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ObjectivesWe aimed to determine (1) the proportion of women authors overall, in first (lead) and last (senior) author positions, (2) the proportion of women research participants and (3) the association between women in first and/or last author positions and the proportion of women research participants in original research articles and editorials/opinion pieces in four sport and exercise medicine/physiotherapy journals.MethodsThe journals evaluated were theBritish Journal of Sports Medicine,Journal of Orthopaedic and Sports Physical Therapy,Physical Therapy in SportandInternational Journal of Sports Physical Therapy.We reviewed all original research articles and editorials/opinion pieces published in 2008, 2009, 2018 and 2019. For each, we aimed to determine the gender/sex of all authors (through gender pronouns, Google Scholar, ResearchGate, institutional profiles, personal websites, photographs and/or social media), and the gender/sex of study participants reported as ‘female’ or ‘male’ or ‘women’ or ‘men’ or ‘girls’ or ‘boys’.ResultsWe included 952 original studies and 219 editorials/opinion pieces. There were 5146 authors of original studies and 706 authors of editorials/opinion pieces. Compared with 2008/2009, the proportion of women as first and last authors was 3.6% (33.0% compared with 29.4%) and 4.8% (33.2% compared with 27.4%) higher respectively in 2018/2019. On average, the proportion of women participants in original studies remained largely unchanged over the 10-year period, only 10% of all participants were women in studies.ConclusionWomen are strikingly under-represented in first and last author positions, as are women participants in sports and exercise medicine/physiotherapy journals.

BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

PurposeTo elicit stakeholder perspectives on the findings from our scoping review on youth participation in mental health policymaking, we conducted a global consultation with young people and adults directly involved in mental health policymaking.MethodForty-four stakeholders from 16 countries, including 15 young people, 9 policymakers and 20 facilitators of youth participation, took part in individual interviews and/or focus groups. They were asked about how the review findings contrasted with their own experiences in mental health policymaking. The transcribed data were thematically analyzed.ResultsAll participants viewed lived experience as valuable in identifying policy gaps. Youth pointed out that children and youth with disabilities, diverse sexual orientations, and/or gender identities were often excluded, and spoke about feelings of being an “accessory”, illustrating a lack of power-sharing in a tokenized policymaking process. Adult participants’ accounts highlighted the challenges inherent in policymaking such as the need for political knowledge and institutional time constraints. A range of cultural, socio-economic, and political barriers to youth participation, that were often context-specific, were identified.ConclusionsThe diverse perspectives of stakeholders extended the review results. Based on our findings, we recommend that adults and institutions: (1) recognize lived experience as expertise in shaping mental health policies; (2) include diverse groups; (3) reduce tokenistic relationships through the creation of safer spaces, adult feedback, co-production, and social accountability; and (4) adopt an intersectional approach to address cultural, socio-economic, and political barriers to participation. Methodologically, our work demonstrates why stakeholder consultations are an essential component of scoping reviews.

ObjectiveTo identify and quantify potential risk factors for osteoarthritis (OA) following traumatic knee injury.DesignSystematic review and meta-analyses that estimated the odds of OA for individual risk factors assessed in more than four studies using random-effects models. Remaining risk factors underwent semiquantitative synthesis. The modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach for prognostic factors guided the assessment.Data sourcesMEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched from inception to 2009–2021.EligibilityRandomised controlled trials and cohort studies assessing risk factors for symptomatic or structural OA in persons with a traumatic knee injury, mean injury age ≤30 years and minimum 2-year follow-up.ResultsAcross 66 included studies, 81 unique potential risk factors were identified. High risk of bias due to attrition or confounding was present in 64% and 49% of studies, respectively. Ten risk factors for structural OA underwent meta-analysis (sex, rehabilitation for anterior cruciate ligament (ACL) tear, ACL reconstruction (ACLR), ACLR age, ACLR body mass index, ACLR graft source, ACLR graft augmentation, ACLR+cartilage injury, ACLR+partial meniscectomy, ACLR+total medial meniscectomy). Very-low certainty evidence suggests increased odds of structural OA related to ACLR+cartilage injury (OR=2.31; 95% CI 1.35 to 3.94), ACLR+partial meniscectomy (OR=1.87; 1.45 to 2.42) and ACLR+total medial meniscectomy (OR=3.14; 2.20 to 4.48). Semiquantitative syntheses identified moderate-certainty evidence that cruciate ligament, collateral ligament, meniscal, chondral, patellar/tibiofemoral dislocation, fracture and multistructure injuries increase the odds of symptomatic OA.ConclusionModerate-certainty evidence suggests that various single and multistructure knee injuries (beyond ACL tears) increase the odds of symptomatic OA. Risk factor heterogeneity, high risk of bias, and inconsistency in risk factors and OA definition make identifying treatment targets for preventing post-traumatic knee OA challenging.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

To (1) identify the education priorities that physical therapists have for people with knee osteoarthritis, including perceived importance and capability to provide, and (2) match priorities to education-specific content recommendations in knee osteoarthritis guidelines.Concept mapping methodology.Physical therapists generated, sorted (based on themes), and rated (5-point Likert scales: importance and capability) patient education priorities. Priorities were matched against education-specific content recommendations in knee osteoarthritis guidelines. Additional education-specific content recommendations were added from guidelines and expert opinion if necessary. Multidimensional scaling and hierarchical cluster analysis produced a cluster map with overarching domains.Physical therapists (brainstorming, n = 41; sorting, n = 20; rating, n = 22) generated 56 priorities, with 13 added (n = 2 from guidelines, n = 11 from expert opinion). Few priorities were clearly included as education-specific content recommendations in guidelines (ACR [2%, n = 1/56], EULAR [14%, 8/56], NICE [11%, 6/56], and OARSI [0%, 0/56]). An 8-cluster map emerged with 3 overarching domains: (i) first-line care (exercise therapy, lifestyle modification and general health, and weight management), (ii) knowledge formation and countering misconceptions (radiology misconceptions, understanding and managing pain and disability, and general beliefs and understanding about osteoarthritis), and (iii) decision making for medical management (surgery and medications). The exercise therapy cluster was rated the highest for both importance (3.84/5) and capability (4.00). The medications and weight management clusters were rated the lowest for importance (2.54) and capability (2.82), respectively.Physical therapists prioritize a range of education topics for people with knee osteoarthritis, focusing on exercise therapy. Physical therapists feel least capable of providing weight management education.

The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different basolateral amygdala (BLA) projections are potentiated following reward or punishment learning(1–7). However, we do not yet understand how valence specific information is routed to the BLA neurons with the appropriate downstream projections. Nor do we understand how to reconcile the subsecond timescales of synaptic plasticity(8–11) with the longer timescales separating the predictive cues from their outcomes. Here, we demonstrate that neurotensin (NT) neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, while PVT-BLA projection-specific Nt gene knockout augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nt gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference to active behavioral strategies to reward and punishment predictive cues. Taken together, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviorally-relevant timescales.

Whether to perform umbilical hernia repair in patients with cirrhosis is a common dilemma for surgeons. We aimed to determine the incidence, morbidity, and mortality associated with emergency and nonemergency umbilical hernia repair in patients with and without cirrhosis, and to explore opportunities for nonemergency repair.Veterans diagnosed with cirrhosis between 2001 and 2014 and a frequency-matched sample of veterans without cirrhosis were followed through September 2017. Veterans Affairs Surgical Quality Improvement Program data provided outcomes and risk factors for mortality after umbilical hernia repair. We performed chart review of a random sample of patients undergoing emergency umbilical hernia repair.Among 119,605 veterans with cirrhosis and 118,125 matched veterans without cirrhosis, the Veterans Affairs Surgical Quality Improvement Program database included 1,475 and 552 open umbilical hernia repairs, respectively. In patients with cirrhosis, 30-day mortality was 1.2% after nonemergency umbilical hernia repair and 12.2% after emergency umbilical hernia repair, contrasting with zero deaths in patients without cirrhosis undergoing these repairs. In patients with cirrhosis but no ascites in the prior month, 30-day mortality after nonemergency umbilical hernia repair was 0.7%, compared to 2.2% in those with ascites. Chart review of patients requiring emergency umbilical hernia repair revealed that elective umbilical hernia repair may have been feasible in 30% of these patients in the prior year; fewer than half of those undergoing emergency umbilical hernia repair had received a general surgery consultation in the prior 2 years.Nonemergency open umbilical hernia repair was associated with relatively low perioperative mortality in patients with cirrhosis and no recent ascites. About 30% of patients undergoing emergency umbilical hernia repair may have been candidates for nonemergency repair in the prior year.

The IOC made recommendations for recording and reporting epidemiological data on injuries and illness in sports in 2020, but with little, if any, focus on female athletes. Therefore, the aims of this supplement to the IOC consensus statement are to (i) propose a taxonomy for categorisation of female athlete health problems across the lifespan; (ii) make recommendations for data capture to inform consistent recording and reporting of symptoms, injuries, illnesses and other health outcomes in sports injury epidemiology and (iii) make recommendations for specifications when applying the Strengthening the Reporting of Observational Studies in Epidemiology-Sport Injury and Illness Surveillance (STROBE-SIIS) to female athlete health data.In May 2021, five researchers and clinicians with expertise in sports medicine, epidemiology and female athlete health convened to form a consensus working group, which identified key themes. Twenty additional experts were invited and an iterative process involving all authors was then used to extend the IOC consensus statement, to include issues which affect female athletes.Ten domains of female health for categorising health problems according to biological, life stage or environmental factors that affect females in sport were identified: menstrual and gynaecological health; preconception and assisted reproduction; pregnancy; postpartum; menopause; breast health; pelvic floor health; breast feeding, parenting and caregiving; mental health and sport environments.This paper extends the IOC consensus statement to include 10 domains of female health, which may affect female athletes across the lifespan, from adolescence through young adulthood, to mid-age and older age. Our recommendations for data capture relating to female athlete population characteristics, and injuries, illnesses and other health consequences, will improve the quality of epidemiological studies, to inform better injury and illness prevention strategies.

BACKGROUND: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined. METHODS: We evaluated the utility of the Centers for Disease Control and Prevention’s COVID-19–Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots. RESULTS: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. CONCLUSIONS: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

Computer vision has emerged as a powerful tool to elevate behavioral research. This protocol describes a computer vision machine learning pipeline called AlphaTracker, which has minimal hardware requirements and produces reliable tracking of multiple unmarked animals, as well as behavioral clustering. AlphaTracker pairs a top-down pose-estimation software combined with unsupervised clustering to facilitate behavioral motif discovery that will accelerate behavioral research. All steps of the protocol are provided as open-source software with graphic user interfaces or implementable with command-line prompts. Users with a graphical processing unit (GPU) can model and analyze animal behaviors of interest in less than a day. AlphaTracker greatly facilitates the analysis of the mechanism of individual/social behavior and group dynamics.

Background Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population especially when the population affected is undefined. Methods We evaluated the utility of CDC COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), COVID-19 Case Surveillance System (CCSS), and 2020 U.S. Census data to determine demographic representation in the four stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at U.S. ACTT sites, with the respective 95% confidence intervals, to the reference data in forest plots. Results U.S. ACTT sites enrolled 3,509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic or Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with U.S. Census and CCSS. The proportion of participants ages 65 years was either similar or lower than COVID-NET and higher than CCSS and U.S. Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions While surveillance data of hospitalized cases may not be available early in an outbreak, it is a better comparator than U.S. Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

The world needs people who understand the crucial importance of global governance. Training students to participate in a Model United Nations (MUN) simulation provides them with the critical thinking, negotiation, and diplomacy skills that prepare them to work in international relations positions and address negotiation and diplomacy challenges. This article provides a fresh look at why MUN is important by analyzing MUN training guides used to teach students how to participate in MUN simulations. It finds that the training guides offer excellent insight into the functions and structure of the United Nations, but little in the form of learning how to negotiate or engage in diplomacy. Specifically missing are discussions of leadership, negotiation from interest, not position (also known as principled negotiation), and how to train students to be inclusive and respond to discrimination or bias during negotiations. The article includes a description of active learning and learner-centered teaching techniques and provides insight into how a specific MUN team implemented professionalism training in the 2010s. The article is written in collaboration between an MUN advisor and students who trained as MUN delegates, integrating the voices and perspectives of those who train and those who are trained.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

Background We evaluated clinical and laboratory findings among patients with nonsevere or severe dengue in Puerto Rico to examine whether clinical manifestations vary by age. Methods During 2012–2014, we enrolled patients who arrived at the emergency department with fever or history of fever within 7 days of presentation. Serum samples were tested for dengue virus (DENV) by reverse transcriptase-polymerase chain reaction (RT-PCR) and IgM enzyme-linked immunosorbent assay (ELISA). Severe dengue was defined as severe plasma leakage or shock, severe bleeding, or organ involvement at presentation, during hospitalization, or follow-up. Results Of 1089 dengue patients identified, 281 (26%) were severe. Compared to those with nonsevere dengue, patients with severe dengue were more often aged 10–19 years (55% vs 40%, P < .001) and hospitalized (87% vs 30%, P < .001). Severe plasma leakage or shock was more common among children aged 0–9 (59%) or 10–19 years (86%) than adults (49%) (P < .01). Severe bleeding was less common among 10–19 year olds (24%) compared to 0–9 year olds (45%) and adults (52%; P < .01). Conclusions Severe plasma leakage was the most common presentation among children, highlighting important differences from adults. Vaccination against dengue could help prevent severe dengue among children in Puerto Rico.

The current cross-sectional study aimed to extend the literature on childhood adversity by examining the unique associations between potentially traumatic events (PTEs) and a range of mental health concerns, including domain-specific versus comorbid concerns. Participants were 11,877 preadolescents (47.8% female, 15.0% Black, 20.3% Hispanic/Latinx, M(age) = 9.5 years) taking part in the Adolescent Brain and Cognitive Development (ABCD) Study®. The Kiddie Schedule for Affective Disorders and Schizophrenia was used to measure PTEs and caregiver- and child-reported mental health concerns. Adjusted odds ratios (aORs) were used for the outcomes of interest. Overall, PTEs were consistently associated with increased odds of experiencing comorbid posttraumatic stress disorder (PTSD), internalizing disorders, and externalizing disorders, significant AORs = 1.34–4.30, after accounting for children’s experiences of other PTEs and polyvictimization. In contrast, PTEs were generally not associated with meeting the criteria for diagnoses within only one domain (i.e., internalizing-only or externalizing-only diagnoses). We also found PTEs to be differentially related to the various mental health outcomes. In particular, witnessing domestic violence was consistently associated with children’s psychopathology. Other PTEs, such as witnessing community violence, were not associated with children’s psychopathology in the final model. Associations between PTEs and mental health concerns did not differ as a function of sex. Overall, the results support the notion that PTEs are associated with comorbid concerns rather than individual disorders. These findings have important implications for the screening of PTEs, continued research on the conceptualization of traumatic stress, and the importance of accounting for comorbidities across mental health domains.

Supplementary Materials and Methods. Supplementary Figure S1: Cell viability in various concentrations of DNA-damaging agents and novel ATR pathway inhibitors. Supplementary Figure S2: Effects of novel and established ATR pathway inhibitors on Chk1 phosphorylation induced by hydroxyurea or cisplatin as assessed by flow cytometry.

IntroductionRunning is one of the most popular recreational activities worldwide, due to its low cost and accessibility. However, little is known about the impact of running on knee joint health in runners with and without a history of knee surgery. The primary aim of this longitudinal cohort study is to compare knee joint structural features on MRI and knee symptoms at baseline and 4-year follow-up in runners with and without a history of knee surgery. Secondary aims are to explore the relationships between training load exposures (volume and/or intensity) and changes in knee joint structure and symptoms over 4 years; explore the relationship between baseline running biomechanics, and changes in knee joint structure and symptoms over 4 years. In addition, we will explore whether additional variables confound, modify or mediate these associations, including sex, baseline lower-limb functional performance, knee muscle strength, psychological and sociodemographic factors.Methods and analysisA convenience sample of at least 200 runners (sex/gender balanced) with (n=100) and without (n=100) a history of knee surgery will be recruited. Primary outcomes will be knee joint health (MRI) and knee symptoms (baseline; 4 years). Exposure variables for secondary outcomes include training load exposure, obtained daily throughout the study from wearable devices and three-dimensional running biomechanics (baseline). Additional variables include lower limb functional performance, knee extensor and flexor muscle strength, biomarkers, psychological and sociodemographic factors (baseline). Knowledge and beliefs about osteoarthritis will be obtained through predefined questions and semi-structured interviews with a subset of participants. Multivariable logistic and linear regression models, adjusting for potential confounding factors, will explore changes in knee joint structural features and symptoms, and the influence of potential modifiers and mediators.Ethics and disseminationApproved by the La Trobe University Ethics Committee (HEC-19524). Findings will be disseminated to stakeholders, peer-review journals and conferences.

The primary cause for cancer-related death is metastasis, and although this phenomenon is the hallmark of cancer, it remains poorly understood. Since studies on the underlying mechanisms are still demanding by experimental means prognostic tools based on computer models can be of great value, not only for elucidating metastasis formation but also for assessing the prospective benefits as well as risks of a therapy for patients with advanced cancer. Here, we present an agent-based model (ABM), describing the complete process of platelet-assisted extravasation of circulating tumor cells (CTCs) from the chemoattraction of blood platelets by the CTCs up to the embedding of the CTCs in the epithelial tissue by computational means. From the simulation results, we conclude that the ABM produces results in consistency with experimental observations, which opens new perspectives for the development of computer models for predicting the efficacity of drug-based tumor therapies and assisting precision medicine approaches. This article is protected by copyright. All rights reserved.

To investigate whether training load monitoring data could be used to predict injuries in elite Australian football players, data were collected from elite athletes over 3 seasons at an Australian football club. Loads were quantified using GPS devices, accelerometers and player perceived exertion ratings. Absolute and relative training load metrics were calculated for each player each day (rolling average, exponentially weighted moving average, acute:chronic workload ratio, monotony and strain). Injury prediction models (regularised logistic regression, generalised estimating equations, random forests and support vector machines) were built for non-contact, non-contact time-loss and hamstring specific injuries using the first two seasons of data. Injury predictions were generated for the third season and evaluated using the area under the receiver operator characteristic (AUC). Predictive performance was only marginally better than chance for models of non-contact and non-contact time-loss injuries (AUC$, Comment: 15 pages, 5 figures

Aims: (1) To investigate whether a daily acute:chronic workload ratio informs injury risk in Australian football players; (2) to identify which combination of workload variable, acute and chronic time window best explains injury likelihood. Methods: Workload and injury data were collected from 53 athletes over 2 seasons in a professional Australian football club. Acute:chronic workload ratios were calculated daily for each athlete, and modelled against non-contact injury likelihood using a quadratic relationship. 6 workload variables, 8 acute time windows (2-9 days) and 7 chronic time windows (14-35 days) were considered (336 combinations). Each parameter combination was compared for injury likelihood fit (using R 2). Results: The ratio of moderate speed running workload (18-24 km/h) in the previous 3 days (acute time window) compared with the previous 21 days (chronic time window) best explained the injury likelihood in matches (R 2 =0.79) and in the immediate 2 or 5 days following matches (R 2 =0.76-0.82). The 3:21 acute:chronic workload ratio discriminated between high-risk and low-risk athletes (relative risk=1.98-2.43). Using the previous 6 days to calculate the acute workload time window yielded similar results. The choice of acute time window significantly influenced model performance and appeared to reflect the competition and training schedule. Conclusions: Daily workload ratios can inform injury risk in Australian football. Clinicians and conditioning coaches should consider the sport-specific schedule of competition and training when choosing acute and chronic time windows. For Australian football, the ratio of moderate speed running in a 3-day or 6-day acute time window and a 21-day chronic time window best explained injury risk.

Additional file 7: Summary of meta-regression analyses exploring associations between sex, age, and activity duration/repetitions and cartilage thickness and volume changes.

Supplemental material, sj-docx-1-dhj-10.1177_20552076231163810 for Co-design of the web-based ‘My Knee’ education and self-management toolkit for people with knee osteoarthritis by Anthony J Goff, Danilo De Oliveira Silva, Allison M Ezzat, Kay M Crossley, Marcella F Pazzinatto, Christian J Barton and in Digital Health

The ability of machine learning techniques to predict athlete ratings of perceived exertion (RPE) was investigated in professional Australian football players. RPE is commonly used to quantifying internal training loads and manage injury risk in team sports. Data from global positioning systems, heart-rate monitors, accelerometers and wellness questionnaires were recorded for each training session (n=3398) from 45 professional Australian football players across a full season. A variety of modelling approaches were considered to investigate the ability of objective data to predict RPE. Models were compared using nested cross validation and root mean square error (RMSE) on RPE predictions. A random forest model using player normalised running and heart rate variables provided the most accurate predictions (RMSE ± SD = 0.96 ± 0.08 au). A simplification of the model using only total distance, distance covered at speeds between 18-24 km·h−1, and the product of total distance and mean speed provided similarly accurate predictions (RMSE ± SD = 1.09 ± 0.05 au), suggesting that running distances and speeds are the strongest predictors of RPE in Australian football players. The ability of non-linear machine learning models to accurately predict athlete RPE has applications in live player monitoring and training load planning.

Additional file 3: Risk of bias assessment using the NOS.

Additional file 4: GRADE Certainty of the evidence assessment.

Additional file 1: Search strategy.

Additional file 2: The modified Newcastle-Ottawa Quality Assessment Scale (NOS) for risk of bias assessment.

While virtual, augmented, and mixed reality technologies are being used for military medical training and beyond, these component technologies are oftentimes utilized in isolation. eXtended Reality (XR) combines these immersive form factors to support a continuum of virtual training capabilities to include full immersion, augmented overlays that provide multimodal cues to personalize instruction, and physical models to support embodiment and practice of psychomotor skills. When combined, XR technologies provide a multi-faceted training paradigm in which the whole is greater than the sum of the constituent capabilities in isolation. When XR applications are adaptive, and thus vary operational stressors, complexity, learner assistance, and fidelity as a function of trainee proficiency, substantial gains in training efficacy are expected. This paper describes a continuum of XR technologies and how they can be coupled with numerous adaptation strategies and supportive artificial intelligence (AI) techniques to realize personalized, competency-based training solutions that accelerate time to proficiency. Application of this training continuum is demonstrated through a Tactical Combat Casualty Care training use case. Such AI-enabled XR training solutions have the potential to support the military in meeting their growing training demands across military domains and applications, and to provide the right training at the right time.

Summary Objective To evaluate if returning to pivoting sport following anterior cruciate ligament reconstruction (ACLR) is associated with longitudinal structural and symptomatic osteoarthritis outcomes. Design Eighty-one adults aged 18–50 years were followed prospectively 1- to 5-years post-ACLR. Return to pivoting sport was assessed at 1-, 3- and 5-years. Longitudinal changes in osteoarthritis features were evaluated from 1- and 5-year magnetic resonance imaging (MRI)s using MRI Osteoarthritis Knee Score (MOAKS). Radiographic osteoarthritis and self-reported knee symptoms, function and quality of life were assessed using the Osteoarthritis Research Society International (OARSI) atlas and Knee injury Osteoarthritis Outcome Score (KOOS), respectively, at 5 years post-ACLR. Generalised linear models (adjusted for baseline characteristics) assessed whether returning to pivoting sport was associated with risk of worsening osteoarthritis features on MRI, radiographic osteoarthritis and KOOS. Results Thirty participants returned to pivoting sport 1-year post-ACLR and 50 returned at any time (i.e., 1-, 3- or 5-years). Returning to pivoting sport was not associated with worsening of any MRI osteoarthritis feature (risk ratio (RR) range: 0.59–2.91) or 5-year KOOS (β range: −2.73–3.69). Returning to pivoting sport at 1-year and up to 5-years post-ACLR was associated with a 50% (RR 0.49, 95%CI 0.10–2.37) and 40% (RR 0.60, 95%CI 0.16–2.17) reduced risk of radiographic osteoarthritis, respectively, but these risk reductions were inconclusive due to wide confidence intervals. Conclusion After ACLR, returning to pivoting sport was not associated with increased risk of worsening knee osteoarthritis features on MRI, radiographic osteoarthritis or knee symptoms. Participation in pivoting sport need not be avoided as part of osteoarthritis secondary prevention strategies.

Magnetic resonance elastography (MRE) of the liver has emerged as the non-invasive standard for the evaluation of liver fibrosis in chronic liver diseases (CLDs). The utility of MRE in the evaluation of different CLD in both adults and children has been demonstrated in several studies, and MRE has been recommended by several clinical societies. Consequently, the clinical indications for evaluation of CLD with MRE have increased, and MRE is currently used as an add-on test during routine liver MRI studies or as a standalone test. To meet the increasing clinical demand, MRE is being installed in many academic and private practice imaging centers. There is a need for a comprehensive practical guide to help these practices to deliver high-quality liver MRE studies as well as troubleshoot the common issues with MRE to ensure smooth running of the service. This comprehensive clinical practice review summarizes the indications and provides an overview on why to use MRE, technical requirements, system set-up, patient preparation, acquiring the data, and interpretation.

Background Efficacious injury prevention programs exist, yet translation to practice in real-world settings is poor. Little is known about how women playing elite team ball-sports perceive and experience injury prevention programs in practice. Understanding the end-user's (athlete's) perspective is essential to improve program uptake and adherence. Objective To explore the perspectives and experiences of injury prevention practices in athletes from the elite Australian Football League for Women (AFLW). Methods Convenience sample of 13 athletes from three AFLW clubs. Semi-structured interviews were audio-recorded and transcribed verbatim, analysed with a thematic analysis approach, and classified within the Socio-Ecological Model (SEM). Results Women playing elite Australian Football: (1) believe injury prevention programs have multiple aims and benefits, (2) perceive varying injury prevention practices between and within AFLW clubs, (3) believe injury prevention program adoption and implementation is complex and multi-factorial, and (4) think implementing injury prevention programs in the AFLW could be enhanced through education and resources. Mapping our results onto the SEM highlighted that athletes perceive multiple ecological levels (i.e. individual, interpersonal, community, and organizational) are involved in sports injury prevention. Conclusions Multi-level engagement strategies are required to enhance injury prevention program adoption and implementation and to maximise athlete adherence.

Objective Examine whether football players with hip and/or groin (hip/groin) pain have impaired running biomechanics when compared to pain-free players, analysing men and women independently. Design Cross-sectional. Setting Biomechanics laboratory. Participants Seventy-eight (62 men, 16 women) football players with >6months of hip/groin pain and a positive flexion-adduction-internal rotation test and 38 (25 men, 13 women) asymptomatic players. Main outcome measures Pelvis angles and hip, knee, and ankle joint angles and moments were analysed during the stance phase of overground running at 3–3.5 m s−1. Continuous joint angle and moment data were compared between symptomatic and asymptomatic football players of the same sex using statistical parametric mapping. Joint moment impulses (area under the curve) were compared between groups using linear regression models. Results Symptomatic football players did not display significant differences in pelvis angles or lower-limb joint angles, moments, or moment impulses during the stance phase of running, when compared to asymptomatic players of the same sex. Conclusion Our large sample of football players with hip/groin pain who were still participating in competitive sport displayed similar running biomechanics to asymptomatic players. Impaired running biomechanics might exist in people with worse hip/groin pain, warranting future investigation.

Aim: To determine the knowledge and confidence of physiotherapists in managing knee osteoarthritis (OA) and patellofemoral pain (PFP); and explore their learning behaviors and preferences related to the management of these knee conditions.Methods: One hundred and sixteen Australian and Canadian Physiotherapists were recruited via social media, e-mail, and an online course. Part 1: Quantitative involved an online survey evaluating knowledge of evidence and confidence in providing treatments for knee OA and PFP. Part 2: Qualitative involved semi-structured interviews with 13 participants exploring current practice and learning needs, that were analyzed using an initial framework structured on interview questions, followed by inductive approach to identify additional themes.Results: Awareness regarding evidence supporting exercise for knee OA and PFP was good (89-96%), and qualitative themes indicated physiotherapists emphasized exercise-therapy and education. Perceived value of passive treatments and surgery varied. Preference for face-to-face workshops to address learning needs, alongside describing time and cost barriers to access them, emerged from qualitative findings. Online learning formats were viewed as convenient, but not as effective as face-to-face learning.Conclusion: Knowledge and confidence related to interventions for knee OA and PFP of Australian and Canadian physiotherapist participants broadly aligns with guidelines. Knowledge translation strategies focused on face-to-face workshops, supported by online education may help to bridge evidence-to-practice gaps.

The goal of the OPTIKNEE consensus is to improve knee and overall health, to prevent osteoarthritis (OA) after a traumatic knee injury. The consensus followed a seven-step hybrid process. Expert groups conducted 7 systematic reviews to synthesise the current evidence and inform recommendations on the burden of knee injuries; risk factors for post-traumatic knee OA; rehabilitation to prevent post-traumatic knee OA; and patient-reported outcomes, muscle function and functional performance tests to monitor people at risk of post-traumatic knee OA. Draft consensus definitions, and clinical and research recommendations were generated, iteratively refined, and discussed at 6, tri-weekly, 2-hour videoconferencing meetings. After each meeting, items were finalised before the expert group (n=36) rated the level of appropriateness for each using a 9-point Likert scale, and recorded dissenting viewpoints through an anonymous online survey. Seven definitions, and 8 clinical recommendations (who to target, what to target and when, rehabilitation approach and interventions, what outcomes to monitor and how) and 6 research recommendations (research priorities, study design considerations, what outcomes to monitor and how) were voted on. All definitions and recommendations were rated appropriate (median appropriateness scores of 7–9) except for two subcomponents of one clinical recommendation, which were rated uncertain (median appropriateness score of 4.5–5.5). Varying levels of evidence supported each recommendation. Clinicians, patients, researchers and other stakeholders may use the definitions and recommendations to advocate for, guide, develop, test and implement person-centred evidence-based rehabilitation programmes following traumatic knee injury, and facilitate data synthesis to reduce the burden of knee post-traumatic knee OA.

Over the last 30 years, remarkable efforts have been made to understand, support, and protect children and young people’s participation rights as outlined in the UN Convention on the Rights of the Child (UNCRC). Despite these efforts, challenges remain consistently the same, such as tokenism, lack of sustainability, and accountability. This article reviews the progress and challenges for children and young people’s participation over the past 30 years. It then considers the potential of activism as a relatively novel concept for the children’s rights field. Drawing on activism literature more generally, and considering particular examples of child activism, the article explores the potential of identity politics and social movements to challenge adult power, growing on-line activism and the tension between best interests, protection and participation. The article concludes that activism recognises children as political actors and problem solvers. The article develops the idea of an ‘ecology of participation’, which values respectful intergenerational relationships that develop ‘critical social capital’ for child activism and multiple participation forms – ranging from the more conventional, to protest, to transformation – using a number of modes, such as the internet and social media. This more extended conceptualisation of children and young people’s participation builds on all the participation rights within the UNCRC, recognising them as minimum standards rather than final destinations, to create more expansive understandings and practices.

Highlights • Australian physical therapists typically prescribed strength-focused home exercise. • Aerobic and neuromuscular exercise are prescribed some of the time. • Confidence is associated with aerobic and neuromuscular exercise prescription frequency. • Less than half surveyed had been trained to deliver education and exercise therapy. • Just one in nine could name an accepted osteoarthritis guideline., Background Physical therapists play a key role in providing first-line knee osteoarthritis treatments, including patient education and exercise therapy. Objectives Describe Australian physical therapists’ awareness of guidelines; reported practices; and beliefs about capability, opportunity, motivation, and evidence. Methods An online cross-sectional survey was completed by physical therapists prior to attending the Good Living with osteoArthritis from Denmark (GLA:D®) Australia training courses (March 2017 to December 2019). The survey instrument was developed by an expert panel and was informed by the Theoretical Domains Framework. Results 1064 physical therapists from all Australian states and territories participated. 11% (n = 121) could name an accepted guideline, 98% agreed it was their job to deliver patient education and exercise therapy, and 92% agreed this would optimise outcomes. Most reported providing strength exercise (99%), written exercise instructions (95%), treatment goal discussion (88%), and physical activity advice (83%) all or most of the time. Fewer provided aerobic exercise (66%), neuromuscular exercise (54%), and weight management discussion (56%) all or most of the time. Approximately one quarter (23–24%) believed they did not have the skills, knowledge, or confidence to provide education and exercise therapy recommended by guidelines, and just 48% agreed they had been trained to do so. Conclusion Australian physical therapists treating knee osteoarthritis typically provide strength-based home exercise with written instructions, alongside goal setting and physical activity advice. Just one in nine could name a guideline. Education and training activities are needed to support physical therapists to access, read and implement guidelines, especially for aerobic and neuromuscular exercise, and weight management.

Kinase activity can be modulated reversibly or irreversibly by the reaction of targeted covalent inhibitors with nucleophilic residues in protein active sites. Herein, we present thiol reactivity studies that support α-methylene-γ-lactams as tunable surrogates for the highly reactive α-methylene-γ-lactones. The reactivity of the α-methylene is modulated via the N substituent, and the reaction rates toward glutathione were determined via mass spectrometry. Density functional theory calculations of transition states of thiol additions to α-methylene-γ-lactams revealed that the use of the M06-2X functional with the SMD solvation model and methyl thiolate as a model nucleophile reliably predicts the relative reactivities of the α-methylene-γ-lactams, and quasiharmonic approximations improve the agreement between experiment and computation.