Applying the Cytocentric Principles to Regenerative Medicine for Reproducibility.

Purpose of Review: Cell and tissue products do not just reflect their present conditions; they are the culmination of all they have encountered over time. Currently, routine cell culture practices subject cell and tissue products to highly variable and non-physiologic conditions. This article defines five cytocentric principles that place the conditions for cells at the core of what we do for better reproducibility in Regenerative Medicine. Recent Findings: There is a rising awareness of the cell environment as a neglected, but critical variable. Recent publications have called for controlling culture conditions for better, more reproducible cell products. Summary: Every industry has basic quality principles for reproducibility. Cytocentric principles focus on the fundamental needs of cells: protection from contamination, physiologic simulation, and full-time conditions for cultures that are optimal, individualized, and dynamic. Here, we outline the physiologic needs, the technologies, the education, and the regulatory support for the cytocentric principles in regenerative medicine.

Delineating between-subject heterogeneity in alpha networks with Spatio-Spectral Eigenmodes.

Between subject variability in the spatial and spectral structure of oscillatory networks can be highly informative but poses a considerable analytic challenge. Here, we describe a data-driven modal decomposition of a multivariate autoregressive model that simultaneously identifies oscillations by their peak frequency, damping time and network structure. We use this decomposition to define a set of Spatio-Spectral Eigenmodes (SSEs) providing a parsimonious description of oscillatory networks. We show that the multivariate system transfer function can be rewritten in these modal coordinates, and that the full transfer function is a linear superposition of all modes in the decomposition. The modal transfer function is a linear summation and therefore allows for single oscillatory signals to be isolated and analysed in terms of their spectral content, spatial distribution and network structure. We validate the method on simulated data and explore the structure of whole brain oscillatory networks in eyes-open resting state MEG data from the Human Connectome Project. We are able to show a wide between participant variability in peak frequency and network structure of alpha oscillations and show a distinction between occipital 'high-frequency alpha' and parietal 'low-frequency alpha'. The frequency difference between occipital and parietal alpha components is present within individual participants but is partially masked by larger between subject variability; a 10Hz oscillation may represent the high-frequency occipital component in one participant and the low-frequency parietal component in another. This rich characterisation of individual neural phenotypes has the potential to enhance analyses into the relationship between neural dynamics and a person's behavioural, cognitive or clinical state.

Recommendations for workforce development in regenerative medicine biomanufacturing.

In its 2019 report, The Skilled Technical Workforce: Crafting America's Science and Engineering Enterprise, the National Science Board recommended a national charge to create a skilled technical workforce (STW) driven by science and engineering. The RegenMed Development Organization (ReMDO), through its RegeneratOR Workforce Development Initiative, has taken on this challenge beginning with an assessment of regenerative medicine (RM) biomanufacturing knowledge, skills, and abilities (KSAs) needed for successful employment. While STW often refers only to associate degree or other prebaccalaureate prepared technicians, the RM biomanufacturing survey included responses related to baccalaureate prepared technicians. Three levels of preparation were articulated in the research: basic employability skills, core bioscience skills, and RM biomanufacturing technical skills. The first two of these skill levels have been defined by previous research and are generally accepted as foundational-the Common Employability Skills developed by the National Network of Business and Industry Associations and the Core Skill Standards for Bioscience Technicians developed by the National Center for the Biotechnology Workforce. Fifteen skill sets addressing the specialized needs of RM and related biotechnology sectors were identified in the ReMDO survey, defining a third level of KSAs needed for entry-level employment in RM biomanufacturing. The purpose of the article is to outline the KSAs necessary for RM biomanufacturing, quantify the skills gap that currently exists between skills required by employers and those acquired by employees and available in the labor market, and make recommendations for the application of these findings.

Prevalence of Inflammatory Heart Disease Among Professional Athletes With Prior COVID-19 Infection Who Received Systematic Return-to-Play Cardiac Screening.

Importance: The major North American professional sports leagues were among the first to return to full-scale sport activity during the coronavirus disease 2019 (COVID-19) pandemic. Given the unknown incidence of adverse cardiac sequelae after COVID-19 infection in athletes, these leagues implemented a conservative return-to-play (RTP) cardiac testing program aligned with American College of Cardiology recommendations for all athletes testing positive for COVID-19. Objective: To assess the prevalence of detectable inflammatory heart disease in professional athletes with prior COVID-19 infection, using current RTP screening recommendations. Design, Setting, and Participants: This cross-sectional study reviewed RTP cardiac testing performed between May and October 2020 on professional athletes who had tested positive for COVID-19. The professional sports leagues (Major League Soccer, Major League Baseball, National Hockey League, National Football League, and the men's and women's National Basketball Association) implemented mandatory cardiac screening requirements for all players who had tested positive for COVID-19 prior to resumption of team-organized sports activities. Exposures: Troponin testing, electrocardiography (ECG), and resting echocardiography were performed after a positive COVID-19 test result. Interleague, deidentified cardiac data were pooled for collective analysis. Those with abnormal screening test results were referred for additional testing, including cardiac magnetic resonance imaging and/or stress echocardiography. Main Outcomes and Measures: The prevalence of abnormal RTP test results potentially representing COVID-19-associated cardiac injury, and results and outcomes of additional testing generated by the initial screening process. Results: The study included 789 professional athletes (mean [SD] age, 25 [3] years; 777 men [98.5%]). A total of 460 athletes (58.3%) had prior symptomatic COVID-19 illness, and 329 (41.7%) were asymptomatic or paucisymptomatic (minimally symptomatic). Testing was performed a mean (SD) of 19 (17) days (range, 3-156 days) after a positive test result. Abnormal screening results were identified in 30 athletes (3.8%; troponin, 6 athletes [0.8%]; ECG, 10 athletes [1.3%]; echocardiography, 20 athletes [2.5%]), necessitating additional testing; 5 athletes (0.6%) ultimately had cardiac magnetic resonance imaging findings suggesting inflammatory heart disease (myocarditis, 3; pericarditis, 2) that resulted in restriction from play. No adverse cardiac events occurred in athletes who underwent cardiac screening and resumed professional sport participation. Conclusions and Relevance: This study provides large-scale data assessing the prevalence of relevant COVID-19-associated cardiac pathology with implementation of current RTP screening recommendations. While long-term follow-up is ongoing, few cases of inflammatory heart disease have been detected, and a safe return to professional sports activity has thus far been achieved.

Examining Batting Performance After a Sports-Related Concussion Among Major League Baseball Position Players.

BACKGROUND: An ongoing challenge in sports-related concussion (SRC) is determining full recovery. This study examines performance metrics in baseball after an SRC and provides a template for assessment of return-to-performance parameters. PURPOSE: To determine whether batting performance returns to baseline after an SRC. STUDY DESIGN: Descriptive epidemiological study. METHODS: Participants were all Major League Baseball (MLB) position players with confirmed SRCs that occurred during the 2011-2015 seasons. A retrospective review and assessment of performance metrics before and after injury were conducted as defined relative to the number of plate appearances (PAs) to yield reliable performance statistics. Seven batting metrics were considered as outcomes in longitudinal regressions: batting average, on-base percentage, slugging percentage, on-base plus slugging, bases on balls, strikeouts, and home runs. Metrics were calculated for each player 60, 30, and 14 days before their SRCs, as well as for the 14, 30, and 60 days after returning to play. Other variables controlled for included defensive position, player age at the time of SRC, number of days missed, mechanism of injury, whether the player completed a rehabilitation stint, and year in which the mild traumatic brain injury (MTBI) occurred (2011-2015). RESULTS: A total of 77 MTBI case events occurred in MLB position players over 5 seasons. These injuries resulted in a mean 11.4 days lost to injury. For all performance metrics using 60 or 30 days before MTBI as baseline, no statistically significant differences were found in batting performance. In total, 63 events met PA criteria before injury. Varying the PA cutoff thresholds to be more inclusive or more restrictive yielded similar regression results. For the 48 events that met PA criteria before and after injury, most performance metrics showed no significant performance change after MTBI and, in some events, a slight though mostly nonsignificant performance improvement after MTBI. CONCLUSIONS: MLB position players who are medically cleared to return to play after an SRC perform at the same offensive performance levels as their preinjury statistics when an adequate number of PAs is used to compare performance before and after injury.

Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis.

AIMS: Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence. METHODS AND RESULTS: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs. CONCLUSIONS: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

Preventing Concussions From Foul Tips and Backswings in Professional Baseball: Catchers' Perceptions of and Experiences With Conventional and Hockey-Style Masks.

OBJECTIVE: To understand catchers' preferences for mask type and perceptions regarding safety, comfort, and fit, and determine whether mask type is correlated with self-reported concussion and related symptoms after impacts from foul tips or backswings. DESIGN: Cross-sectional study. SETTING: Survey of active baseball catchers. PARTICIPANTS: Professional baseball catchers. INTERVENTION: From May 1, 2015, to June 30, 2015, an online survey was administered in English and Spanish to all Major and Minor League catchers (n = 836). MAIN OUTCOME MEASURES: Survey items addressed the type of mask routinely and previously used (conventional or hockey style); brand and material (steel or titanium); perceptions regarding safety, comfort, and fit; and experiences with concussions. RESULTS: The sample consisted of 596 catchers of which 26% reported being diagnosed with a concussion. Some concussions occurred from non-baseball activities, such as car accidents or off the field incidents. For those that occurred playing baseball, 35% resulted from a foul tip. Once catchers entered professional baseball, the use of a conventional mask rose significantly: 71% of catchers reported wearing conventional-style masks, and 30% hockey-style masks at the time the survey was conducted (P < 0.05). Both conventional and hockey-style mask wearers significantly selected hockey-style masks as providing better overall safety and protection than conventional masks (P < 0.05). CONCLUSIONS: This research supports foul tips as an important cause of concussion in catchers and provides important information about preferences among catchers for masks that are not perceived as the safest and strongest. Future research should supplement these data by conducting laboratory testing to determine which masks are stronger and by collecting qualitative data to explore why some players are more likely to wear a mask type that they perceive as offering less safety or protection.

Return to sport for North American professional sport leagues in the context of COVID-19.

COVID-19 is a respiratory illness that can spread from person to person. A range of clinical scenarios exist, from an asymptomatic disease course to SARS and death. This document describes important considerations for 5 North American professional sports leagues (Major League Baseball, Major League Soccer, National Basketball Association, National Football League and National Hockey league) assessing when and how to resume phased operations, including practices and games. Sports should prioritise and promote the health and safety of athletes, team and operational staff, and other participants, and should not unduly increase those individuals' relative health risk while contributing to economic recovery, providing entertainment for the public and leading a responsible restoration of civic life. Because elite professional sport ordinarily is conducted in a controlled environment, professional sports leagues may be able to achieve these goals. This document is focused on professional sports leagues in North America, and although many of the statements are generalisable to professional sporting settings throughout the world, other considerations may apply to sports in other countries.

Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (ß-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1F/F (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated ß-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

Lipomatous hypertrophy of the interventricular septum.

BACKGROUND AND AIMS: Lipomatous hypertrophy of the interatrial septum is an uncommon type of cardiac adipose tumor. It is extremely rare for these lesions to be located in the interventricular septum. METHODS: We report this case of incidentally diagnosed lipomatous hypertrophy of the interventricular septum with right ventricular outflow obstruction which caused minimal symptoms and Wolff-Parkinson-White pattern on EKG. CONCLUSION: We also discuss the diagnosis and management of this condition.

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics.

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological "signatures" of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies.

Concussion Guidelines in National and International Professional and Elite Sports.

The Berlin statement on sport-related concussion was published in 2017 using evidence-based recommendations. We aimed to examine (1) the implementation of, distribution and education based on the Berlin recommendations, and the development of sport-specific protocols/guidelines among professional and elite sports, (2) the implementation of guidelines at the community level, (3) translation of guidelines into different languages, and (4) research activities. Senior medical advisers and chief medical officers from Australian Football League, All Japan Judo Federation, British Horseracing Authority, Cricket Australia, Fédération Equestre Internationale, Football Association, Gaelic Athletic Association, International Boxing Association, Irish Horseracing Regulatory Board, Major League Baseball, National Football League, National Hockey League, National Rugby League, and World Rugby completed a questionnaire. The results demonstrated that all 14 sporting organizations have published concussion protocols/guidelines based on the Berlin recommendations, including Recognize, Removal from play, Re-evaluation, Rest, Recovery, and Return to play. There is variable inclusion of Prolonged symptoms. Prevention and Risk reduction and Long-term effects are addressed in the guidelines, rules and regulations, and/or sport-specific research. There is variability in education programs, monitoring compliance with guidelines, and publication in other languages. All sporting bodies are actively involved in concussion research. We conclude that the Berlin recommendations have been included in concussion protocols/guidelines by all the sporting bodies, with consistency in the essential components of the recommendations, whilst also allowing for sport- and regional-specific variations. Education at the elite, community, and junior levels remains an ongoing challenge, and future iterations of guidelines may consider multiple language versions, and community- and junior-level guidelines.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Public Health Responses to COVID-19 Outbreaks on Cruise Ships - Worldwide, February-March 2020.

An estimated 30 million passengers are transported on 272 cruise ships worldwide each year* (1). Cruise ships bring diverse populations into proximity for many days, facilitating transmission of respiratory illness (2). SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) was first identified in Wuhan, China, in December 2019 and has since spread worldwide to at least 187 countries and territories. Widespread COVID-19 transmission on cruise ships has been reported as well (3). Passengers on certain cruise ship voyages might be aged ≥65 years, which places them at greater risk for severe consequences of SARS-CoV-2 infection (4). During February-March 2020, COVID-19 outbreaks associated with three cruise ship voyages have caused more than 800 laboratory-confirmed cases among passengers and crew, including 10 deaths. Transmission occurred across multiple voyages of several ships. This report describes public health responses to COVID-19 outbreaks on these ships. COVID-19 on cruise ships poses a risk for rapid spread of disease, causing outbreaks in a vulnerable population, and aggressive efforts are required to contain spread. All persons should defer all cruise travel worldwide during the COVID-19 pandemic.

Peripheral blood leukocyte telomere length is associated with survival of sepsis patients.

Shorter peripheral blood leukocyte (PBL) telomere length (TL) has been associated with poor outcomes in various chronic lung diseases. Whether PBL-TL is associated with survival from critical illness was tested in this study.We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). PBL-TL was measured using quantitative PCR of DNA isolated from PBLs. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF).In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted hazard ratio (aHR) 1.3, 95% CI 1.1-1.6 per 1 kb TL decrease; p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (aHR 1.5, 95% CI 1.2-2.0 per 1 kb TL decrease; p=0.001), but not trauma. Although not associated with development of acute respiratory distress syndrome (ARDS), among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7, 95% CI 1.2-2.5 per 1 kb TL decrease; p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6, 95% CI 1.2-2.1 per 1 kb TL decrease; p=0.003) and risk for developing severe ARDS (OR 2.5, 95% CI 1.1-6.3 per 1 kb TL decrease; p=0.044) were validated in the UCSF cohort.Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness.

Coronary artery fistula.

BACKGROUND: Coronary artery fistula is a rare anomaly of the coronary arteries which results from an abnormal connection between a coronary artery with a cardiac chamber or vessel. Coronary steal phenomenon can lead to functional ischemia of the myocardium. The condition has been described extensively, however, the modalities for diagnosing this condition continue to advance. METHODS: This review summarizes the approach to managing this uncommon condition. RESULTS: We discuss the various surgical options, including the technique involved in treating specific types of fistulas. CONCLUSION: We also review minimally-invasive options and trans-catheter closure along with indications for use of the different modalities.

Association Between a Rule Change to Reduce Home Plate Collisions and Mild Traumatic Brain Injury and Other Injuries in Professional Baseball Players.

BACKGROUND: Improved player safety is an important goal of professional baseball. Prevention of mild traumatic brain injury (concussion) is an area of emphasis because of the potential for long-term as well as short-term sequelae. HYPOTHESIS: A rule change can lower the incidence of concussions and other injuries in professional baseball. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study included a retrospective review of data entered concurrently into professional baseball's electronic medical record system. All minor and major league teams are required to use this system. All injuries are captured by creation of a new record in the system at the time of the injury. All active minor and major league players from 2011 to 2017 were included. The 30 major league clubs have 1200 roster players and play 162 games per season. The approximately 200 minor league clubs have about 7500 active players and play 56 to 144 games annually that combine for approximately 330,000 athlete-exposures per season. Before the 2014 season, Major League Baseball, in conjunction with its players association, instituted a rule limiting home plate collisions between base runners and catchers that applied to both Major League Baseball and Minor League Baseball. All concussions and other injuries at home plate from 2011 to 2017 were analyzed by mechanism and player position. RESULTS: From 2011 to 2013, an annual mean of 100 injuries occurred from home plate collisions in the minor and major leagues, resulting in a mean loss of 2148 days annually. After the rule change, there was a mean 55 home plate collision injuries with 936 days lost per season (P < .0001 for injuries and days lost). A mean 11 concussions attributed to these collisions occurred annually in the minor and major leagues before the rule change, as compared with 2.3 per year after (P = .0029). There were no major league concussions from these collisions after the rule change. The mean annual number of days missed because of concussions at home plate dropped from 276 before 2014 to 36 per year after 2014 (P = .0001). CONCLUSION: This rule change was associated with significant reductions in the numbers of concussions and other injuries caused by collisions at home plate as well as significant decreases in time lost from play.

International consensus definitions of video signs of concussion in professional sports.

BACKGROUND: The use of video to assist professional sporting bodies with the diagnosis of sport-related concussion (SRC) has been well established; however, there has been little consistency across sporting codes with regards to which video signs should be used, and the definitions of each of these signs. AIM: The aims of this study were to develop a consensus for the video signs considered to be most useful in the identification of a possible SRC and to develop a consensus definition for each of these video signs across the sporting codes. METHODS: A brief questionnaire was used to assess which video signs were considered to be most useful in the identification of a possible concussion. Consensus was defined as >90% agreement by respondents. Existing definitions of these video signs from individual sports were collated, and individual components of the definitions were assessed and ranked. A modified Delphi approach was then used to create a consensus definition for each of the video signs. RESULTS: Respondents representing seven sporting bodies (Australian Football League, Cricket Australia, Major League Baseball, NFL, NHL, National Rugby League, World Rugby) reached consensus on eight video signs of concussion. Thirteen representatives from the seven professional sports ranked the definition components. Consolidation and refinement of the video signs and their definitions resulted in consensus definitions for six video signs of possible concussion: lying motionless, motor incoordination, impact seizure, tonic posturing, no protective action-floppy and blank/vacant look. CONCLUSIONS: These video signs and definitions have reached international consensus, are indicated for use by professional sporting bodies and will form the basis for further collaborative research.

Histopathological and molecular analysis of idiopathic pulmonary fibrosis lungs from patients treated with pirfenidone or nintedanib.

AIMS: The objective of this study was to quantify the impact of pirfenidone or nintedanib treatment on lung histopathology and molecular mediators of fibrosis in patients with idiopathic pulmonary fibrosis (IPF). METHODS AND RESULTS: We collected lung tissue from IPF patients at the time of lung transplantation. Histopathological changes were quantified using a blinded scoring method. Proteins associated with senescence or active TGF-ß were quantified in lung tissues by immunoblot and immunostaining. Histopathological quantification showed similar amounts of dense collagen fibrosis, fibroblast foci and alveolar macrophages in untreated or pirfenidone- or nintedanib-treated IPF patients. There was less diffuse alveolar damage and organising pneumonia in pirfenidone-treated IPF patients. Lungs of nintedanib-treated patients had a trend towards less lymphocytic interstitial infiltration. There was no difference in expression of p-SMAD3, p21 or p16 in the lungs of untreated, pirfenidone- or nintedanib-treated IPF patients. Alveolar epithelial cells, but not fibroblast foci, were immunoreactive to p16. Pirfenidone or nintedanib treatment did not inhibit activation of senescence programming in cultured lung epithelial cells mediated by hydrogen peroxide. CONCLUSION: Pirfenidone and nintedanib do not modulate expression of senescence markers, levels of p-SMAD3 or the amount of fibrosis in IPF lungs. Treated patients have less histopathological evidence of acute lung injury at the time of lung transplantation.

International study of video review of concussion in professional sports.

BACKGROUND: Video review has become an important tool in professional sporting codes to help sideline identification and management of players with a potential concussion. AIM: To assess current practices related to video review of concussion in professional sports internationally, and compare protocols and diagnostic criteria used to identify and manage potential concussions. METHODS: Current concussion management guidelines from professional national and international sporting codes were reviewed. Specific criteria and definitions of video signs associated with concussion were compared between codes. Rules and regulations adopted across the codes for processes around video review were also assessed. RESULTS: Six sports with specific diagnostic criteria and definitions for signs of concussion identified on video review participated in this study (Australian football, American football, world rugby, cricket, rugby league and ice hockey). Video signs common to all sports include lying motionless/loss of responsiveness and motor incoordination. The video signs considered by the majority of sports as most predictive of a diagnosis of concussion include motor incoordination, impact seizure, tonic posturing and lying motionless. Regulatory requirements, sideline availability of video, medical expertise of video reviewers and use of spotters differ across sports and geographical boundaries. By and large, these differences reflect a pragmatic approach from each sport, with limited underlying research and development of the video review process in some instances. CONCLUSIONS: The use of video analysis in assisting medical staff with the diagnosis or identification of potential concussion is well established across different sports internationally. The diagnostic criteria used and the expertise of the video review personnel are not clearly established, and research efforts would benefit from a collaborative harmonisation across sporting codes.