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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.

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.

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 .

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.

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.

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

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.

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 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 Age-related changes in midfoot mobility have the potential to influence success with foot orthoses intervention in people with patellofemoral pain (PFP). The aim of this study was to determine whether older people with PFP demonstrate less foot mobility than younger adults with PFP. Methods One hundred ninety four participants (113 (58%) women, age 32 ± 7 years, BMI 25 ± 4.9 kg/m2) with PFP (≥ 6 weeks duration) were included, with foot mobility quantified using reliable and valid methods. K-means cluster analysis classified participants into three homogenous groups based on age. After cluster formation, univariate analyses of co-variance (covariates: sex, weight) were used to compare midfoot height mobility, midfoot width mobility, and foot mobility magnitude between age groups (significance level 0.05). Results Cluster analysis revealed three distinct age groups: 18–29 years (n = 70); 30–39 years (n = 101); and 40–50 years (n = 23). There was a significant main effect for age for midfoot height mobility (p 0.05). Conclusion Individuals with PFP aged 40–50 years have less foot mobility than younger adults with PFP. These findings may have implications for evaluation and treatment of older individuals with PFP.

Abstract Background Patellofemoral joint osteoarthritis is a common condition, yet information regarding conservative management is lacking. Foot orthoses are an effective intervention for improving pain and function in younger individuals with patellofemoral pain and may be effective in those with patellofemoral osteoarthritis. This pilot study will seek to establish the feasibility of a phase III randomised controlled trial to investigate whether foot orthoses worn in prescribed motion controlled footwear are superior to prescribed motion control footwear alone in the management of patellofemoral osteoarthritis. Methods/design This phase II pilot clinical trial is designed as a randomized, single-blind, parallel group, two arm, superiority trial. The trial will recruit 44 participants from Queensland and Tasmania, Australia. Volunteers aged 40 years and over must have clinical symptoms and radiographic evidence of patellofemoral osteoarthritis to be eligible for inclusion. Those eligible will be randomized to receive either foot orthoses and prescribed motion control shoes, or prescribed motion control shoes alone, to be worn for a period of 4 months. The feasibility of a phase III clinical trial will be evaluated by assessing factors such as recruitment rate, number of eligible participants, participant compliance with the study protocol, adverse events, and drop-out rate. A secondary aim of the study will be to determine completion rates and calculate effect sizes for patient reported outcome measures such as knee-related symptoms, function, quality of life, kinesiophobia, self-efficacy, general and mental health, and physical activity at 2 and 4 months. Primary outcomes will be reported descriptively while effect sizes and 95% confidence intervals will be calculated for the secondary outcome measures. Data will be analysed using an intention-to-treat principle. Discussion The results of this pilot trial will help determine the feasibility of a phase III clinical trial investigating whether foot orthoses plus motion control footwear are superior to motion control footwear alone in individuals with patellofemoral osteoarthritis. A Phase III clinical trial will help guide footwear and foot orthoses recommendations in the clinical management of this disorder. Trial registration Retrospectively registered with the Australian New Zealand Clinical Trials Registry: ACTRN12615000002583 . Date registered: 07/01/15.