An e-Learning Program for Physiotherapists to Manage Knee Osteoarthritis Via Telehealth During the COVID-19 Pandemic: Real-World Evaluation Study Using Registration and Survey Data.

BACKGROUND: The COVID-19 pandemic necessitated clinicians to transition to telehealth, often with little preparation or training. The Physiotherapy Exercise and Physical Activity for Knee Osteoarthritis (PEAK) e-learning modules were developed to upskill physiotherapists in management of knee osteoarthritis (OA) via telehealth and in-person. In the research setting, the e-learning modules are perceived by physiotherapists as effective when they are part of a comprehensive training program for a clinical trial. However, the effectiveness of the modules on their own in a real-world setting is unknown. OBJECTIVE: This study aims to evaluate the reach, effectiveness, adoption, and implementation of PEAK e-learning modules. METHODS: This longitudinal study was informed by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Participants were clinicians, researchers, educators, and health care students who registered for access to the modules between April 1 and November 30, 2020. Reach was evaluated by outcomes (countries, referral sources, and attrition) extracted from registration data and embedded within precourse surveys in the Learning Management System (LMS). Effectiveness was evaluated by outcomes (confidence with videoconferencing; likelihood of using education, strengthening exercise, and physical activity in a treatment plan for knee OA; usefulness of modules) measured using a 10-point numeric rating scale (NRS; score range from 1=not confident or likely or useful at all to 10=extremely confident or likely or useful) in pre- and postcourse (on completion) surveys in the LMS. Adoption and implementation were evaluated by demographic and professional characteristics and outcomes related to the use of learning and usefulness of program elements (measured via a 4-point Likert scale, from not at all useful to extremely useful) in a survey administered 4 months after module completion. RESULTS: Broad reach was achieved, with 6720 people from 97 countries registering for access. Among registrants, there were high levels of attrition, with 36.65% (2463/6720) commencing the program and precourse survey and 19.61% (1318/6720) completing all modules and the postcourse survey. The program was effective. Learners who completed the modules demonstrated increased confidence with videoconferencing (mean change 3.1, 95% CI 3.0-3.3 NRS units) and increased likelihood of using education, strengthening and physical activity in a knee OA treatment plan, compared to precourse. Adoption and implementation of learning (n=149 respondents) occurred at 4 months. More than half of the respondents used their learning to structure in-person consultations with patients (80/142, 56.3%) and patient information booklets in their clinical practice (75/142, 52.8%). CONCLUSIONS: Findings provide evidence of the reach and effectiveness of an asynchronous self-directed e-learning program in a real-world setting among physiotherapists. The e-learning modules offer clinicians an accessible educational course to learn about best-practice knee OA management, including telehealth delivery via videoconferencing. Attrition across the e-learning program highlights the challenges of keeping learners engaged in self-directed web-based learning.

Puppy love in the time of Corona: Dog ownership protects against loneliness for those living alone during the COVID-19 lockdown.

BACKGROUND: The COVID-19 pandemic has resulted in many countries enforcing a 'lockdown', whereby people are instructed to stay at home. AIM: The aim of this study was to capture the experience of such a lockdown in Australians living alone, with and without a dog or a cat. METHOD: Three hundred and eighty-four participants completed an online survey evaluating their levels of loneliness, mindfulness and mood. For participants who owned a dog or a cat, a measure of dog/cat interactions was also administered as well as two open-ended questions about how being a pet owner affected their experience of COVID-19 and how COVID-19 affected their pet. RESULTS: Contrary to expectations, cat owners were found to be less mindful than non-owners and pet interactions did not account for levels of loneliness or levels of mindfulness. In line with our expectations, however, stress and depression positively predicted loneliness, while mindfulness and being a dog owner were protective against it. Insights from qualitative responses suggest that this might be due to the fact that dogs encourage a routine which involves getting out of the house and walking, which itself offers opportunities to socialise with other people doing the same thing. CONCLUSION: These findings add to the emerging literature on mental well-being during a lockdown and the unique role that pets play in their owners' experiences.

An alternative theory for hormone effects on sex differences in PTSD: The role of heightened sex hormones during trauma.

Women are at least twice as susceptible to developing post-traumatic stress disorder (PTSD) compared to men. Although most research seeking to explain this discrepancy has focussed on the role of oestradiol during fear extinction learning, the role of progesterone has been overlooked, despite relatively consistent findings being reported concerning the role of progesterone during consolidation of emotional and intrusive memories. In this review article, we outline literature supporting the role of progesterone on memory formation, with particular emphasis on potential memory-enhancing properties of progesterone when subjects are placed under stress. It is possible that progesterone directly and indirectly exerts memory-enhancing effects at the time of trauma, which is an effect that may not be necessarily captured during non-stressful paradigms. We propose a model whereby progesterone's steroidogenic relationship to cortisol and brain-derived neurotrophic factor in combination with elevated oestradiol may enhance emotional memory consolidation during trauma and therefore present a specific vulnerability to PTSD formation in women, particularly during the mid-luteal phase of the menstrual cycle.

Modulation of the endocannabinoid system by sex hormones: Implications for posttraumatic stress disorder.

The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations.

Autologous Stem Cells in Achilles Tendinopathy (ASCAT): protocol for a phase IIA, single-centre, proof-of-concept study.

INTRODUCTION: Achilles tendinopathy (AT) is a cause of pain and disability affecting both athletes and sedentary individuals. More than 150 000 people in the UK every year suffer from AT.While there is much preclinical work on the use of stem cells in tendon pathology, there is a scarcity of clinical data looking at the use of mesenchymal stem cells to treat tendon disease and there does not appear to be any studies of the use of autologous cultured mesenchymal stem cells (MSCs) for AT. Our hypothesis is that autologous culture expanded MSCs implanted into an area of mid-portion AT will lead to improved pain-free mechanical function. The current paper presents the protocol for a phase IIa clinical study. METHODS AND ANALYSIS: The presented protocol is for a non-commercial, single-arm, open-label, phase IIa proof-of-concept study. The study will recruit 10 participants and will follow them up for 6 months. Included will be patients aged 18-70 years with chronic mid-portion AT who have failed at least 6 months of non-operative management. Participants will have a bone marrow aspirate collected from the posterior iliac crest under either local or general anaesthetic. MSCs will be isolated and expanded from the bone marrow. Four to 6 weeks after the harvest, participants will undergo implantation of the culture expanded MSCs under local anaesthetic and ultrasound guidance. The primary outcome will be safety as defined by the incidence rate of serious adverse reaction. The secondary outcomes will be efficacy as measured by patient-reported outcome measures and radiological outcome using ultrasound techniques. ETHICS AND DISSEMINATION: The protocol has been approved by the National Research Ethics Service Committee (London, Harrow; reference 13/LO/1670). Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02064062.

The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review.

BACKGROUND: The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. SHORT CONCLUSIONS: This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place.

Total ankle replacement versus arthrodesis (TARVA): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Total ankle replacement (TAR) or ankle arthrodesis (fusion) is the main surgical treatments for end-stage ankle osteoarthritis (OA). The popularity of ankle replacement is increasing while ankle fusion rates remain static. Both treatments have efficacy but to date all studies comparing the 2 have been observational without randomisation, and there are no published guidelines as to the most appropriate management. The TAR versus arthrodesis (TARVA) trial aims to compare the clinical and cost-effectiveness of TAR against ankle arthrodesis in the treatment of end-stage ankle OA in patients aged 50-85 years. METHODS AND ANALYSIS: TARVA is a multicentre randomised controlled trial that will randomise 328 patients aged 50-85 years with end-stage ankle arthritis. The 2 arms of the study will be TAR or ankle arthrodesis with 164 patients in each group. Up to 16 UK centres will participate. Patients will have clinical assessments and complete questionnaires before their operation and at 6, 12, 26 and 52 weeks after surgery. The primary clinical outcome of the study is a validated patient-reported outcome measure, the Manchester Oxford foot questionnaire, captured preoperatively and 12 months after surgery. Secondary outcomes include quality-of-life scores, complications, revision, reoperation and a health economic analysis. ETHICS AND DISSEMINATION: The protocol has been approved by the National Research Ethics Service Committee (London, Bloomsbury 14/LO/0807). This manuscript is based on V.5.0 of the protocol. The trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02128555.

Selection of phage-displayed human antibody fragments specific for CD1b presenting the Mycobacterium tuberculosis glycolipid Ac2SGL.

OBJECTIVE/BACKGROUND: The development of new tools capable of targeting Mycobacterium tuberculosis (Mtb)-infected cells have potential applications in diagnosis, treatment, and prevention of tuberculosis. In Mtb-infected cells, CD1b molecules present Mtb lipids to the immune system (Mtb lipid-CD1b complexes). Because of the lack of CD1b polymorphism, specific Mtb lipid-CD1b complexes could be considered as universal Mtb infection markers. 2-Stearoyl-3-hydroxyphthioceranoyl-2'-sulfate-α-α'-d-trehalose (Ac2SGL) is specific for Mtb, and is not present in other mycobacterial species. The CD1b-Ac2SGL complexes are expressed on the surface of human cells infected with Mtb. The aim of this study was to generate ligands capable of binding these CD1b-Ac2SGL complexes. METHODS: A synthetic human scFv phage antibody library was used to select phage-displayed antibody fragments that recognized CD1b-Ac2SGL using CD1b-transfected THP-1 cells loaded with Ac2SGL. RESULTS: One clone, D11-a single, light-variable domain (kappa) antibody (dAbκ11)-showed high relative binding to the Ac2SGL-CD1b complex. CONCLUSION: A ligand recognizing the Ac2SGL-CD1b complex was obtained, which is a potential candidate to be further tested for diagnostic and therapeutic applications.

Gender differences in salivary alpha-amylase and attentional bias towards negative facial expressions following acute stress induction.

This study investigated gender differences in two key processes involved in anxiety, arousal and attentional bias towards threat. Arousal was assessed using salivary alpha-amylase (sAA), a biomarker of noradrenergic arousal and attention bias using a dot-probe task. Twenty-nine women and 27 men completed the dot-probe task and provided saliva samples before and after a stress induction [cold pressor stress (CPS) test]. Women displayed a significant increase in arousal (sAA) following the stressor compared to men, who displayed a significant reduction in arousal. Reaction time data revealed a significant avoidance of threat in women at baseline, but a significant change to an attention bias towards threat following the stressor. Men did not significantly respond to the stressor in terms of attentional bias. These findings suggest that women are more reactive to a stressor than men, and display an initial avoidance response to threat, but an attentional bias towards threat following stress.

A Comparison of Self-Reported and Objective Physical Activity Measures in Young Australian Women.

BACKGROUND: The evidence for beneficial effects of recommended levels of physical activity is overwhelming. However, 70% of Australians fail to meet these levels. In particular, physical activity participation by women falls sharply between ages 16 to 25 years. Further information about physical activity measures in young women is needed. Self-administered questionnaires are often used to measure physical activity given their ease of application, but known limitations, including recall bias, compromise the accuracy of data. Alternatives such as objective measures are commonly used to overcome this problem, but are more costly and time consuming. OBJECTIVE: To compare the output between the Modified Active Australia Survey (MAAS), the International Physical Activity Questionnaire (IPAQ), and an objective physical activity measure-the SenseWear Armband (SWA)-to evaluate the test-retest reliability of the MAAS and to determine the acceptability of the SWA among young women. METHODS: Young women from Victoria, Australia, aged 18 to 25 years who had participated in previous studies via Facebook advertising were recruited. Participants completed the two physical activity questionnaires online, immediately before and after wearing the armband for 7 consecutive days. Data from the SWA was blocked into 10-minute activity times. Follow-up IPAQ, MAAS, and SWA data were analyzed by comparing the total continuous and categorical activity scores, while concurrent validity of IPAQ and MAAS were analyzed by comparing follow-up scores. Test-retest reliability of MAAS was analyzed by comparing MAAS total physical activity scores at baseline and follow-up. Participants provided feedback in the follow-up questionnaire about their experience of wearing the armband to determine acceptability of the SWA. Data analyses included graphical (ie, Bland-Altman plot, scatterplot) and analytical (ie, canonical correlation, kappa statistic) methods to determine agreement between MAAS, IPAQ, and SWA data. RESULTS: A total of 58 participants returned complete data. Comparisons between the MAAS and IPAQ questionnaires (n=52) showed moderate agreement for both categorical (kappa=.48, P<.001) and continuous data (r=.69, P<.001). Overall, the IPAQ tended to give higher scores. No significant correlation was observed between SWA and IPAQ or MAAS continuous data, for both minute-by-minute and blocked SWA data. The SWA tended to record lower scores than the questionnaires, suggesting participants tended to overreport their amount of physical activity. The test-retest analysis of MAAS showed moderate agreement for continuous outcomes (r=.44, P=.001). However, poor agreement was seen for categorical outcomes. The acceptability of the SWA to participants was high. CONCLUSIONS: Moderate agreement between the MAAS and IPAQ and moderate reliability of the MAAS indicates that the MAAS may be a suitable alternative to the IPAQ to assess total physical activity in young women, due to its shorter length and consequently lower participant burden. The SWA, and likely other monitoring devices, have the advantage over questionnaires of avoiding overreporting of self-reported physical activity, while being highly acceptable to participants.

Dysregulation in cortical reactivity to emotional faces in PTSD patients with high dissociation symptoms.

BACKGROUND: Predominant dissociation in posttraumatic stress disorder (PTSD) is characterized by restricted affective responses to positive stimuli. To date, no studies have examined neural responses to a range of emotional expressions in PTSD with high dissociative symptoms. OBJECTIVE: This study tested the hypothesis that PTSD patients with high dissociative symptoms will display increased event-related potential (ERP) amplitudes in early components (N1, P1) to threatening faces (angry, fearful), and reduced later ERP amplitudes (Vertex Positive Potential (VPP), P3) to happy faces compared to PTSD patients with low dissociative symptoms. METHODS: Thirty-nine civilians with PTSD were classified as high dissociative (n=16) or low dissociative (n=23) according to their responses on the Clinician Administered Dissociative States Scale. ERPs were recorded, whilst participants viewed emotional (happy, angry, fear) and neutral facial expressions in a passive viewing task. RESULTS: High dissociative PTSD patients displayed significantly increased N120 amplitude to the majority of facial expressions (neutral, happy, and angry) compared to low dissociative PTSD patients under conscious and preconscious conditions. The high dissociative PTSD group had significantly reduced VPP amplitude to happy faces in the conscious condition. CONCLUSION: High dissociative PTSD patients displayed increased early (preconscious) cortical responses to emotional stimuli, and specific reductions to happy facial expressions in later (conscious), face-specific components compared to low dissociative PTSD patients. Dissociation in PTSD may act to increase initial pre-attentive processing of affective stimuli, and specifically reduce cortical reactivity to happy faces when consciously processing these stimuli.

Phage display of functional αß single-chain T-cell receptor molecules specific for CD1b:Ac2SGL complexes from Mycobacterium tuberculosis-infected cells.

The development of molecules specific for M. tuberculosis-infected cells has important implications, as these tools may facilitate understanding of the mechanisms regulating host pathogen interactions in vivo. In addition, development of new tools capable to targeting M. tuberculosis-infected cells may have potential applications to diagnosis, treatment, and prevention of tuberculosis (TB). Due to the lack of CD1b polymorphism, M. tuberculosis lipid-CD1b complexes could be considered as universal tuberculosis infection markers. The aim of the present study was to display on the PIII surface protein of m13 phage, a human αß single-chain T-cell receptor molecule specific for CD1b:2-stearoyl-3-hydroxyphthioceranoyl-2´-sulfate-α-α´-D-trehalose (Ac2SGL) which is a complex presented by human cells infected with M. tuberculosis. The results showed the pIII fusion particle was successfully displayed on the phage surface. The study of the recognition of the recombinant phage in ELISA and immunohistochemistry showed the recognition of CD1b:Ac2SGL complexes and cells in human lung tissue from a tuberculosis patient respectively, suggesting the specific recognition of the lipid-CD1b complex.

Modulation of cell death by M. tuberculosis as a strategy for pathogen survival.

It has been clearly demonstrated that in vitro, virulent M. tuberculosis can favor necrosis over apoptosis in infected macrophages, and this has been suggested as a mechanism for evading the host immune response. We recently reported that an effect consistent with this hypothesis could be observed in cells from the blood of TB patients, and in this paper, we review what is known about evasion strategies employed by M. tuberculosis and in particular consider the possible interaction of the apoptosis-inhibiting effects of M. tuberculosis infection with another factor (IL-4) whose expression is thought to play a role in the failure to control M. tuberculosis infection. It has been noted that IL-4 may exacerbate TNF-α-induced pathology, though the mechanism remains unexplained. Since pathology in TB typically involves inflammatory aggregates around infected cells, where TNF-α plays an important role, we predicted that IL-4 would inhibit the ability of cells to remove M. tuberculosis by apoptosis of infected cells, through the extrinsic pathway, which is activated by TNF-α. Infection of human monocytic cells with mycobacteria in vitro, in the presence of IL-4, appears to promote necrosis over apoptosis in infected cells-a finding consistent with its suggested role as a factor in pathology during M. tuberculosis infection.

Natural exposure to cutaneous anthrax gives long-lasting T cell immunity encompassing infection-specific epitopes.

There has been a long history of defining T cell epitopes to track viral immunity and to design rational vaccines, yet few data of this type exist for bacterial infections. Bacillus anthracis, the causative agent of anthrax, is both an endemic pathogen in many regions and a potential biological warfare threat. T cell immunity in naturally infected anthrax patients has not previously been characterized, which is surprising given concern about the ability of anthrax toxins to subvert or ablate adaptive immunity. We investigated CD4 T cell responses in patients from the Kayseri region of Turkey who were previously infected with cutaneous anthrax. Responses to B. anthracis protective Ag and lethal factor (LF) were investigated at the protein, domain, and epitope level. Several years after antibiotic-treated anthrax infection, strong T cell memory was detectable, with no evidence of the expected impairment in specific immunity. Although serological responses to existing anthrax vaccines focus primarily on protective Ag, the major target of T cell immunity in infected individuals and anthrax-vaccinated donors was LF, notably domain IV. Some of these anthrax epitopes showed broad binding to several HLA class alleles, but others were more constrained in their HLA binding patterns. Of specific CD4 T cell epitopes targeted within LF domain IV, one is preferentially seen in the context of bacterial infection, as opposed to vaccination, suggesting that studies of this type will be important in understanding how the human immune system confronts serious bacterial infection.

Expression of apoptosis-related genes in an Ethiopian cohort study correlates with tuberculosis clinical status.

Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic ("death receptor initiated") pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-alpha and its receptors, Fas and FasL and pro-Caspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-alpha and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages--the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen.

The pathogen recognition sensor, NOD2, is variably expressed in patients with pulmonary tuberculosis.

BACKGROUND: NOD2, an intracellular pathogen recognition sensor, modulates innate defences to muropeptides derived from various bacterial species, including Mycobacterium tuberculosis (MTB). Experimentally, NOD2 attenuates two key putative mycobactericidal mechanisms. TNF-alpha synthesis is markedly reduced in MTB-antigen stimulated-mononuclear cells expressing mutant NOD2 proteins. NOD2 agonists also induce resistance to apoptosis, and may thus facilitate the survival of MTB in infected macrophages. To further define a role for NOD2 in disease pathogenesis, we analysed NOD2 transcriptional responses in pulmonary leucocytes and mononuclear cells harvested from patients with pulmonary tuberculosis (PTB). METHODS: We analysed NOD2 mRNA expression by real-time polymerase chain-reaction in alveolar lavage cells obtained from 15 patients with pulmonary tuberculosis and their matched controls. We compared NOD2 transcriptional responses, in peripheral leucocytes, before and after anti-tuberculous treatment in 10 patients. In vitro, we measured NOD2 mRNA levels in MTB-antigen stimulated-mononuclear cells. RESULTS: No significant differences in NOD2 transcriptional responses were detected in patients and controls. In some patients, however, NOD2 expression was markedly increased and correlated with toll-like-receptor 2 and 4 expression. In whole blood, NOD2 mRNA levels increased significantly after completion of anti-tuberculosis treatment. NOD2 expression levels did not change significantly in mononuclear cells stimulated with mycobacterial antigens in vitro. CONCLUSION: There are no characteristic NOD2 transcriptional responses in PTB. Nonetheless, the increased levels of NOD2 expression in some patients with severe tuberculosis, and the increases in expression levels within peripheral leucocytes following treatment merit further studies in selected patient and control populations.