An exploration of psychological trauma and positive adaptation in adults with congenital heart disease during the COVID-19 pandemic

Introduction: The growing population of adults with congenital heart disease (CHD) often have lifelong experience of dealing with potentially traumatic health crises and medical uncertainty whilst facing increased vulnerability to post-traumatic stress disorder (PTSD). The COVID-19 pandemic presents additional challenges for this population including increased risk of health complications, shielding and strict social distancing, changes to medical care provision and social stigma. Despite such challenges, adults with CHD have the potential to also experience positive changes, yet little is known as to what helps cultivate positive adaptation and post-traumatic growth (PTG) within this context. Methods: The current study comprised a cross-sectional, anonymous, online study exploring psychosocial measures of traumatic experiences as well as protective factors that mitigate the risks to mental health on the mental health for adults with CHD (n=236) during the pandemic. Closed and open-ended questions and a series of standardised psychosocial measures of traumatic experiences, coping mechanisms, emotional regulation and PTG were measured. Results: Findings suggest the CHD population are at increased risk of PSTD which may be exacerbated by the COVID-19 pandemic. However, positive adaptation may promote post traumatic growth. In particular, health adversity is associated with greater appreciation whilst emotional regulation is associated with post-traumatic growth. Conclusions: We recommend a growth-focused, psychologically and trauma-informed approach to medicine and public health, recognising the importance of supporting mental health and promoting living well with CHD during the COVID-19 pandemic and beyond. These findings are likely generalisable to other lifelong health conditions and shielding populations

Developments in fieldwork procedures and monitoring in longitudinal surveys: case prioritisation and electronic contact sheets on the UK Millennium Cohort Study

Maximising response is important in any survey and especially so in a longitudinal survey where non-response at a particular wave contributes to attrition. A key element of response maximisation in face-to-face surveys is the adoption and implementation of thorough fieldwork procedures. The introduction of electronic sample management systems has provided more timely and accurate para-data with which to monitor interviewers’ compliance with fieldwork procedures. One of the major advantages of longitudinal surveys is that they are able to make use of prior wave data in order to identify cases at highest risk of non-response and thereby target appropriate fieldwork interventions designed to minimise non-response. This paper examines two developments in the fieldwork procedures used on the UK Millennium Cohort Study (MCS) designed to maximise response: case prioritisation for low-contact propensity cases and electronic contact sheets to help ensure adherence to contact protocols. We compare fieldwork procedures used in the fifth wave in 2012 (at age 11) with those used at the sixth wave in 2015 (at age 14), utilising wave-on-wave changes in procedures to compare the effectiveness of different approaches to response maximisation. In the first part of our paper, we compare our two different approaches to case prioritisation: response propensity models employed at wave 5 and a simpler approach using prior wave outcomes only used at waves 6. We conclude that the simpler approach to identifying cases which are likely to have low contact propensity, based on prior wave outcomes only, is more effective than a more complex approach based on response propensity models. The second part of our paper, we evaluate the effectiveness of using of electronic contact sheets (ECS) at wave 6 to improve compliance with fieldwork procedures, cost-effectiveness and reduce non-response. We show that at wave 6 interviewer compliance rates were higher and non-contact rates were lower than at wave 5, and argue that the introduction of the ECS has led to this improvement in fieldwork quality and reduction in nonresponse

Clinical characteristics and outcomes of adult patients admitted with COVID-19 in East London: a retrospective cohort analysis.

BACKGROUND: Descriptions of clinical characteristics of patients hospitalised withCOVID-19, their clinical course and short-term inpatient and outpatient outcomes in deprived urban populations in the UK are still relatively sparse. We describe the epidemiology, clinical course, experience of non-invasive ventilation and intensive care, mortality and short-term sequelae of patients admitted to two large District General Hospitals across a large East London National Health Service Trust during the first wave of the pandemic. METHODS: A retrospective analysis was carried out on a cohort of 1946 patients with a clinical or laboratory diagnosis of COVID-19, including descriptive statistics and survival analysis. A more detailed analysis was undertaken of a subset of patients admitted across three respiratory units in the trust. RESULTS: Increasing age, male sex and Asian ethnicity were associated with worse outcomes. Increasing severity of chest X-ray abnormalities trended with mortality. Radiological changes persisted in over 50% of cases at early follow-up (6 weeks). Ongoing symptoms including hair loss, memory impairment, breathlessness, cough and fatigue were reported in 70% of survivors, with 39% of patients unable to return to work due to ongoing symptoms. CONCLUSIONS: Understanding the acute clinical features, course of illness and outcomes of COVID-19 will be crucial in understanding the effect of differences in risk, as well as the effectiveness of new interventions and vaccination between the successive waves of the pandemic

Views on social media and its linkage to longitudinal data from two generations of a UK cohort study

Background: Cohort studies gather huge volumes of information about a range of phenotypes but new sources of information such as social media data are yet to be integrated. Participant’s long-term engagement with cohort studies, as well as the potential for their social media data to be linked to other longitudinal data, could provide novel advances but may also give participants a unique perspective on the acceptability of this growing research area. Methods: Two focus groups explored participant views towards the acceptability and best practice for the collection of social media data for research purposes. Participants were drawn from the Avon Longitudinal Study of Parents and Children cohort; individuals from the index cohort of young people (N=9) and from the parent generation (N=5) took part in two separate 90-minute focus groups. The discussions were audio recorded and subjected to qualitative analysis. Results: Participants were generally supportive of the collection of social media data to facilitate health and social research. They felt that their trust in the cohort study would encourage them to do so. Concern was expressed about the collection of data from friends or connections who had not consented. In terms of best practice for collecting the data, participants generally preferred the use of anonymous data derived from social media to be shared with researchers. Conclusion: Cohort studies have trusting relationships with their participants; for this relationship to extend to linking their social media data with longitudinal information, procedural safeguards are needed. Participants understand the goals and potential of research integrating social media data into cohort studies, but further research is required on the acquisition of their friend’s data. The views gathered from participants provide important guidance for future work seeking to integrate social media in cohort studies

Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults.

BACKGROUND: Identification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status. METHODS: We prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis and benchmarked against WHO recommendations. RESULTS: Of 932 included individuals, 255 (27%) had culture-confirmed pulmonary TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0·80 (95% confidence interval 0·77-0·83), with sensitivity 93% (89-95%) and specificity 54% (50-58%) using a primary cut-off of ≥10 mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive pulmonary TB case diagnosed (threshold probability 5%). If it is possible to perform more confirmatory tests than this, a 'confirmatory test for all' strategy performed better. CONCLUSIONS: CRP achieved the WHO-defined sensitivity, but not specificity, targets for a triage test for pulmonary TB and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status. FUNDING: South African Medical Research Council, EDCTP2, Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, Royal College of Physicians

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects

Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells

A new mechanism for focal adhesion disassembly is described involving microtubule-stimulated endocytosis of integrins at focal adhesions

Dynamics of sputum conversion during effective tuberculosis treatment: A systematic review and meta-analysis.

BACKGROUND: Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. METHODS AND FINDINGS: For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. CONCLUSIONS: This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. TRIAL REGISTRATION: Systematic review registration: PROSPERO 85226

NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

<p>Abstract</p> <p>Background</p> <p>Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.</p> <p>Methods</p> <p>We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for <it>in vitro </it>experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.</p> <p>Results</p> <p>NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. <it>In vitro</it>, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β₁integrin engagement. <it>In vivo</it>, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.</p> <p>Conclusions</p> <p>This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.</p