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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca2+) is crucial for NK cell effector functions. Growing research recognises Ca2+ signalling dysregulation in ME/CFS patients and implicates transient receptor potential ion channel dysfunction. TRPM7 (melastatin) was recently considered in the pathoaetiology of ME/CFS as it participates in several Ca2+-dependent processes that are central to NK cell cytotoxicity which may be compromised in ME/CFS. TRPM7-dependent Ca2+ influx was assessed in NK cells isolated from n = 9 ME/CFS patients and n = 9 age- and sex-matched healthy controls (HCs) using live cell fluorescent imaging techniques. Slope (p < 0.05) was significantly reduced in ME/CFS patients compared with HCs following TRPM7 activation. Half-time of maximal response (p < 0.05) and amplitude (p < 0.001) were significantly reduced in the HCs compared with the ME/CFS patients following TRPM7 desensitisation. Findings from this investigation suggest that TRPM7-dependent Ca2+ influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs. The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition suggesting that ME/CFS is a TRP ion channelopathy.

Microbial metabolism of specific dietary components, such as fiber, contributes to the sophisticated inter-kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber-derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision-making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, the importance of appropriate timing of intervention to target any potential window of opportunity, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions, and outcomes were too heterogeneous for meta-analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health.

BACKGROUND: Coronary artery bypass grafting (CABG) is the most common revascularization approach for the treatment of multi-vessel coronary artery disease. While the internal mammary artery is nearly universally used to bypass the left anterior descending coronary artery, autologous saphenous vein grafts (SVGs) are still the most frequently used conduits to grafts the remaining coronary artery targets Long-term failure of these grafts, however, continues to limit the benefits of surgery. DESIGN: The Cardiothoracic Surgical Trials Network trial of the safety and effectiveness of a Venous External Support (VEST) device is a randomized, multicenter, within-patient trial comparing VEST-supported versus unsupported saphenous vein grafts in patients undergoing CABG. Key inclusion criteria are the need for CABG with a planned internal mammary artery to the left anterior descending and two or more saphenous vein grafts to other coronary arteries. The primary efficacy endpoint of the trial is SVG intimal hyperplasia (plaque + media) area assessed by intravascular ultrasound at 12 months post randomization. Occluded grafts are accounted for in the analysis of the primary endpoint. Secondary confirmatory endpoints are lumen diameter uniformity and graft failure (>50% stenosis) assessed by coronary angiography at 12 months. The safety endpoints are the occurrence of major adverse cardiac and cerebrovascular events and hospitalization within 5 years from randomization. CONCLUSIONS: The results of the VEST trial will determine whether the VEST device can safely limit SVG intimal hyperplasia in patients undergoing CABG as treatment for coronary atherosclerotic disease.

Internet usage is a salient developmental factor in adolescents’ lives. Although relevant correlates of internet use have been documented earlier, there is a lack of information on lower socioeconomic status groups. This is important, as these adolescents have increased risk for negative online experiences. The current survey aimed to explore internet use and parental involvement amongst adolescents from areas of socio-economic disadvantage in 30 urban schools across five European countries. A total of 2,594 students participated, of whom 90% were 14-16 years. Virtually all adolescents of socioeconomic disadvantage had internet access, with 88.5% reporting spending more than two hours per day online, often on apps such as Instagram, Snapchat, and YouTube. Almost one-third of adolescents did not talk with their parents about their internet use and almost two-thirds indicated that their parents were only a little or not interested in their internet use. A consistent finding across countries was that girls more often talked with their parents about their internet use and more often reported that their parents were interested in their internet use than boys. The results suggest that parents have an important task in explicitly showing interest in their adolescents’ internet use, with special attention needed for boys.

Background Allergic rhinitis (AR) is a complex disease involving both mucosal and systemic immune compartments. Greater understanding of the immune networks underpinning AR pathophysiology may assist with further refining disease‐specific biomarkers. Objective To compare immune gene expression profiles in nasal mucosa and peripheral blood samples between adults with AR and controls without AR. Methods This cross‐sectional study included 45 adults with moderate‐severe and persistent AR (37.6 ± 12.8 years; mean ± SD) and 24 adults without AR (36.6 ± 10.2). Gene expression analysis was performed using the NanoString nCounter PanCancer Immune profiling panel (n = 730 immune genes) in combination with the panel plus probe set (n = 30 allergy‐related genes) with purified RNA from peripheral blood and cell lysates prepared from combined nasal lavage and nasal brushing. Results One hundred and thirteen genes were significantly differentially expressed in peripheral blood samples between groups (p, A series of genes were differentially expressed in both peripheral blood and nasal mucosal samples from adults with moderate‐severe persistent allergic rhinitis compared with adults without a history of allergic rhinitis.

This review summarizes information relating to dietary intake during pregnancy, lactation and early life that may prevent childhood asthma. This review also summarizes how future studies may be improved.Recent findings from observational studies suggest that eating according to certain dietary patterns during pregnancy, such as the dietary inflammatory index, Mediterranean diet and Maternal diet index, may reduce asthma and or wheeze in the child. Vitamin D supplementation with higher doses than recommended during pregnancy may be associated with reduced early transient childhood wheezing in the offspring. Higher levels of omega-3 fatty acids in breast milk may be protective against childhood asthma. Breastfeeding infants has been shown to offer many benefits to mother and child but a direct relationship between breastfeeding and the development of asthma has not been established. During childhood, infants and children may need to reduce their intake of advanced glycation end products, increase their food intake according to the traditional Mediterranean diet and increase the diversity of foods eaten.Current evidence provides limited suggestions regarding dietary changes for preventing early transient childhood wheezing. In order to harmonize methods for future data collection and reporting, it is important to harmonize relevant definitions and other important factors. The aim of the considerations described here is to enable a better comparison of future studies and provide better guidance to patients and families.

There are limited therapeutic options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents.Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-induced respiratory failure.Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to standard of care. We hypothesized that cell therapy would be superior to sham-control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis.At the third interim analysis, the Data and Safety Monitoring Board recommended that the trial halt enrollment as the pre-specified mortality reduction from 40% to 23% was unlikely to be achieved (n=222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (RR 0.88;95% CI 0.64,1.21;p=0.43). There were no significant differences in days alive off ventilation within 60 days (median rank 117.3 [IQR:60.0,169.5] in cell patients and 102.0 [IQR:54.0,162.5] in controls; higher is better). Resolution or improvement of ARDS at 30-days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) of control patients (OR 1.36;95% CI 0.57, 3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar.Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate/severe COVID-related acute respiratory distress syndrome. Clinical trial registration available at www.gov, ID:NCT04371393. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background The role of simulation-based training in coronary artery bypass grafting remains undefined. Barriers to simulator use include clinical and personal obligations, insufficient materials, and lack of mentorship. The purpose of this study was to implement a longitudinal, residency-wide coronary anastomosis simulation curriculum. Methods A prospective observational study was conducted from 2018 to 2019 at a single academic center. All residents of the Thoracic Surgery training program participated. Each participant was provided a low-fidelity coronary anastomosis simulator, high-quality instruments, and faculty mentor. Formal assessments were held quarterly, and residents were encouraged to practice alone and with their mentor. Baseline and follow-up metrics were compared with simple descriptive statistics. Results Seventeen residents and 12 faculty participated in the study. Residents demonstrated increased use of the simulator, with 21% participating in independent practice at baseline and 82% in the fourth quarter (P = .02). The median score on the Thoracic Surgery Directors Association Vessel Anastomosis Assessment improved from 42 out of 65 at baseline to 54 out of 65 in the fourth quarter (P = .04), and mean anastomosis time was reduced by 5 minutes 6 seconds (P = .02). Over 12 months, junior residents demonstrated a mean reduction in anastomosis time of 6 minutes 36 seconds, and senior residents decreased anastomosis time by 3 minutes 6 seconds (P = .02). Conclusions Providing residents with a low-fidelity coronary anastomosis trainer with high-quality instruments and a faculty mentor improved rates of independent practice, Thoracic Surgery Directors Association assessment scores, and anastomosis time. Our next step is validating the coronary simulator curriculum by measuring improvement of resident performance in the operating room.

To report the prevalence of MRI features commonly associated with posterior ankle impingement syndrome in elite ballet dancers and athletes and to compare findings between groups. Thirty-eight professional ballet dancers (47.4% women) were age- and sex-matched to 38 elite soccer or cricket fast bowler athletes. All participants were training, playing, and performing at full workload and underwent 3.0-T standardised magnetic resonance imaging of one ankle. De-identified images were assessed by one senior musculoskeletal radiologist for findings associated with posterior ankle impingement syndrome (os trigonum, Stieda process, posterior talocrural and subtalar joint effusion-synovitis, flexor hallucis longus tendon pathology and tenosynovitis, and posterior ankle bone marrow oedema). Imaging scoring reliability testing was performed. Posterior talocrural effusion-synovitis (90.8%) and subtalar joint effusion-synovitis (93.4%) were common in both groups, as well as the presence of either an os trigonum or Stieda process (61.8%). Athletes had a higher prevalence of either os trigonum or Stieda process than dancers (74%, 50% respectively, P = 0.03). Male athletes had a higher prevalence of either os trigonum or Stieda process than male dancers (90%, 50% respectively, P = 0.01), or female athletes (56%, P = 0.02). Posterior subtalar joint effusion-synovitis size was larger in dancers than athletes (P = 0.02). Male and female dancers had similar imaging findings. There was at least moderate interobserver and intraobserver agreement for most MRI findings. Imaging features associated with posterior impingement were prevalent in all groups. The high prevalence of os trigonum or Stieda process in male athletes suggests that this is a typical finding in this population.

Kerry L Hancock,1 Sinthia Bosnic-Anticevich,2– 4 John D Blakey,5,6 Mark Hew,7,8 Li Ping Chung,9 Biljana Cvetkovski,3 Scott Claxton,10 Peter Del Fante,11 Eve Denton,7,8 Joe Doan,12 Kanchanamala Ranasinghe,13,14 Lucy Morgan,15– 17 Anita Sharma,18 Peter K Smith,19 Deb Stewart,20 Philip J Thompson,21– 23 Russell Wiseman,24 John W Upham,25 Kwok Y Yan,26 Victoria Carter,27 Kiranjeet Dhillon,28 Florian Heraud,28 Thao Le,27 Rebecca Vella,28 David Price27– 30 On behalf of the OPCA Improving Asthma outcomes in Australia Research Group1Chandlers Hill Surgery, Happy Valley, SA, 5159, Australia; 2Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; 3Woolcock Institute of Medical Research, Glebe, MSW, 2037, Australia; 4Sydney Local Health District, Camperdown, NSW, 2050, Australia; 5Respiratory Medicine, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA, 6009, Australia; 6Curtin University Medical School, Bentley, Western Australia, 6102, Australia; 7Allergy, Asthma & Clinical Immunology, Alfred Health, Melbourne, VIC, 3004, Australia; 8Public Health and Preventive Medicine, Monash University, Victoria, 3800, Australia; 9Fiona Stanley Hospital, 11 Robin Warren Dr, Murdoch, WA, 6150, Australia; 10Genesis Care Sleep and Respiratory, Joondalup, WA, 6027, Australia; 11Hutt Street General Practice, Adelaide, SA, 5000, Australia; 12HealthPlus Medical Centre, Kogarah, NSW, 2217, Australia; 13School of Medicine, Griffith University, Nathan, QLD, Australia; 14Cannon Hill Family Doctors, Cannon Hill, QLD, 4170, Australia; 15Sydney Medical School, University of Sydney, Sydney, NSW, Australia; 16Department of Thoracic Medicine, Concord Hospital, Sydney, NSW, Australia; 17Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia; 18Platinum Medical Centre, Chermside, QLD, 4032, Australia; 19Griffith University, Southport, QLD, Australia; 20Adjunct Lecturer, School of Medicine, University of Tasmania, Churchill Ave, Hobart, TAS, 7005, Australia; 21The Lung Health Clinic, Hollywood Medical Centre, Nedlands, 6009, Australia; 22The University of Western Australia, Perth, Western Australia, 6009, Australia; 23Curtin University, Bentley, Western Australia, 6102, Australia; 24Suncoast Medical Centre, Coolum Beach, QLD, 4573, Australia; 25Diamantina Institute & PA-Southside Clinical Unit, the University of Queensland, Woolloongabba, QLD, 4102, Australia; 26Department of Respiratory Medicine, W, Camperdown, NSW, 2050, Australia; 27Optimum Patient Care, Cambridgeshire, CB24 3BA, UK; 28Optimum Patient Care Australia, Brisbane, QLD, 4000, Australia; 29Observational and Pragmatic Research Institute, Midview City, 573969, Singapore; 30Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UKCorrespondence: David Price, Optimum Patient Care Australia, 320 Adelaide St, Brisbane, QLD, 4000, Australia, Tel +4 05 764 842, Email dprice@opri.sgIntroduction: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced.Methods: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with > 800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities.Results: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥ 1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43– 2.66) and sleep apnoea (OR 1.78, 95% CI 1.30– 2.46).Conclusion: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition.Keywords: asthma, exacerbations, oral corticosteroids, adults, Australia

The cognitive representation of oneself is central to other sociocognitive processes, including relations with others. It is reflected in faster, more accurate processing of self-relevant information, a “self-prioritisation effect” (SPE) which is inconsistent across studies in autism. Across two tasks with autistic and non-autistic participants, we explored the SPE and its relationship to autistic traits, mentalizing ability and loneliness. A SPE was intact in both groups, but together the two tasks suggested a reduced tendency of late-diagnosed autistic participants to differentiate between familiar and unfamiliar others and greater ease disengaging from the self-concept. Correlations too revealed a complex picture, which we attempt to explore and disentangle with reference to the inconsistency across self-processing studies in autism, highlighting implications for future research.

Whether to repair nonsevere tricuspid regurgitation (TR) during surgery for ischemic mitral valve regurgitation (IMR) remains uncertain.The goal of this study was to investigate the incidence, predictors, and clinical significance of TR progression and presence of ≥moderate TR after IMR surgery.Patients (n = 492) with untreated nonsevere TR within 2 prospectively randomized IMR trials were included. Key outcomes were TR progression (either progression by ≥2 grades, surgery for TR, or severe TR at 2 years) and presence of ≥moderate TR at 2 years.Patients' mean age was 66 ± 10 years (67% male), and TR distribution was 60% ≤trace, 31% mild, and 9% moderate. Among 2-year survivors, TR progression occurred in 20 (6%) of 325 patients. Baseline tricuspid annular diameter (TAD) was not predictive of TR progression. At 2 years, 37 (11%) of 323 patients had ≥moderate TR. Baseline TR grade, indexed TAD, and surgical ablation for atrial fibrillation were independent predictors of ≥moderate TR. However, TAD alone had poor discrimination (area under the curve, ≤0.65). Presence of ≥moderate TR at 2 years was higher in patients with MR recurrence (20% vs. 9%; p = 0.02) and a permanent pacemaker/defibrillator (19% vs. 9%; p = 0.01). Clinical event rates (composite of ≥1 New York Heart Association functional class increase, heart failure hospitalization, mitral valve surgery, and stroke) were higher in patients with TR progression (55% vs. 23%; p = 0.003) and ≥moderate TR at 2 years (38% vs. 22%; p = 0.04).After IMR surgery, progression of unrepaired nonsevere TR is uncommon. Baseline TAD is not predictive of TR progression and is poorly discriminative of ≥moderate TR at 2 years. TR progression and presence of ≥moderate TR are associated with clinical events. (Comparing the Effectiveness of a Mitral Valve Repair Procedure in Combination With Coronary Artery Bypass Grafting [CABG] Versus CABG Alone in People With Moderate Ischemic Mitral Regurgitation, NCT00806988; Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation, NCT00807040).

We evaluate the utility of coefficients of variation of response propensities (CVs) as measures of risks of survey variable non-response biases when monitoring survey data collection. CVs quantify variation in sample response propensities estimated given a set of auxiliary attribute covariates observed for all subjects. If auxiliary covariates and survey variables are correlated, low levels of propensity variation imply low bias risk. CVs can also be decomposed to measure associations between auxiliary covariates and propensity variation, informing collection method modifications and post-collection adjustments to improve dataset quality. Practitioners are interested in such approaches to managing bias risks, but risk indicator performance has received little attention. We describe relationships between CVs and expected biases and how they inform quality improvements during and post-data collection, expanding on previous work. Next, given auxiliary information from the concurrent 2011 UK census and details of interview attempts, we use CVs to quantify the representativeness of the UK Labour Force Survey dataset during data collection. Following this, we use survey data to evaluate inference based on CVs concerning survey variables with analogues measuring the same quantities among the auxiliary covariate set. Given our findings, we then offer advice on using CVs to monitor survey data collection.

Background The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg). Objective We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. Methods Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. Results Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). Conclusions These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

Introduction: Unique gut microbial colonisation patterns are associated with the onset of allergic disease in infants; however, there is insufficient evidence to determine if aberrant microbial composition patterns persist in adult allergic rhinitis (AR) sufferers. Objective: To compare the gut microbiome composition between adult AR sufferers and controls. Methods: Gut microbial composition in stool samples was compared between 57 adult AR sufferers (39.06 ± 13.29 years) and 23 controls (CG; 36.55 ± 10.51 years) via next-generation sequencing of the V3–V4 hypervariable regions of the 16S rRNA gene. Taxonomic classification and identity assignment was performed using a reference-based approach with the NCBI database of 16S rRNA gene sequences. Results: Species richness determined via the Shannon index was significantly reduced in the AR cohort compared to the CG (4.35 ± 0.59 in AR vs. 4.65 ± 0.55 in CG, p = 0.037); trends for reductions in operational taxonomic unit (OTU) counts, inverse Simpson, and CHAO1 diversity indices were also noted. Bacteroidetes (p = 0.014) was significantly more abundant in the AR group than in the CG. In contrast, the Firmicutes phylum was significantly less abundant in the AR group than in the CG (p = 0.006). An increased abundance of Parabacteroides (p = 0.008) and a reduced abundance of Oxalobacter (p = 0.001) and Clostridiales (p = 0.005) were also observed in the AR cohort compared to the CG. Conclusion: Adult AR sufferers have a distinct gut microbiome profile, marked by a reduced microbial diversity and altered abundance of certain microbes compared to controls. The results of this study provide evidence that unique gut microbial patterns occur in AR sufferers in adulthood and warrant further examination in the form of mechanistic studies.

We propose a comprehensive and coherent approach for mortality projection using a maximum-likelihood method which benefits from full use of the substantial data available on mortality rates, their improvement rates, and the associated variability. Under this approach, we fit a negative binomial distribution to overcome one of the several limitations of existing approaches such as insufficiently robust mortality projections as a result of employing a model (e.g. Poisson) which provides a poor fit to the data. We also impose smoothness in parameter series which vary over age, cohort, and time in an integrated way. Generalised Additive Models (GAMs), being a flexible class of semi-parametric statistical models, allow us to differentially smooth components, such as cohorts, more heavily in areas of sparse data for the component concerned. While GAMs can provide a reasonable fit for the ages where there is adequate data, estimation and extrapolation of mortality rates using a GAM at higher ages is problematic due to high variation in crude rates. At these ages, parametric models can give a more robust fit, enabling a borrowing of strength across age groups. Our projection methodology assumes a smooth transition between a GAM at lower ages and a fully parametric model at higher ages.

Background We recently mitigated a clonal outbreak of hospital-acquired Mycobacterium abscessus complex (MABC), which included a large cluster of adult patients who developed invasive infection after exposure to heater-cooler units during cardiac surgery. Recent studies have detailed Mycobacterium chimaera infections acquired during cardiac surgery; however, little is known about the epidemiology and clinical courses of cardiac surgery patients with invasive MABC infection. Methods We retrospectively collected clinical data on all patients who underwent cardiac surgery at our hospital and subsequently had positive cultures for MABC from 2013 through 2016. Patients with ventricular assist devices or heart transplants were excluded. We analyzed patient characteristics, antimicrobial therapy, surgical interventions, and clinical outcomes. Results Ten cardiac surgery patients developed invasive, extrapulmonary infection from M. abscessus subspecies abscessus in an outbreak setting. Median time from presumed inoculation in the operating room to first positive culture was 53 days (interquartile range [IQR], 38–139 days). Disseminated infection was common, and the most frequent culture-positive sites were mediastinum (n = 7) and blood (n = 7). Patients received a median of 24 weeks (IQR, 5–33 weeks) of combination antimicrobial therapy that included multiple intravenous agents. Six patients required antibiotic changes due to adverse events attributed to amikacin, linezolid, or tigecycline. Eight patients underwent surgical management, and 6 patients required multiple sternal debridements. Eight patients died within 2 years of diagnosis, including 4 deaths directly attributable to MABC infection. Conclusions Despite aggressive medical and surgical management, invasive MABC infection after cardiac surgery caused substantial morbidity and mortality. New treatment strategies are needed, and compliance with infection prevention guidelines remains critical.

The present study aimed at giving voice to students from disadvantaged socio-economic backgrounds using a co-participatory approach. Participants were 59 adolescents (52.5% males) aged between 14 and 16 from five European countries who created ten comics to illustrate cyberbullying for a broader audience of peers. We analyzed texts and images according to four primary themes: cyberbullying episodes (types, platforms, co-occurrence with bullying), coping strategies, characters (roles, gender, and group membership), and emotions. The content analysis showed that online denigration on social media platforms was widely represented and that cyberbullying co-existed with bullying. Social strategies were frequently combined with passive and confrontational coping, up to suicide. All roles (cyberbully, cybervictim, bystander, reinforcer, defender) were portrayed among the 154 characters identified, even if victims and defenders appeared in the vignettes more often. Males, females, peers, and adults were represented in all roles. Among the 87 emotions detected, sadness was the most frequently expressed, followed by joy, surprise, anger, and fear. Emotions, mainly represented by drawings or drawings with text, were most often represented in association with cybervictims. The results are discussed in terms of their methodological and practical implications, as they emphasize the importance of valorizing young peoples’ voices in research and interventions against cyberbullying.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

BackgroundThe rise of SARS-CoV-2 variants has made the pursuit to define correlates of protection more troublesome, despite the availability of the World Health Organisation (WHO) International Standard for anti-SARS-CoV-2 Immunoglobulin sera, a key reagent used to standardise laboratory findings into an international unitage.MethodsUsing pseudotyped virus, we examine the capacity of convalescent sera, from a well-defined cohort of healthcare workers (HCW) and Patients infected during the first wave from a national critical care centre in the UK to neutralise B.1.1.298, variants of interest (VOI) B.1.617.1 (Kappa), and four VOCs, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta), including the B.1.617.2 K417N, informally known as Delta Plus. We utilised the WHO International Standard for anti-SARS-CoV-2 Immunoglobulin to report neutralisation antibody levels in International Units per mL.FindingsOur data demonstrate a significant reduction in the ability of first wave convalescent sera to neutralise the VOCs. Patients and HCWs with more severe COVID-19 were found to have higher antibody titres and to neutralise the VOCs more effectively than individuals with milder symptoms. Using an estimated threshold for 50% protection, 54 IU/mL, we found most asymptomatic and mild cases did not produce titres above this threshold.InterpretationExpressing our data in IU/ml, we provide a benchmark pre-vaccine standardised dataset that compares disease severity with neutralising antibody titres. Our data may now be compared across multiple laboratories. The continued use and aggregation of standardised data will eventually assist in defining correlates of protection.FundingUKRI and NIHR; grant number G107217Research in contextEvidence before this studyDuring the first wave outbreak, much focus was placed on the role of neutralising antibodies and titres generated upon infection to ancestral SARS-CoV-2. Due to the large amounts of different assays used to elucidate the antibody-mediated immunity and laboratory to laboratory, large amounts of invaluable data could not be directly compared in order to define a correlate of protection, due to variability in the results. The WHO International Standard for anti-SARS-CoV-2 Immunoglobulin sera was made in order to standardise future data so that comparisons may take place.Added value of this studyOur study compares the neutralisation capacity of sera from patients and healthcare workers (HCWs) from the ancestral strain of SARS-CoV-2 against new variants, including the current variants of concern in circulation. We also provide data in International Units per mL, a standardised unitage, for infected individuals that have a clinical severity score, allowing us to assess levels of neutralising antibodies across different severities of COVID-19 disease. By providing a method to calibrate most of the variants of concern so that the WHO International Standard for anti-SARS-CoV-2 Immunoglobulin reagent could be used to standardise our results, therefore making them comparable to other laboratories who also standardised their data in an identical manner.Implications of all the available evidenceContinual use and accumulation of standardised data would eventually lead to defining the correlates of protection against SARS-CoV-2. This could help to inform medical staff to identify which individuals would be a greater risk of a potential reinfection to SARS-CoV-2.

The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days.Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life.By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01).Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

Public interest in stratifying hospital performance has led to the proliferation of commercial, consumer-oriented hospital rankings. In cardiac surgery, little is known about how these rankings correlate with clinical registry quality ratings.The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database was queried for isolated coronary artery bypass grafting or coronary artery bypass grafting/valve patients at hospitals among the top 100 U.S. NewsWorld Report (USNWR) CardiologyHeart Surgery rankings from 2016 to 2020. Hospitals were grouped into deciles by risk-adjusted observed/expected (O/E) ratios for morbidity and mortality using the STS 2018 risk models. Agreement between STS Adult Cardiac Surgery Database and USNWR ranked deciles was calculated by Bowker symmetry test. The association between each center's annual change in STS O/E ratio and change in USNWR ranking was modeled in repeated measures regression analysis.Inclusion criteria were met by 524 393 patients from 149 hospitals that ranked in USNWR top 100 at least once during the study period. There was no agreement between USNWR ranking and STS major morbidity and mortality O/E ratio (P.50 for all years). Analysis of patients undergoing surgery at the 65 hospitals that were consistently ranked in the top 100 during the study period demonstrated no association between annual change in hospital ranking and change in O/E ratio (P all.3).There was no agreement between annual USNWR hospital ranking and corresponding risk-adjusted STS morbidity or mortality. Furthermore, annual changes in USNWR rankings could not be accounted for using clinical outcomes. These findings suggest that factors unrelated to key surgical outcomes may be driving consumer-directed rankings.

The benefits of physical activity are likely universal for all children, including children and adolescents with disabilities (CWD). The participation of CWD in physical activity, including adaptive or therapeutic sports and recreation, promotes inclusion, minimizes deconditioning, optimizes physical functioning, improves mental health as well as academic achievement, and enhances overall well-being. Despite these benefits, CWD face barriers to participation and have lower levels of fitness, reduced rates of participation, and a higher prevalence of overweight and obesity compared with typically developing peers. Pediatricians and caregivers may overestimate the risks or overlook the benefits of physical activity in CWD, which further limits participation. Preparticipation evaluations often include assessment of health status, functional capacity, individual activity preferences, availability of appropriate programs, and safety precautions. Given the complexity, the preparticipation evaluation for CWD may not occur in the context of a single office visit but rather over a period of time with input from the child’s multidisciplinary team (physicians, coaches, physical education teachers, school nurses, adaptive recreation specialists, physical and occupational therapists, and others). Some CWD may desire to participate in organized sports to experience the challenge of competition, and others may prefer recreational activities for enjoyment. To reach the goal of inclusion in appropriate physical activities for all children with disabilities, child, family, financial, and societal barriers to participation need to be identified and addressed. Health care providers can facilitate participation by encouraging physical activity among CWD and their families during visits. Health care providers can create “physical activity prescriptions” for CWD on the basis of the child’s preferred activities, functional status, need for adaptation of the activity and the recreational opportunities available in the community. This clinical report discusses the importance of participation in sports, recreation, and physical activity for CWD and offers practical suggestions to health care providers.

BACKGROUND: The optimal revascularisation strategy for patients with left main coronary artery disease is uncertain. We therefore aimed to evaluate long-term outcomes for patients treated with percutaneous coronary intervention (PCI) with drug-eluting stents versus coronary artery bypass grafting (CABG).METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane database using the search terms "left main", "percutaneous coronary intervention" or "stent", and "coronary artery bypass graft*" to identify randomised controlled trials (RCTs) published in English between database inception and Aug 31, 2021, comparing PCI with drug-eluting stents with CABG in patients with left main coronary artery disease that had at least 5 years of patient follow-up for all-cause mortality. Two authors (MSS and BAB) identified studies meeting the criteria. The primary endpoint was 5-year all-cause mortality. Secondary endpoints were cardiovascular death, spontaneous myocardial infarction, procedural myocardial infarction, stroke, and repeat revascularisation. We used a one-stage approach; event rates were calculated by use of the Kaplan-Meier method and treatment group comparisons were made by use of a Cox frailty model, with trial as a random effect. In Bayesian analyses, the probabilities of absolute risk differences in the primary endpoint between PCI and CABG being more than 0·0%, and at least 1·0%, 2·5%, or 5·0%, were calculated.FINDINGS: Our literature search yielded 1599 results, of which four RCTs-SYNTAX, PRECOMBAT, NOBLE, and EXCEL-meeting our inclusion criteria were included in our meta-analysis. 4394 patients, with a median SYNTAX score of 25·0 (IQR 18·0-31·0), were randomly assigned to PCI (n=2197) or CABG (n=2197). The Kaplan-Meier estimate of 5-year all-cause death was 11·2% (95% CI 9·9-12·6) with PCI and 10·2% (9·0-11·6) with CABG (hazard ratio 1·10, 95% CI 0·91-1·32; p=0·33), resulting in a non-statistically significant absolute risk difference of 0·9% (95% CI -0·9 to 2·8). In Bayesian analyses, there was an 85·7% probability that death at 5 years was greater with PCI than with CABG; this difference was more likely than not less than 1·0% (INTERPRETATION: Among patients with left main coronary artery disease and, largely, low or intermediate coronary anatomical complexity, there was no statistically significant difference in 5-year all-cause death between PCI and CABG, although a Bayesian approach suggested a difference probably exists (more likely than not FUNDING: No external funding.

BACKGROUND: Cough features a complex peripheral and central neuronal network. The function of the chemosensitive and stretch (afferent) cough receptors is well described but partly understood. It is speculated that chronic cough reflects a neurogenic inflammation of the cough reflex, which becomes hypersensitive. This is mediated by neuromediators, cytokines, inflammatory cells, and a differential expression of neuronal (chemo/stretch) receptors, such as transient receptor potential (TRP) and purinergic P2X ion channels; yet the overall interaction of these mediators in neurogenic inflammation of cough pathways remains unclear. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on neuroanatomy and pathophysiology of chronic cough. The role of TRP ion channels in pathogenic mechanisms of the hypersensitive cough reflex was also examined. OUTCOMES: Chemoreceptors are better studied in cough neuronal pathways compared to stretch receptors, likely due to their anatomical overabundance in the respiratory tract, but also their distinctive functional properties. Central pathways are important in suppressive mechanisms and behavioral/affective aspects of chronic cough. Current evidence strongly suggests neurogenic inflammation induces a hypersensitive cough reflex marked by increased expression of neuromediators, mast cells, and eosinophils, among others. TRP ion channels, mainly TRP V1/A1, are important in the pathogenesis of chronic cough due to their role in mediating chemosensitivity to various endogenous and exogenous triggers, as well as a crosstalk between neurogenic and inflammatory pathways in cough-associated airways diseases. ispartof: WORLD ALLERGY ORGANIZATION JOURNAL vol:14 issue:12 ispartof: location:United States status: published