Search

Abstract Few studies have explored hip morphology and cartilage composition in female athletes or the impact of asymmetric repetitive loading, such as occurs during softball pitching. The current cross-sectional study assessed bilateral bony hip morphology on computed tomography imaging in collegiate-level softball pitchers (‘Pitch1’, n = 25) and cross-country runners (‘Run’, n = 13). Magnetic resonance imaging was used to assess cartilage relaxation times in a second cohort of pitchers (‘Pitch2’, n = 10) and non-athletic controls (‘Con’, n = 4). Pitch1 had 52% greater maximum alpha angle than Run (p

Abstract Filoviruses, including Ebola, Marburg, Sudan, and Taï Forest viruses, are zoonotic pathogens that can cause severe viral hemorrhagic fever and death. Developing vaccines that provide durable, broad immunity against multiple filoviruses is a high global health priority. In this Phase 1 trial, we enrolled 60 healthy U.S. adults and evaluated the safety, reactogenicity and immunogenicity of homologous and heterologous MVA-BN®-Filo and Ad26.ZEBOV prime-boost schedules followed in select arms by MVA-BN®-Filo boost at 1 year (NCT02891980). We found that all vaccine regimens had acceptable safety and reactogenicity. The heterologous prime-boost strategy elicited superior Ebola binding and neutralizing antibody, antibody-dependent cellular cytotoxicity (ADCC), and cellular responses compared to homologous prime-boost. The MVA-BN®-Filo boost administered at 1 year resulted in robust humoral and cellular responses that persisted through 6-month follow-up. Overall, our data demonstrated that a heterologous Ad26.ZEBOV/MVA-BN®-Filo prime-boost was safe and immunogenic and established immunologic memory primed to respond after re-exposure. Clinicaltrials.gov, NCT02891980, registered September 1, 2016.

ABSTRACT Background Hip‐related pain (HRP) affects young to middle‐aged active adults and impacts physical activity, finances and quality of life. HRP includes conditions like femoroacetabular impingement syndrome and labral tears. Lateral hip muscle dysfunction and atrophy in HRP are more pronounced in advanced hip pathology, with limited evidence in younger populations. While MRI use for assessing hip muscle morphology is increasing, with automated deep‐learning techniques showing promise, studies assessing their accuracy are limited. Therefore, we aimed to compare hip intramuscular fat infiltrate (MFI) and muscle volume, in individuals with and without HRP as well as assess the reliability and accuracy of automated machine‐learning segmentations compared with human‐generated segmentation. Methods This cross‐sectional study included sub‐elite/amateur football players (Australian football and soccer) with a greater than 6‐month history of HRP [n = 180, average age 28.32, (standard deviation 5.88) years, 19% female] and a control group of sub‐elite/amateur football players without pain [n = 48, 28.89 (6.22) years, 29% female]. Muscle volume and MFI of gluteus maximus, medius, minimis and tensor fascia latae were assessed using MRI. Associations between muscle volume and group were explored using linear regression models, controlling for body mass index, age, sport and sex. A convolutional neural network (CNN) machine‐learning approach was compared with human‐performed muscle segmentations in a subset of participants (n = 52) using intraclass correlation coefficients and Sorensen–Dice index. Results When considering adjusted estimates of muscle volume, there were significant differences observed between groups for gluteus medius (adjusted mean difference 23 858 mm3 [95% confidence interval 7563, 40 137]; p = 0.004) and tensor fascia latae (6660 mm3 [2440, 13 075]; p = 0.042). No differences were observed between groups for gluteus maximus (18 265 mm3 [−21 209, 50 782]; p = 0.419) or minimus (3893 mm3 [−2209, 9996]; p = 0.21). The CNN was trained for 30 000 iterations and assessed its accuracy and reliability on an independent testing dataset, achieving high segmentation accuracy (mean Sorenson–Dice index >0.900) and excellent muscle volume and MFI reliability (ICC2,1 > 0.900). The CNN outperformed manual raters, who had slightly lower interrater accuracy (Sorensen–Dice index >0.800) and reliability (ICC2,1 > 0.800). Conclusions The increased muscle volumes in the symptomatic group compared with controls could be associated with increased myofibrillar size, sarcoplasmic hypertrophy or both. These changes may facilitate greater muscular efficiency for a given load, enabling the athlete to maintain their normal level of function. In addition, the CNNs for muscle segmentation was more efficient and demonstrated excellent reliability in comparison to manual segmentations.

Background: Sports medicine (injury and illnesses) requires distinct coding systems because the International Classification of Diseases is insufficient for sports medicine coding. The Orchard Sports Injury and Illness Classification System (OSIICS) is one of two sports medicine coding systems recommended by the International Olympic Committee. Regular updates of coding systems are required. Methods: For Version 15, updates for mental health conditions in athletes, sports cardiology, concussion sub-types, infectious diseases, and skin and eye conditions were considered particularly important. Results: Recommended codes were added from a recent International Olympic Committee consensus statement on mental health conditions in athletes. Two landmark sports cardiology papers were used to update a more comprehensive list of sports cardiology codes. Rugby union protocols on head injury assessment were used to create additional concussion codes. Conclusion: It is planned that OSIICS Version 15 will be translated into multiple new languages in a timely fashion to facilitate international accessibility. The large number of recently published sport-specific and discipline-specific consensus statements on athlete surveillance warrant regular updating of OSIICS.

Objective: To evaluate adiposity after anterior cruciate ligament reconstruction (ACLR): i) cross-sectionally (1-year post-ACLR) compared to uninjured controls; ii) longitudinally up to 5 years post-ACLR; and iii) associations with patient-reported symptoms and physical performance. Methods: In 107 individuals post-ACLR and 19 controls, we assessed global (BMI), peripheral (subcutaneous adipose tissue thickness on the posteromedial side of knee MRI), and central (waist circumference in ACLR group) adiposity. Patient-reported symptoms (Knee injury and Osteoarthritis Outcome Score) and physical performance (hop for distance) were evaluated at 1 and 5 years post-ACLR. Linear regression models evaluated adiposity between groups. Paired t-tests evaluated changes in adiposity from 1- to 5 years post-ACLR. Linear regression models analyzed adiposity's associations with patient-reported symptoms and physical performance at 1-year post-ACLR, changes in symptoms and performance over 4 years post-ACLR, and longitudinal changes in adiposity and symptoms and performance, controlling for age, sex, and activity level. Results: Individuals 1-year post-ACLR were associated with higher average global (3 ​kg/m2) and peripheral adiposity (2.3 ​mm). From 1- to 5 years post-ACLR, higher average global (0.58 ​kg/m2) and central (5 ​cm) adiposity, and lower average peripheral adiposity (1.3 ​mm) were observed. In general, adiposity at one-year post-ACLR was negatively associated with patient-reported symptoms and physical performance, and changes from 1 to 5 years post-ACLR. Increases in adiposity were negatively associated with changes in patient-reported symptoms and physical performance over four years post-ACLR. Conclusion: Greater global and central adiposity is a feature of young adults following ACLR and influences current and future patient-reported symptoms and physical performance.

Background: Suboptimal clinical trial recruitment contributes to research waste. Evidence suggests there may be gender-based differences in willingness to participate in clinical research. Identifying gender-based differences impacting the willingness of trial participation may assist trial recruitment. Objectives: To examine factors that influence the willingness of men and women to participate in clinical trials and to identify modifiable factors that may be targeted to optimise trial participation. Material and methods: Electronic databases were searched with key words relating to ‘gender’, ‘willingness to participate’ and ‘trial’. Included studies were English language and reported gender-based differences in willingness to participate in clinical trials, or factors that influence a single gender to participate in clinical trials. Studies were excluded if they described the demographic factors of trial participants or if the majority of participants were pregnant. Extracted data were coded, categorized, analysed thematically and interpreted using Arksey and O'Malley's framework. Results: Sixty-three studies were included. Two main themes were identified: trial characteristics and participant characteristics. A number of gender-based differences moderating willingness to participate were observed although only one, ‘concern for self’ was found to influence actual trial participation rates between genders. Conclusion: The relationship between factors influencing willingness to participate in clinical trials is complex. The influence of gender on willingness to participate, while important, may be moderated by other factors including socioeconomic status, ethnicity and health condition. Exploring factors that influence willingness to participate specific to a study cohort likely offers the most promise to optimise trial recruitment of that cohort.

Objectives The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants.Methods The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18–40 years) with ongoing symptoms (ie, mean score of

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Abstract Background The impact of activity-related joint loading on cartilage is not clear. Abnormal loading is considered to be a mechanical driver of osteoarthritis (OA), yet moderate amounts of physical activity and rehabilitation exercise can have positive effects on articular cartilage. Our aim was to investigate the immediate effects of joint loading activities on knee and hip cartilage in healthy adults, as assessed using magnetic resonance imaging. We also investigated delayed effects of activities on healthy cartilage and the effects of activities on cartilage in adults with, or at risk of, OA. We explored the association of sex, age and loading duration with cartilage changes. Methods A systematic review of six databases identified studies assessing change in adult hip and knee cartilage using MRI within 48 h before and after application of a joint loading intervention/activity. Studies included adults with healthy cartilage or those with, or at risk of, OA. Joint loading activities included walking, hopping, cycling, weightbearing knee bends and simulated standing within the scanner. Risk of bias was assessed using the Newcastle–Ottawa Scale. Random-effects meta-analysis estimated the percentage change in compartment-specific cartilage thickness or volume and composition (T2 relaxation time) outcomes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system evaluated certainty of evidence. Results Forty studies of 653 participants were included after screening 5159 retrieved studies. Knee cartilage thickness or volume decreased immediately following all loading activities investigating healthy adults; however, GRADE assessment indicated very low certainty evidence. Patellar cartilage thickness and volume reduced 5.0% (95% CI 3.5, 6.4, I 2 = 89.3%) after body weight knee bends, and tibial cartilage composition (T2 relaxation time) decreased 5.1% (95% CI 3.7, 6.5, I 2 = 0.0%) after simulated standing within the scanner. Hip cartilage data were insufficient for pooling. Secondary outcomes synthesised narratively suggest knee cartilage recovers within 30 min of walking and 90 min of 100 knee bends. We found contrasting effects of simulated standing and walking in adults with, or at risk of, OA. An increase of 10 knee bend repetitions was associated with 2% greater reduction in patellar thickness or volume. Conclusion There is very low certainty evidence that minimal knee cartilage thickness and volume and composition (T2 relaxation time) reductions (0–5%) occur after weightbearing knee bends, simulated standing, walking, hopping/jumping and cycling, and the impact of knee bends may be dose dependent. Our findings provide a framework of cartilage responses to loading in healthy adults which may have utility for clinicians when designing and prescribing rehabilitation programs and providing exercise advice.

Basal forebrain cholinergic neurons modulate how organisms process and respond to environmental stimuli through impacts on arousal, attention, and memory. It is unknown, however, whether basal forebrain cholinergic neurons are directly involved in conditioned behavior, independent of secondary roles in the processing of external stimuli. Using fluorescent imaging, we found that cholinergic neurons are active during behavioral responding for a reward – even prior to reward delivery and in the absence of discrete stimuli. Photostimulation of basal forebrain cholinergic neurons, or their terminals in the basolateral amygdala (BLA), selectively promoted conditioned responding (licking), but not unconditioned behavior nor innate motor outputs. In vivo electrophysiological recordings during cholinergic photostimulation revealed reward-contingency-dependent suppression of BLA neural activity, but not prefrontal cortex. Finally, ex vivo experiments demonstrated that photostimulation of cholinergic terminals suppressed BLA projection neuron activity via monosynaptic muscarinic receptor signaling, while also facilitating firing in BLA GABAergic interneurons. Taken together, we show that the neural and behavioral effects of basal forebrain cholinergic activation are modulated by reward contingency in a target-specific manner.

Objective: Describe the injury characteristics, game circumstances, and immediate action and management of injuries sustained by boys and girls participating in junior community Australian football. Design: Cohort Study. Methods: All community junior Australian football players from one Victorian-based league were eligible to participate if they were injured during a game and presented to the gameday first aid medics. Injured players were subsequently followed up with a phone call to undertake an injury surveillance survey. The injury surveillance survey gathered information relating to the injury characteristics, game circumstances and management undertaken. Additionally, all players who sustained a head impact were asked about the presence or absence of concussion-related symptoms. Results: 439 players sustained an injury in the 2022 season, with 354 (80.6 ​%) participating in the survey. The head was the most frequently reported injured body region (n ​= ​194, 54.8 ​%), with approximately half (n ​= ​101) being a diagnosed or suspected sports-related concussion. The next three most frequently reported body regions were the ankle (n ​= ​29, 8.2 ​%), knee (n ​= ​24, 6.8 ​%), and shoulder (n ​= ​20, 5.6 ​%). Almost all injuries were acute onset (n ​= ​340, 96.0 ​%) and resulted from a contact-based mechanism (94.9 ​%, n ​= ​222 direct contact, n ​= ​114 indirect contact). Tackling was the most frequently reported game circumstance resulting in an injury (n ​= ​160, 45.2 ​%). Conclusion: The head was the most frequently reported injured body region, with approximately one in every two reported head impacts resulting in a diagnosed/suspected sports-related concussion. Injury prevention strategies that promote safety when tackling and being tackled may reduce the frequency of injury, warranting further investigation.

Objective: To explore outcomes of anterior cruciate ligament (ACL) reconstructive surgery (ACLR) between individuals using private and public healthcare. Methods: We conducted a cross-sectional study of participants, 9–36 months post-ACLR using public or private healthcare services. Multivariable linear regression assessed the association between healthcare service used (private versus public) with self-reported outcomes (Knee injury and Osteoarthritis Outcome Score (KOOS) subscales of pain, symptoms, sport/recreation, knee-related quality of life (QoL); 0–100 scale), adjusting for potential confounders. Results: A total of 314 participants were included (median age 29 years, 35 ​% female). One hundred and thirty-nine (44 ​%) underwent ACLR using private healthcare. Individuals using private healthcare for ACLR reported better post-ACLR knee-related QoL (mean difference 5.1; 95%CI 0.6 to 9.7) than individuals using public healthcare, when adjusted for available confounders. No other KOOS subscale scores (pain, symptoms, sport/recreation) differed between healthcare groups in our adjusted analysis. Conclusions: Australian young adults who underwent ACLR using private healthcare (compared to public healthcare) services reported better knee-related QoL post-operatively in this cross-sectional cohort. Sociodemographic and socioeconomic factors contributed little to the differences observed. Future research should consider potential disparities in outcomes between participants using differing healthcare services both clinically and when recruiting participants into research studies evaluating outcomes post-ACLR.

Background: Developing context-specific, evidence-informed, and implementable injury-prevention programs is challenging. Women playing in the elite Australian Football League for Women are at high risk of serious knee injuries, and no specific injury-prevention program exists. The objective of the study was to describe the collaborative process used to create a context-specific injury-prevention program. Methods: A previously used intervention-development process was modified to incorporate a partnership with the sport's governing organization and focus on engaging program implementers. The Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) Sports Setting Matrix guided program development and implementation strategies. Results: The 7-step process, aligned with the RE-AIM Sports Setting Matrix, was applied to develop the injury-prevention program and was titled Prep to Play PRO. The steps were: (Step 1) gaining organizational support and establishing a project partnership; (Step 2) using research evidence and clinical experience; (Step 3) consulting content and context experts; (Step 4) engaging the organization, experts, program implementers, and end-users to concreate the intervention and develop implementation strategies; (Step 5) testing the intervention acceptability and feasibility; (Step 6) evaluating the intervention and implementation strategies against theory; and (Step 7) obtaining feedback from early implementers and end-users. Conclusion: Engaging critical stakeholders at multiple ecological levels (organization, team, and athlete) throughout program development and implementation planning support real-world use. The processes and activities described can guide future sports injury-prevention program development and implementation.

Objective The objective of this study was to determine the feasibility and effectiveness of using SUpported Motivational InTerviewing (SUMIT) to increase physical activity in people with knee osteoarthritis (KOA).Design Randomised controlled trial.Setting We recruited people who had completed Good Life with osteoArthritis Denmark (GLA:D) from private, public and community settings in Victoria, Australia.Interventions Participants were randomised to receive SUMIT or usual care. SUMIT comprised five motivational interviewing sessions targeting physical activity over 10 weeks, and access to a multimedia web-based platform.Participants Thirty-two participants were recruited (17 SUMIT, 15 control) including 22 females (69%).Outcome measures Feasibility outcomes included recruitment rate, adherence to motivational interviewing, ActivPAL wear and drop-out rate. Effect sizes (ESs) were calculated for daily steps, stepping time, time with cadence >100 steps per minute, time in bouts >1 min; 6 min walk distance, Knee Osteoarthritis Outcome Score (KOOS) subscales (pain, symptoms, function, sport and recreation, and quality of life (QoL)), Euroqual, systolic blood pressure, body mass index, waist circumference, 30 s chair stand test and walking speed during 40 m walk test.Results All feasibility criteria were achieved, with 32/63 eligible participants recruited over seven months; with all participants adhering to all motivational interviewing calls and achieving sufficient ActivPAL wear time, and only two drop-outs (6%).12/15 outcome measures showed at least a small effect (ES>0.2) favouring the SUMIT group, including daily time with cadence >100 steps per minute (ES=0.43). Two outcomes, walking speed (ES= 0.97) and KOOS QoL (ES=0.81), showed a large effect (ES>0.8).Conclusion SUMIT is feasible in people with knee osteoarthritis. Potential benefits included more time spent walking at moderate intensity, faster walking speeds and better QoL.Trial registration number ACTRN12621000267853.

Zika virus (ZIKV) is a flavivirus primarily transmitted by Aedes species mosquitoes, first discovered in Africa in 1947, that disseminated through Southeast Asia and the Pacific Islands in the 2000s. The first ZIKV infections in the Americas were identified in 2014, and infections exploded through populations in Brazil and other countries in 2015/16. ZIKV infection during pregnancy can cause severe brain and eye defects in offspring, and infection in adults has been associated with higher risks of Guillain-Barré syndrome. We initiated a study to describe the natural history of Zika (the disease) and the immune response to infection, for which some results have been reported. In this paper, we identify ZIKV-specific CD4+ and CD8+ T cell epitopes that induce responses during infection. Two screening approaches were utilized: an untargeted approach with overlapping peptide arrays spanning the entire viral genome, and a targeted approach utilizing peptides predicted to bind human MHC molecules. Immunoinformatic tools were used to identify conserved MHC class I supertype binders and promiscuous class II binding peptide clusters predicted to bind 9 common class II alleles. T cell responses were evaluated in overnight IFN-γ ELISPOT assays. We found that MHC supertype binding predictions outperformed the bulk overlapping peptide approach. Diverse CD4+ T cell responses were observed in most ZIKV-infected participants, while responses to CD8+ T cell epitopes were more limited. Most individuals developed a robust T cell response against epitopes restricted to a single MHC class I supertype and only a single or few CD8+ T cell epitopes overall, suggesting a strong immunodominance phenomenon. Noteworthy is that many epitopes were commonly immunodominant across persons expressing the same class I supertype. Nearly all of the identified epitopes are unique to ZIKV and are not present in Dengue viruses. Collectively, we identified 31 immunogenic peptides restricted by the 6 major class I supertypes and 27 promiscuous class II epitopes. These sequences are highly relevant for design of T cell-targeted ZIKV vaccines and monitoring T cell responses to Zika virus infection and vaccination.

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.

Objective Describe the co-design process and learnings related to developing the web-based Translating Research Evidence and Knowledge (TREK) ‘My Knee’ education and self-management toolkit for people with knee osteoarthritis. Co-design process Stage (i): Understand and define; systematically reviewed education interventions in published trials; appraised web-based information about knee osteoarthritis; and used concept mapping to identify education priorities of people with knee osteoarthritis and physiotherapists. Stage (ii): Prototype; created a theory-, guideline- and evidence-informed toolkit. Stage (iii): Test and iterate; completed three co-design workshops with end-users (i.e., people with knee osteoarthritis and health professionals); plus an expert review. Results The toolkit is available at myknee.trekeducation.org. Stage (i) identified the need for more accurate and co-designed resources to address broad education needs generated during concept mapping, including guidance on surgery, dispelling common misconceptions and facilitating engagement with exercise therapy and weight management. A theory- and research-informed prototype was created in Stage (ii) to address broad learning and education needs. Stage (iii) co-design workshops ( n = 15 people with osteoarthritis and n = 9 health professionals) informed further content creation and refinement, alongside improvements to optimise usability. Expert opinion review ( n = 8) further refined accuracy and usability. Conclusions The novel co-design methodology employed to create the TREK ‘My Knee’ toolkit facilitated the alignment of the content and usability to meet the broad education needs of people with knee osteoarthritis and health professionals. This toolkit aims to improve and facilitate engagement with guideline-recommended first-line care for people with knee osteoarthritis. Future work will determine its effectiveness in improving clinical outcomes in this population.

Objective The study objective was to determine the relationship of magnetic resonance imaging (MRI)‐detected features of patellofemoral joint osteoarthritis to pain and functional outcomes. Methods We sampled 1,099 participants from the 60‐month visit of the Multicenter Osteoarthritis Study (mean ± SD age: 66.8 ± 7.5 years; body mass index: 29.6 ± 4.8; 65% female). We determined the prevalence of MRI‐detected features of patellofemoral joint osteoarthritis (eg, cartilage damage, bone marrow lesions, and osteophytes) and assessed the relationship between these features and knee pain severity, knee pain on stairs, chair stand time, and walking less than 6,000 steps per day. We evaluated the relationship of MRI features to each outcome using logistic and linear regression, adjusting for potential covariates. Results Participants with cartilage damage in 3‐4 subregions had the highest mean pain severity (22.0/100; 95% confidence interval [CI]: 17.6‐26.4 mm). They also showed higher odds of having at least mild pain on stairs (odds ratio [OR]: 3.3; 95% CI: 1.7‐6.5) and of walking less than 6,000 steps per day (OR: 2.3; 95% CI: 1.1‐4.4) compared with those without cartilage damage. Participants with bone marrow lesions in 3‐4 subregions had higher odds of at least mild pain on stairs than those without (OR: 3.3; 95% CI: 2.2‐5.2). Participants with osteophytes in 3‐4 subregions also had higher odds of walking less than 6,000 steps/day (OR 2.1, 95% CI: 1.3‐3.5, respectively). Conclusion MRI‐detected features of osteoarthritis of the patellofemoral joint are related to pain and functional performance. This knowledge highlights the need to develop treatments for those with patellofemoral joint osteoarthritis to improve pain and maximize function.

Introduction Running 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 analysis A 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 dissemination Approved by the La Trobe University Ethics Committee (HEC-19524). Findings will be disseminated to stakeholders, peer-review journals and conferences.

Introduction Anterior cruciate ligament injury and reconstruction (ACLR) is often associated with pain, functional loss, poor quality of life and accelerated knee osteoarthritis development. The effectiveness of interventions to enhance outcomes for those at high risk of early-onset osteoarthritis is unknown. This study will investigate if SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER) is superior to a minimal intervention control for improving pain, function and quality of life in young adults with ongoing symptoms following ACLR.Methods and analysis The SUPER-Knee Study is a parallel-group, assessor-blinded, randomised controlled trial. Following baseline assessment, 184 participants aged 18–40 years and 9–36 months post-ACLR with ongoing symptoms will be randomly allocated to one of two treatment groups (1:1 ratio). Ongoing symptoms will be defined as a mean score of

During the course of the 2015-2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5-3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings.

Abstract Background Campylobacter jejuni is the leading cause of bacterial gastroenteritis in humans and the handling or consumption of contaminated poultry meat is a key source of infection. Selective breeding of poultry that exhibit elevated resistance to Campylobacter is an attractive control strategy. Here we studied the global transcriptional response of inbred chicken lines that differ in resistance to C. jejuni colonisation at a key site of bacterial persistence. Results Three-week-old chickens of line 61 and N were inoculated orally with C. jejuni strain M1 and caecal contents and tonsils were sampled at 1 and 5 days post-infection. Caecal colonisation was significantly lower in line 61 compared to line N at 1 day post-infection, but not 5 days post-infection. RNA-Seq analysis of caecal tonsils of both lines revealed a limited response to C. jejuni infection compared to age-matched uninfected controls. In line N at days 1 and 5 post-infection, just 8 and 3 differentially expressed genes (DEGs) were detected (fold-change > 2 and false-discovery rate of

# Background Little is known about muscle morphology in people with hip-related pain, without signs of femoro-acetabular impingement syndrome (FAIS). Identifying changes in hip muscle volume, fatty infiltrate and establishing relationships between muscle volume and strength, may provide insight into potential early treatment strategies. # Purposes To: (i) compare the volumes and fatty infiltrate of gluteus maximus, gluteus medius, gluteus minimis, tensor fascia latae and quadratus femoris between symptomatic and less-symptomatic sides of participants with hip-related pain; (ii) compare the volumes and fatty infiltrate of hip muscles between healthy controls and symptomatic participants; and (iii) explore relationships of hip muscle volumes to muscle strength and patient-reported outcome measures in people with hip-related pain. # Study Design Cross-sectional study # Methods Muscle volume and fatty infiltrate (from magnetic resonance imaging), hip muscle strength, patient-reported symptoms, function and quality of life (QOL) were determined for 16 participants with hip-related pain (no clinical signs of FAIS; 37±9 years) and 15 controls (31±9 years). Using One Way Analysis of Co-Variance tests, muscle volume and fatty infiltrate was compared between the symptomatic and less-symptomatic sides in participants with hip-related pain as well as between healthy controls and symptomatic participants. In addition, hip muscle volume was correlated with hip muscle strength, hip-reported symptoms, function and QOL. # Results No differences in all the studied muscle volumes or fatty infiltrate were identified between the symptomatic and less-symptomatic hips of people with hip-related pain; or between people with and without hip-related pain. Greater GMED volume on the symptomatic side was associated with less symptoms and better function and QOL (ρ=0.522-0.617) for those with hip-related pain. Larger GMAX volume was associated with greater hip abduction and internal rotation strength, larger GMED volume was associated with greater hip extension strength, and larger QF volume was associated with greater hip abduction strength (rho=0.507-0.638). # Conclusion People with hip-related pain and no clinical signs of FAIS have hip muscle volumes that are not significantly different than those of matched pain-free controls or their less-symptomatic hip. Larger GMED muscle volume was associated with fewer symptoms and greater strength. # Level of evidence Level 3a

Abstract Background Guided rehabilitation beyond 6-months is rare following anterior cruciate ligament reconstruction (ACLR), despite high prevalence of unacceptable symptoms and quality of life (QoL). Our primary aim was to determine the feasibility of a randomised controlled trial (RCT) evaluating a physiotherapist-guided intervention for individuals 1-year post-ACLR with persistent symptoms. Our secondary aim was to determine if a worthwhile treatment effect could be observed for the lower-limb focussed intervention (compared to the trunk-focussed intervention), for improvement in knee-related QoL, symptoms, and function. Design Participant- and assessor-blinded, pilot feasibility RCT. Methods Participant eligibility criteria: i) 12–15 months post-ACLR; ii) 1 in 3 screened), recruitment rate (> 4 participants/month), retention ( 80%). Between-group differences for knee-related QoL (KOOS-QoL, ACL-QoL), symptoms (KOOS-Pain, KOOS-Symptoms), and function (KOOS-Sport, functional performance tests) were used to verify that the worthwhile effect (greater than the minimal detectable change for each measure) was contained within the 95% confidence interval. Results 47% of those screened were eligible, and 27 participants (3 participants/month; 48% men, 34±12 years) were randomised. Two did not commence treatment, and two were lost to follow-up (16% drop-out). Physiotherapy attendance was > 80% for both groups but reported adherence to unsupervised exercise was low (

Highlights Primary GI MCL is rare. These patients tend to be treated less aggressively in the frontline setting yet have similar outcomes as those with secondary GI MCL. Less aggressive frontline treatment for primary GI MCL is reasonable given decent outcome, although it is unknown whether more aggressive treatment can result in improved outcomes.

Abstract Background Foot and ankle characteristics are associated with patellofemoral pain (PFP) and may also relate to patellofemoral osteoarthritis (PFOA). A greater understanding of these characteristics and PFOA, could help to identify effective targeted treatments. Objectives To determine whether foot and ankle characteristics are associated with knee symptoms and function in individuals with PFOA. Methods For this cross-sectional study we measured weightbearing ankle dorsiflexion range of motion, foot posture (via the Foot Posture Index [FPI]), and midfoot mobility (via the Foot Measurement Platform), and obtained patient-reported outcomes for knee symptoms and function (100 mm visual analogue scales, Anterior Knee Pain Scale [AKPS], Knee injury and Osteoarthritis Outcome Score, repeated single step-ups and double-leg sit-to-stand to knee pain onset). Pearson’s r with significance set at p

Abstract Background Patellofemoral pain (PFP) is a common cause of knee pain in adolescents, but there are limited evidence-based treatment options for this population. Foot orthoses can improve pain and function in adults with PFP, and may be effective for adolescents. The primary aim of this study is to determine the feasibility of conducting a full-scale randomised controlled trial (RCT) evaluating the effects of contoured foot orthoses on knee pain severity and patient-perceived global change, compared to flat shoe insoles, in adolescents with PFP. The secondary aim is to provide an estimate of treatment effects for foot orthoses, compared to flat insoles, in adolescents with PFP. Methods This randomised, controlled, participant- and assessor-blinded, feasibility trial has two parallel groups. Forty adolescents (aged 12–18 years) with clinical symptoms of PFP will be recruited from Queensland, Australia. Participants will be randomised to receive either prefabricated contoured foot orthoses or flat shoe insoles. Both interventions will be fit by a physiotherapist, and worn for 3 months. Feasibility will be evaluated through assessing willingness of volunteers to enrol, number of eligible participants, recruitment rate, adherence with the study protocol, adverse effects, success of blinding, and drop-out rate. Secondary outcomes will evaluate knee-related pain, symptoms, function, quality of life, global rating of change, patient acceptable symptom state, and use of co-interventions, at 6 weeks and 3 months. Primary outcomes will be reported descriptively, while estimates of standard deviation and between-group differences (with 95% confidence intervals) will be reported for secondary outcomes. Discussion Findings of this study will inform the feasibility of a full-scale RCT investigating the efficacy of contoured foot orthoses in adolescents with PFP. This full-scale study is necessary to improve the evidence base for management of adolescent PFP, and enhance outcomes for this population. Trial registration ACTRN12619000957190 .

Background: We are currently in a period of transition, from the pre-COVID-19 (coronavirus disease 2019) era and the initial reactive lockdowns, to now the ongoing living with and potentially the after COVID-19 period. Each country is at its own individual stage of this transition, but many have gone through a period of feeling adrift; disconnected from normal lives, habits and routines, finding oneself betwixt and between stages, similar to that of liminality. Children and young people have been particularly affected. Aim: To increase the understanding of home and community-based strategies that contribute to children and young people’s capacity to adjust to societal changes, both during and after pandemics. Moreover, to identify ways in which children’s actions contribute to the capacity of others to adjust to the changes arising from the pandemic. The potential for these activities to influence and contribute to broader social mobilisation will be examined and promoted. Research design: To achieve the aim of this study, a participatory health research approach will be taken. The overarching theoretical framework of the COVISION study is that of liminality. The study design includes four work packages: two syntheses of literature (a rapid realist review and scoping review) to gain an overview of the emerging international context of evidence of psychosocial mitigations and community resilience in pandemics, and more specifically COVID-19; qualitative exploration of children and young people’s perspective of COVID-19 via creative outlets and reflections; and participatory learning and action through co-production.

Abstract Background Patellofemoral pain (PFP) affects one‐quarter of adolescents, yet there are few evidence‐informed recommendations to treat PFP in this population. HAPPi Kneecaps! is a randomised, controlled, participant‐ and assessor‐blind, parallel‐group feasibility trial of shoe inserts for adolescents with PFP. The aim of this qualitative study was to explore adolescents' perspectives of participating in HAPPi Kneecaps!. Methods All 36 adolescents with PFP from the HAPPi Kneecaps! study were invited to participate in semi‐structured interviews. We used a descriptive qualitative methodology underpinned by a relativist framework to investigate adolescents' perspectives on participating in the trial. Inductive thematic analysis was used to examine patterns regarding how each adolescent experienced the HAPPi Kneecaps! study within their social, cultural, and historical contexts. Results 14 out of 36 HAPPi Kneecaps! participants provided consent and participated in interviews (12 females; mean [SD] age 14.9 [2.4] years). Overall, most adolescents responded positively when discussing their experience, such as improvements in their knee pain and satisfaction with how the study was run. Major themes that were generated from the analysis and feedback were: (1) shoe inserts require little effort to use; (2) perceptions of the program were generally positive; (3) participation in the trial could be made easier; (4) warm weather matters; and (5) life happens. Conclusion Adolescents with PFP who participated in the HAPPi Kneecaps! study found that shoe inserts were easy to wear. Most adolescents experienced an improvement in their symptoms and enhanced participation in sport and exercise. Adolescents with PFP prefer an option for warmer climates (e.g. flip flops or sandals), access to online logbooks, and clinicians who are easily accessible. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000957190. Date registered: 8/07/2019.

Purpose: Magnetic resonance (MR) elastography (E) is a noninvasive technique for quantifying liver stiffness (LS) for fibrosis. This study evaluates whether LS is associated with risk of developing radiation-induced liver disease (RILD) in patients receiving liver-directed radiation therapy (RT). Methods and Materials: Based on prior studies, LS ≤3 kPa was considered normal and LS >3.0 kPa as representing fibrosis. RILD was defined as an increase in Child-Pugh (CP) score of ≥2 from baseline within 1 year of RT. Univariate and multivariate Cox models were used to assess correlation. Results: One hundred two patients, 51 with primary liver tumors and 51 with liver metastases, were identified with sufficient follow-up. In univariate models, pre-RT LS >3.0 kPa (hazard ratio [HR] 4.9; 95% confidence interval [CI], 1.6-14; P = .004), body mass index (BMI), clinical cirrhosis, CP score, albumin-bilirubin (ALBI) grade 2, primary liver tumor, and mean liver dose were significantly associated with risk of post-RT RILD. In a multivariate analysis, LS >3.0 and mean liver dose both were significantly associated with RILD risk. Conclusions: Elevated pre-RT LS is associated with an increased risk of RILD in patients receiving liver-directed RT.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients’ outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9–35) and 82 months (95% CI: 39–115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91–20) versus SMR 1.72 (95% CI: 1.26–2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma–related causes in those achieving EFS 24.

Objective: Evaluate the implementation of Good Life with osteoArthritis from Denmark (GLA:D®) for knee osteoarthritis in Australia using the RE-AIM QuEST (Reach, Effectiveness, Adoption, Implementation, Maintenance Qualitative Evaluation for Systematic Translation) framework. Design: Physiotherapists completed surveys before and after GLA:D® training (2017–2020) to assess practices, and barriers and enablers to implementation. Patients completed online baseline, 3-month (post-treatment) and 12-month patient reported outcomes. Effective implementation was defined as within-participant moderate effect size (ES, ≥0.50) for average pain (100 ​mm VAS) and Knee Injury and Osteoarthritis Outcome Score quality of life scores (KOOS-QoL), and small effect size (≥0.20) for health-related quality of life (EQ-5D-5L). Results: Reach: 1064 physiotherapists and 1945 patients from all states and territories participated. Key barriers included out-of-pocket cost to patients, and program suitability for culturally and linguistically diverse communities. Effectiveness: Following training, more physiotherapists reported discussing treatment goals and weight management, and prescribing supervised, neuromuscular exercise. Patient outcomes at 3- and 12-months (n ​= ​1044 [54%] and 927 [48%]) reflected effective implementation, including reduced pain (ES, 95%CI ​= ​0.72, 0.62–0.84; and 0.65, 0.54–0.77) and improved KOOS-QoL (0.79, 0.69–0.90; and 0.93, 0.81–1.04) and EQ-5D-5L (0.43, 0.31–0.54; and 0.46, 0.35–0.58) scores. Adoption: 297 sites (264 private, 33 public) implemented GLA:D®. Implementation: Most patients completed at least one education (90%), and 10 exercise-therapy (78%) sessions. Adequate staffing to support program delivery was a key enabler. Maintenance: 99% of sites (293/297) continued offering the program in July 2020. Conclusion: Training changed practice and was associated with effective widespread implementation of GLA:D® in Australia.

Abstract Background Foot orthoses have the potential to be an efficacious treatment for patellofemoral osteoarthritis (PFOA) but have not been evaluated in clinical trials in this population. This study aimed to determine the: (i) feasibility of conducting a randomised controlled trial (RCT) investigating the efficacy of foot orthoses in individuals with PFOA; and (ii) effects of foot orthoses versus flat shoe inserts on pain, function, and knee-related quality of life (QOL). Methods This 6-week, single-blinded pilot RCT randomly allocated participants with PFOA to receive foot orthoses or flat inserts. The primary outcome of feasibility was determined via the following parameters: one participant recruited per week, 20% (35 h/week) adherence to the intervention, 50% log book completion rate, and 20% (37.2 [9.8] hours/week) adherence to the intervention, 69.2% (18/26) log-book completion, and 3.8% (1/26) drop-outs. The most common adverse events were arch irritation and shoe fit issues, which were more common in the foot orthoses group (67.9% versus 32.1%). There was a trend for the foot orthoses group to report larger improvements in average and maximum pain than the flat insert group, with the mean difference for maximum knee pain severity (21.9 mm, 95% CI − 2.1 to 46.0) exceeding the minimal clinically important difference (15 mm). The estimated sample size for a full-scale RCT is 160 participants. Suggestions to improve study design include a greater number of face-to-face follow-up appointments, a larger variety of foot orthoses to reduce rates of adverse events, and increasing follow-up time to determine long-term efficacy. Conclusion This study supports the feasibility of a full-scale RCT to determine the efficacy of foot orthoses versus flat inserts in individuals with PFOA. Trial registration The trial protocol was retrospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR number: 12616001287426).

OBJECTIVES:. We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN:. We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING:. A multisite international inpatient trial. PATIENTS:. A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS:. Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS:. For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60–0.68), and improved with addition of age (c-index, 0.66–0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65–0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68–0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59–0.69) and improved with addition of age (c-index, 0.63–0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS:. In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

Abstract Endometriosis is a chronic disease, characterized by the growth of endometrial‐like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well‐characterized progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst‐like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2‐weeks post‐surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analyzed histologically or by qRT‐PCR. Stage of estrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25 mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8 mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p

Introduction This double-blind, randomised controlled trial (RCT) aims to estimate the effect of a physiotherapist-led intervention with targeted strengthening compared with a physiotherapist-led intervention with standardised stretching, on hip-related quality of life (QOL) or perceived improvement at 6 months in people with femoroacetabular impingement (FAI) syndrome. We hypothesise that at 6 months, targeted strengthening physiotherapist-led treatment will be associated with greater improvements in hip-related QOL or greater patient-perceived global improvement when compared with standardised stretching physiotherapist-led treatment.Methods and analysis We will recruit 164 participants with FAI syndrome who will be randomised into one of the two intervention groups, both receiving one-on-one treatment with the physiotherapist over 6 months. The targeted strengthening physiotherapist-led treatment group will receive a personalised exercise therapy and education programme. The standardised stretching physiotherapist-led treatment group will receive standardised stretching and personalised education programme. Primary outcomes are change in hip-related QOL using International Hip Outcome Tool-33 and patient-perceived global improvement. Secondary outcomes include cost-effectiveness, muscle strength, range of motion, functional task performance, biomechanics, hip cartilage structure and physical activity levels. Statistical analyses will make comparisons between both treatment groups by intention to treat, with all randomised participants included in analyses, regardless of protocol adherence. Linear mixed models (with baseline value as a covariate and treatment condition as a fixed factor) will be used to evaluate the treatment effect and 95% CI at primary end-point (6 months).Ethics and dissemination The study protocol was approved (La Trobe University Human Ethics Committee (HEC17-080)) and prospectively registered with the Australian New Zealand Clinical Trials Registry. The findings of this RCT will be disseminated through peer reviewed scientific journals and conferences. Patients were involved in study development and will receive a short summary following the completion of the RCT.Trial registration number ACTRN12617001350314

Abstract Introduction We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. Methods Ten patients with mild cognitive impairment due to underlying AD received 1‐hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. Results Gamma flicker was safe, tolerable, and adherable. Participants’ neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. Discussion These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

Abstract Background Patellofemoral pain (PFP) affects one‐third of adolescents and can persist into adulthood, negatively impacting health and quality of life. Foot orthoses are a recommended treatment for adults with PFP, but have not been evaluated in adolescents. The primary objective was to determine the feasibility of conducting a full‐scale randomised controlled trial (RCT) evaluating effects of contoured, prefabricated foot orthoses on knee pain severity and patient‐perceived global change, compared to flat insoles. The secondary objective was to describe outcomes on a range of patient‐reported outcome measures. Methods We recruited adolescents aged 12–18 years with PFP of ≥2 months duration into a double‐blind, randomised, parallel‐group feasibility trial. Participants were randomised to receive prefabricated contoured foot orthoses or flat shoe insoles, and followed for 3 months. Participants and outcome assessors were blinded to group allocation. Primary outcomes were feasibility of a full‐scale RCT (number of eligible/enrolled volunteers; recruitment rate; adherence with the intervention and logbook completion; adverse effects; success of blinding; drop‐out rate), and credibility and expectancy of interventions. Secondary outcomes were patient‐reported measures of pain, symptoms, function, quality of life, global rating of change, patient acceptable symptom state, and use of co‐interventions. Results 36 out of 279 (12.9%) volunteers (27 female, mean (SD) age 15 (2) years, body mass 60 (13) kg) were eligible and enrolled, at a recruitment rate of 1.2 participants/week. 17 participants were randomised to receive foot orthoses, and 19 to flat insoles. 15 participants returned logbooks; 7/15 (47%) adhered to the intervention. No serious adverse events were reported. 28% (10/36, 4 pandemic‐related) of participants dropped out before 3 months. Blinding was successful. Both groups found the inserts to be credible. Conclusions Based on a priori criteria for feasibility, findings suggest that a full‐scale RCT comparing contoured foot orthoses to flat insoles in adolescents with PFP would not be feasible using the current protocol. Prior to conducting a full‐scale RCT, feasibility issues should be addressed, with protocol modifications to facilitate participant retention, logbook completion and shoe insert wear. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000957190. Date registered: 8/07/2019.

Summary: Objective: This study aims to 1) determine the feasibility of conducting a full-scale randomized controlled trial (RCT) evaluating the efficacy of a gait retraining program on decreasing knee pain and impact loading in people with knee osteoarthritis, and 2) provide an estimate of treatment effects for a gait retraining program compared to a traditional walking program. Methods: Forty individuals with knee osteoarthritis will be enrolled in this randomized, double-blind, feasibility trial with two parallel groups. Participants will be randomly allocated to a gait retraining program aimed to decrease peak axial acceleration of the lower leg (i.e., tibia) by 20% or a traditional walking program. Both programs involve 8 sessions of walking on a treadmill. Feasibility will be assessed with recruitment, enrollment, and retention rates, and number of adverse events and unanticipated problems. Treatment effects will be estimated with measures of knee pain and impact loading collected at baseline, follow-up (

Augmented reality (AR) is rapidly being adopted by industry leaders and militaries around the globe. With the Defense Health Agency pushing AR as a solution to the distributed learning problem, along with AR applications being explored within primary care and operational medical settings, it is crucial for these immersive platforms to have a standardized, scientifically based paradigm on which they are designed and used. One area of particular concern is the potential for physiological maladaptation following prolonged AR exposure, which is expected to vary from that associated with virtual reality exposure. Such maladaptation is potentially driven by limitations that exist with regard to the types and extent of perceptual issues characteristic of AR head-worn displays (e.g., mismatches between visually displayed information and other senses, restricted field of view, mismatched interpupillary distance). Associated perceptual limitations can reduce training effectiveness or impose patient and/or trainee safety concerns. Thus, while AR technology has the potential to advance simulation training, there is a need to approach AR-based research—particularly that which relates to long-exposure-duration scenarios—from a bottom-up perspective, where its physiological impact is more fully understood. In the hopes of assisting this process, this study presents a comparison of cybersickness between two common forms of AR displays. Specifically, by comparing the Microsoft HoloLens, a head-worn display that has seen rapid adoption by the scientific community, with an AR Tablet–based platform within the context of long-duration AR training exposure, it will be possible to determine what differences, if any, exist between the two display platforms in terms of their physiological impact as measured via cybersickness severity and symptom profile. Results from this psychometric assessment will be used to evaluate the physiological impact of AR exposure and develop usage protocols to ensure AR is safe and effective to use for military medical training.

Objective To explore clinical characteristics in individuals with patellofemoral osteoarthritis (PFOA) compared to individually-matched asymptomatic controls. We also explored associations between functional performance and patient-reported symptoms with patellofemoral alignment.Methods We assessed 15 individuals with PFOA and 15 individually-matched asymptomatic controls. In addition to physical examination and patient-reported questionnaires, we evaluated functional performance, lower extremity strength and range of motion, and patellar alignment (using MRI). We analysed group differences with Wilcoxon’s matched-pairs signed rank tests, and within-group associations with Spearman’s rank correlations.Results We included 24 (80%) women with median (IQR) age of 56 (9) years and BMI of 22.8 (5.9) kg/m2. Individuals with PFOA reported lower quality of life (8/100 points lower EQ-5D-5L, p=0.02), and performed worse on two functional tests: repeated one-leg rises (median 16 fewer rises, p=0.04) and timed stair climb (1.2 s slower, p=0.03). There were no differences in strength tests performed or range of motion. Patellar proximal translation correlated with worse functional performance and worse patient-reported pain, function and self-efficacy, while lateral translation and lateral tilt correlated with worse knee-related quality of life (Spearman’s r ranging from 0.5 to 0.7).Conclusion Functional performance was worse in individuals with PFOA, despite those individuals having no significant differences on lower extremity strength testing. Patellofemoral alignment was associated with worse functional performance as well as worse patient-reported outcomes, and it may represent one mechanism underpinning PFOA-related symptoms.

Summary: Objective: To model potential cost savings associated with implementing a first-line management program for moderate-severe knee osteoarthritis (OA) at a national level in Australia. Methods: A budget impact analysis was undertaken using published trial data and publically available data. Australian population projections and OA prevalence data were used to forecast likely need for total knee replacement (TKR) surgery for 2019–2029. Published data were sourced on TKR avoidance following a 12-week non-surgical knee OA management program (exercise therapy, education, insoles, dietary advice, analgesia) and cost per TKR in Australia. The cost of providing the first-line program was estimated on a sliding scale ($AUD750-$3000), with a base case of $AUD1,500. These inputs were used to model potential annual savings associated with national implementation of the program. Results: The number of people in Australia with moderate-severe knee OA requiring TKR was estimated to be 56,007 in 2019, rising to 69,038 by 2029. Avoidance of TKR by 34%–68% of people after the first-line management program could translate to savings of $AUD303million-690 million in 2019. Successively lowering the proportion of people who avoided TKR demonstrated that only 1 in 12 program recipients would need to avoid surgery for the program to generate savings. Conclusions: National implementation of a first-line OA management program as an alternative to TKR could produce substantial cost savings for the Australian healthcare system. Longer term data on TKR avoidance is needed to establish whether cost savings are realised or simply shifted to later years.

Abstract Study design Controlled laboratory study; cross-sectional design. Background Foot and ankle characteristics and dynamic knee valgus differ in people with and without patellofemoral (PF) pain. However, it is unknown if these characteristics are evident in people with PF osteoarthritis (OA), compared to pain-free older adults. Objectives To compare foot and ankle mobility, foot posture and dynamic knee valgus, measured as the frontal plane projection angle (FPPA) during single-leg squatting, between individuals with and without PFOA. Methods Fifty-one participants with PFOA (66% women, mean ± SD age 57 ± 10 years, body mass index (BMI) 27 ± 6 kg/m2), and 23 controls (56% women, age 56 ± 9 years, BMI 24 ± 4 kg/m2) had ankle dorsiflexion measured using the knee-to-wall test, foot mobility calculated as the difference in midfoot height or width between non-weightbearing and weightbearing, and static foot posture characterized utilizing the Foot Posture Index. Peak FPPA was determined from video recordings while participants performed 5 single-leg squats. Linear regressions examined between-groups relationships for foot and ankle characteristics and the FPPA. Results The PFOA group had less ankle dorsiflexion (odds ratio 6.7, 95% confidence interval 2.46–18.2), greater midfoot height mobility (5.2, 1.78–15.14) and width mobility (4.3, 1.33–14.39), and greater foot mobility magnitude (8.4, 2.32–30.69) than controls. There was no difference in FPPA (knee valgus angle) between groups (15, 0.63–377.99). Conclusion Foot and ankle characteristics were different in individuals with PFOA compared to control participants, however there was no difference in dynamic knee valgus during single leg squat. Clinical interventions to address greater foot mobility may be relevant for PFOA.

Abstract Background As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. Methods The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. Results Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1–10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. Conclusion The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.