempted. This was a prospective cross-sectional study of participants with CLBP (n = 21) and age-, sex- and height-matched pain-free controls (n = 21). Nervous system, lumbar spinal tissue and psychosocial factors were collected. Dimensionality reduction was followed by fuzzy c-means clustering to determine sub-groups. Machine learning models (Support Vector Machine, k-Nearest Neighbour, Naïve Bayes and Random Forest) were used to determine the accuracy of classification to sub-groups. The primary analysis showed that four factors (cognitive function, depressive symptoms, general self-efficacy and anxiety symptoms) and two clusters (normal versus impaired psychosocial profiles) optimally classified participants. The error rates in classification models ranged from 4.2 to 14.2% when only CLBP patients were considered and increased to 24.2 to 37.5% when pain-free controls were added. This data-driven pilot study classified participants with CLBP into sub-groups, primarily based on psychosocial factors. This contributes to the literature as it was the first study to evaluate data-driven machine learning CLBP classification based on nervous system, lumbar spinal tissue and psychosocial factors. Future studies with larger sample sizes should validate these findings.

To evaluate the imaging findings following acute hamstring injury. We retrospectively reviewed the imaging findings of hamstring muscle complex (HMC) strain in 170 patients referred to our institution over a 3-year period. A total of 179 injuries to the HMC were demonstrated in 170 patients (154 male, 16 female, mean age 28.2 years). The mean duration of symptoms was 4.7 days (range 1-10 days). MR imaging was performed in 97 cases and sonography in 102 cases (both modalities were performed in 20 examinations). Attention was directed to the frequency of muscle involvement, the location of the injury within the muscle-tendon unit, the extent of the injury and discriminating avulsion from muscle injury. Twenty-one patients had proximal tendon injury, with sixteen avulsions and five partial tears. Sixteen of these patients had surgical confirmation of hamstring avulsion from the ischial tuberosity (14 conjoint, 2 biceps femoris alone) and all were reliably diagnosed with MR imaging (16/16), but less so with sonography (7/12). Four distal tendon avulsions were also observed (three semitendinosus, one biceps femoris). With respect to muscle injury, the biceps femoris was most commonly injured (124/154). Semimembranosus was an uncommon muscle injury (21/154) and semitendinosus rare (9/154). Imaging can discriminate a hamstring tendon avulsion from musculotendinous strain and helps identify which patients necessitate surgical management as opposed to conservative treatment.

Background Knee osteoarthritis (OA) causes substantial pain, physical dysfunction and impaired quality of life. There is no cure for knee OA, and for some people, the disease may involve progressive symptomatic and structural deterioration over time. Platelet-rich plasma (PRP) is a therapeutic agent that aims to address underlying biological processes responsible for OA pathogenesis. As such, it has the potential to improve both symptoms and joint structure. The aim of this clinical trial is to determine whether a series of injections of PRP into the knee joint will lead to a significantly greater reduction in knee pain, and less loss of medial tibial cartilage volume over 12 months when compared to a series of placebo saline injections in people with knee OA. Methods This will be a two-group, superiority, randomised, participant-, interventionist- and assessor-blinded, placebo-controlled trial. Two hundred and eighty-eight participants aged over 50 years with painful knee OA and mild to moderate structural change on x-ray (Kellgren and Lawrence grade 2 and 3) will be randomly allocated to receive either three PRP injections or three normal saline injections into the knee joint at weekly intervals. The primary outcomes will be 12-month change in average overall knee pain severity (numeric rating scale) and medial tibial cartilage volume (magnetic resonance imaging (MRI)). Secondary outcomes include additional measures of knee pain and other symptoms, function in daily living and sport and recreation, quality of life, participant-perceived global ratings of change, and other MRI structural outcomes including meniscal and cartilage morphology, synovitis, effusion, bone marrow lesions and cartilage defects. A range of additional measures will be recorded, and a separate health economic evaluation will be performed. Discussion The findings from this study will help determine whether PRP improves both clinical and structural knee OA outcomes over 12 months when compared to a series of placebo saline injections. Trial registration Australian New Zealand Clinical Trials Registry reference: ACTRN12617000853347 . Prospectively registered 9th of June 2017.

Our objective was to describe the sonographic appearance of the gluteus medius and minimus tendons in normal subjects, and to illustrate the spectrum of sonographic findings in gluteus tendinopathies. Sonography was performed in 20 asymptomatic volunteers. Seventy-five consecutive patients (59 women, 16 men; mean age 57.1 years) presented with pain and point tenderness over the greater trochanter. There were 43 right hips and 32 left hips. Ten patients provided a history of a traumatic incident with subsequent symptoms (mean duration 3.2 months). All patients underwent sonography to assess the site and severity of injury, and to discriminate tendinosis from partial and complete tear. Calcific foci, bony change, and fluid in the trochanteric bursae were noted. Twenty-two patients subsequently underwent surgery. Fifty-three (53 of 75) patients showed sonographic evidence of gluteus medius tendinopathy. Twenty-eight patients were thought to have tendinopathy without discrete tear. Sixteen patients had partial tears and 9 full-thickness tears. Gluteus minimus tendinopathy was detected in 10 of 75 patients. Foci of tendinopathy and partial tears were more common in the deep and anterior portions of the gluteus medius tendon attachment. Eight patients had fluid pooling in the trochanteric bursae. Findings were confirmed in 22 patients at surgery. Sonography can identify gluteus medius and minimus tendinopathy and provides information about the severity of the disease.