Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade.

Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.

Seroprevalence and risk factors for Lassa virus infection in South-West and North-Central Nigeria: a community-based cross-sectional study.

BACKGROUND: Understanding the level of exposure to Lassa virus (LASV) in at-risk communities allows for the administration of effective preventive interventions to mitigate epidemics of Lassa fever. We assessed the seroprevalence of LASV antibodies in rural and semiurban communities of two cosmopolitan cities in Nigeria with poorly understood Lassa epidemiology. METHODS: A cross-sectional study was conducted in ten communities located in the Abuja Municipal Area Council (AMAC), Abuja, and Ikorodu Local Government Area (LGA), Lagos, from February 2nd to July 5th, 2022. Serum samples collected from participants were analyzed for IgG and IgM antibodies using a ReLASV® Pan-Lassa NP IgG/IgM enzyme-linked immunosorbent assay (ELISA) kit. A questionnaire administered to participants collected self-reported sociodemographic and LASV exposure information. Seroprevalence of LASV IgG/IgM was estimated overall, and by study site. Univariate and multivariate log-binomial models estimated unadjusted and adjusted prevalence ratios (aPRs) and 95% confidence intervals (CI) for site-specific risk factors for LASV seropositivity. Grouped Least Absolute Shrinkage and Selection Operator (LASSO) was used for variable selection for multivariate analysis. RESULTS: A total of 628 participants with serum samples were included in the study. Most participants were female (434, 69%), married (459, 73%), and had a median age of 38 years (interquartile range 28-50). The overall seroprevalence was 27% (171/628), with a prevalence of 33% (126/376) in Abuja and 18% (45/252) in Lagos. Based on site-specific grouped LASSO selection, enrollment in the dry season (vs. wet; aPR, 95% CI: 1.73, 1.33-2.24), reported inconsistent washing of fruits and vegetables (aPR, 95% CI: 1.45, 1.10-1.92), and a positive malaria rapid test (aPR, 95% CI: 1.48, 1.09-2.00) were independently associated with LASV seropositivity in Abuja, whereas, only a self-reported history of rhinorrhea (PR, 95% CI: 2.21, 1.31-3.72) was independently associated with Lassa seropositivity in Lagos. CONCLUSIONS: The LASV seroprevalence was comparable to that in other areas in Nigeria. Our findings corroborate those from other studies on the importance of limiting human exposure to rodents and focusing on behavioral factors such as poor hygiene practices to reduce exposure to LASV.

Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques.

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Postpyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage fluid. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage fluid following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that postpyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques. IMPORTANCE SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution, and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however, no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here, we report that oral administration of live SARS-CoV-2 in nonhuman primates may offer prophylactic benefits, but the formulation and route of administration will require further optimization.

Clustered cases of human adenovirus types 4, 7, and 14 infections in US Department of Defense Beneficiaries during the 2018-2019 season.

Human adenoviruses (HAdV) are genetically diverse and can infect a number of tissues with severities varied from mild to fatal. HAdV types 3, 4, 7, 11, 14, 21, and 55 were associated with acute respiratory illnesses outbreaks in the United States and in other countries. The risk of outbreaks can be effectively controlled by HAdV vaccination or mitigated by screening and preventive measures. During the influenza season 2018-2019, the DoD Global Respiratory Pathogen Surveillance Program (DoDGRS) received 24 300 respiratory specimens. HAdV samples that produced positive cytopathic effects in viral cultivation were subjected to next-generation sequencing for genome sequence assembly, genome typing, whole genome phylogeny, and sequence comparative analyses. A variety of HAdV types were identified in this study, including HAdV types 1-7, 14, 55, and 56. HAdV types 4, 7, and 14 were found in clustered cases in Colorado, Florida, New York, and South Carolina. Comparative sequence analyses of these isolates revealed the emergence of novel genetic mutations despite the stability of adenovirus genomes. Genomic surveillance of HAdV suggested possible undetected outbreaks and shed light on prevalence, genetic divergence, and viral evolution of HAdV. Continued surveillance will inform risk assessment and countermeasures.

In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.

Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

Automating Case Reporting of Chlamydia and Gonorrhea to Public Health Authorities in Oregon Clinics.

BACKGROUND: Optimizing sexually transmitted disease (STD) reporting to state public health authorities is important to reduce incidence and manage outbreaks of STDs. Electronic laboratory reporting (ELR) is the standard through which local clinics report STDs to state public health authority. Electronic case reporting (eCR) is an alternative approach which automates transmission of case reports to public health jurisdictions using electronic health record (EHR) data. METHODS: Working with 3 community health centers in Oregon between February 3, 2020 and May 15, 2020, we piloted an automated eCR approach for gonorrhea (GC) and chlamydia (CT) from these clinics to the Oregon Health Authority. We compared the eCR approach to the existing ELR approach to determine completeness of case reporting for GC/CT. RESULTS: A total of 365 eCRs from 206 unique patients were generated. Among 154 instances where the case detection logic was satisfied for CT, 37% (54 instances) were based on the presence of a diagnosis and 63% (97 instances) were based on laboratory data. Among 232 instances where logic was satisfied for GC, 44% (102 instances) reflected a diagnosis and 56% (130 instances) reflected laboratory results. Data completeness was uniformly equal or higher for eCRs versus ELRs. CONCLUSIONS: The eCR approach was successful in identifying CT and GC cases and provided a more complete set of information to assist public health authorities when compared with ELRs. Electronic case reporting has the potential to automate and relieve staff burden on an important reporting requirement for clinical providers.

SARS-CoV-2 show no infectivity at later stages in a prolonged COVID-19 patient despite positivity in RNA testing.

Inpatient coronavirus disease 2019 (COVID-19) cases present enormous costs to patients and health systems in the United States. Many hospitalized patients may continue testing COVID-19 positive even after the resolution of symptoms. Thus, a pressing concern for clinicians is the safety of discharging these asymptomatic patients if they have any remaining infectivity. This case report explores the viral viability in a patient with persistent COVID-19 over the course of a 2-month hospitalization. Positive nasopharyngeal swab samples were collected and isolated in the laboratory and analyzed by quantitative reverse-transcription polymerase chain reactions (qRT-PCR), and serology was tested for neutralizing antibodies throughout the hospitalization period. The patient experienced waning symptoms by hospital day 40 and had no viable virus growth by hospital day 41, suggesting no risk of infectivity, despite positive RT-PCR results which prolonged his hospital stay. Notably, this case showed infectivity for at least 24 days after disease onset, which is longer than the discontinuation of transmission-based precautions recommended by the Center for Disease Control and Prevention. Thus, our findings suggest that the timeline for discontinuing transmission-based precautions may need to be extended for patients with severe and prolonged COVID-19 disease. Additional large-scale studies are needed to draw definitive conclusions on the appropriate clinical management for these patients. ​.

New insights into intrinsic foot muscle morphology and composition using ultra-high-field (7-Tesla) magnetic resonance imaging.

BACKGROUND: The intrinsic muscles of the foot are key contributors to foot function and are important to evaluate in lower limb disorders. Magnetic resonance imaging (MRI), provides a non-invasive option to measure muscle morphology and composition, which are primary determinants of muscle function. Ultra-high-field (7-T) magnetic resonance imaging provides sufficient signal to evaluate the morphology of the intrinsic foot muscles, and, when combined with chemical-shift sequences, measures of muscle composition can be obtained. Here we aim to provide a proof-of-concept method for measuring intrinsic foot muscle morphology and composition with high-field MRI. METHODS: One healthy female (age 39 years, mass 65 kg, height 1.73 m) underwent MRI. A T1-weighted VIBE - radio-frequency spoiled 3D steady state GRE - sequence of the whole foot was acquired on a Siemens 7T MAGNETOM scanner, as well as a 3T MAGNETOM Prisma scanner for comparison. A high-resolution fat/water separation image was also acquired using a 3D 2-point DIXON sequence at 7T. Coronal plane images from 3T and 7T scanners were compared. Using 3D Slicer software, regions of interest were manually contoured for each muscle on 7T images. Muscle volumes and percentage of muscle fat infiltration were calculated (muscle fat infiltration % = Fat/(Fat + Water) x100) for each muscle. RESULTS: Compared to the 3T images, the 7T images provided superior resolution, particularly at the forefoot, to facilitate segmentation of individual muscles. Muscle volumes ranged from 1.5 cm3 and 19.8 cm3, and percentage muscle fat infiltration ranged from 9.2-15.0%. CONCLUSIONS: This proof-of-concept study demonstrates a feasible method of quantifying muscle morphology and composition for individual intrinsic foot muscles using advanced high-field MRI techniques. This method can be used in future studies to better understand intrinsic foot muscle morphology and composition in healthy individuals, as well as those with lower disorders.

REPORT-PFP: a consensus from the International Patellofemoral Research Network to improve REPORTing of quantitative PatelloFemoral Pain studies.

Patellofemoral pain is a common and often debilitating musculoskeletal condition. Clinical translation and evidence synthesis of patellofemoral pain research are compromised by heterogenous and often inadequately reported study details. This consensus statement and associated checklist provides standards for REPORTing of quantitative PatelloFemoral Pain (REPORT-PFP) research to enhance clinical translation and evidence synthesis, and support clinician engagement with research and data collection. A three-stage Delphi process was initiated at the 2015 International Patellofemoral Research Network (iPFRN) retreat. An initial e-Delphi activity (n=24) generated topics and items, which were refined at the 2017 iPFRN retreat, and voted on prior to and following the 2019 iPFRN retreat (n=51 current and past retreat participants). Voting criteria included 'strongly recommended' (essential), 'recommended' (encouraged) and uncertain/unsure. An item was included in the checklist if ≥70% respondents voted 'recommended'. Items receiving ≥70% votes for 'strongly recommended' were labelled as such. The final REPORT-PFP checklist includes 31 items (11 strongly recommended, 20 recommended), covering (i) demographics (n=2,4); (ii) baseline symptoms and previous treatments (n=3,7); (iii) outcome measures (2,4); (iv) outcomes measure description (n=1,2); (v) clinical trial methodology (0,3) and (vi) reporting study results (n=3,0). The REPORT-PFP checklist is ready to be used by researchers and clinicians. Strong stakeholder engagement from clinical academics during development means consistent application by the international patellofemoral pain research community is likely. Checklist adherence will improve research accessibility for clinicians and enhance future evidence synthesis.

Human Adenovirus Type 55 Distribution, Regional Persistence, and Genetic Variability.

Human adenovirus type 55 (HAdV-55) causes acute respiratory disease of variable severity and has become an emergent threat in both civilian and military populations. HAdV-55 infection is endemic to China and South Korea, but data from other regions and time periods are needed for comprehensive assessment of HAdV-55 prevalence from a global perspective. In this study, we subjected HAdV-55 isolates from various countries collected during 1969-2018 to whole-genome sequencing, genomic and proteomic comparison, and phylogenetic analyses. The results show worldwide distribution of HAdV-55; recent strains share a high degree of genomic homogeneity. Distinct strains circulated regionally for several years, suggesting persistent local transmission. Several cases of sporadic introduction of certain strains to other countries were documented. Among the identified amino acid mutations distinguishing HAdV-55 strains, some have potential impact on essential viral functions and may affect infectivity and transmission.

The use of interval-compressed chemotherapy with the addition of vincristine, irinotecan, and temozolomide for pediatric patients with newly diagnosed desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma that affects children and young adults, and portends poor outcomes despite intensive multimodal treatment approaches. We report toxicity, response, and outcomes of patients with DSRCT treated with the addition of vincristine, irinotecan, and temozolomide (VIT) to interval-compressed chemotherapy as per Children's Oncology Group ARST08P1. METHODS: All newly diagnosed pediatric patients with DSRCT treated at Dana-Farber Cancer Institute and Boston Children's Hospital between 2014 and 2019 as per ARST08P1, Arm P2 with replacement of VAC cycles with VIT, were identified. Medical records were reviewed for clinical and disease characteristics, and treatment response and outcomes. RESULTS: Six patients were treated as per the above regimen. Median age at diagnosis was 15.1 years (range 3.2-16.4) and five patients were male. Five patients had abdominal primary tumors, of which one had exclusively intraabdominal and four had extraabdominal metastases. Two initial cycles of VIT were well tolerated with nausea, vomiting, diarrhea, and constipation as the most common adverse events. Overall response rate defined as partial or complete response after two initial cycles of VIT was 50%. For local control, all patients had surgical resection followed by radiotherapy, and two patients received hyperthermic intraperitoneal chemotherapy at the time of surgery. Of the four patients who have completed therapy to date, three remain disease-free with median follow-up time of 46.7 months. CONCLUSIONS: The addition of VIT to interval-compressed chemotherapy is tolerable and active in DSRCT, with activity warranting additional investigation.

Does adding hip exercises to quadriceps exercises result in superior outcomes in pain, function and quality of life for people with knee osteoarthritis? A systematic review and meta-analysis.

OBJECTIVES: To determine, in people with knee osteoarthritis (KOA): i) the effectiveness of adding hip strengthening exercises to quadriceps exercises and ii) the type of hip strengthening exercise with the greatest evidence for improving pain, function and quality of life. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Medline, Embase, Cochrane, CINAHL and SportDiscus databases were searched from inception to January 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials investigating the effect of adding hip exercises to quadriceps exercises in people with KOA on pain, function and/or quality of life were included. Three subgroups of hip exercises were included: resistance, functional neuromuscular or multimodal exercise. RESULTS: Eight studies were included. Pooled data provide evidence that combined hip and quadriceps exercise is significantly more effective than quadriceps exercise alone for improving walking function (standardised mean difference -1.06, 95% CI -2.01 to -0.12), but not for outcomes of pain (-0.09, 95% CI -0.96 to 0.79), patient-reported function (-0.74, 95% CI -1.56 to 0.08) or stair function (-0.7, 95% CI -1.67 to 0.26). Subgroup analyses reveal that hip resistance exercises are more effective than functional neuromuscular exercises for improving pain (p<0.0001) and patient-reported function (p<0.0001). Multimodal exercise is no more effective than quadriceps strengthening alone for pain (0.13, 95% CI -0.31 to 0.56), patient-reported function (-0.15, 95% CI -0.58 to 0.29) or stair function (0.13, 95% CI -0.3 to 0.57). CONCLUSION: Walking improved after the addition of hip strengthening to quadriceps strengthening in people with KOA. The addition of resistance hip exercises to quadriceps resulted in greater improvements in patient-reported pain and function.

Is Self-Reported Knee Stability Associated With Symptoms, Function, and Quality of Life in People With Knee Osteoarthritis After Anterior Cruciate Ligament Reconstruction?

OBJECTIVE: This study aimed to investigate the association of self-reported knee stability with symptoms, function, and quality of life in individuals with knee osteoarthritis after anterior cruciate ligament reconstruction (ACLR). SETTING: Cross-sectional. PARTICIPANTS: Twenty-eight individuals with knee osteoarthritis, 5 to 12 years after ACLR. MAIN OUTCOME MEASURES: Self-reported knee stability was assessed using visual analogue scales (VAS) during hop for distance (HD), side-to-side hop (SSH), and one-leg rise (OLR). Symptoms [Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, Anterior Knee Pain Scale (AKPS), and International Knee Documentation Committee form], self-reported function (KOOS-sport/rec), performance-based function (hopping and OLR), and quality of life (KOOS-QOL) were assessed. K-means clustering categorized individuals into low (n = 8) and high self-reported knee stability (n = 20) groups based on participants' VAS scores during functional tasks. RESULTS: The low self-reported knee stability group had worse knee symptoms than the high self-reported knee stability group [KOOS-pain: mean difference -17 (95% confidence interval, -28 to -5); AKPS: -10 (-20 to -1)], and worse self-reported function [KOOS-sport/rec: -33 (-48 to -18)] and performance-based function [HD: -28 (-53 to -3); SSH: -10 (-20 to -1), OLR: -18 (-32 to -50)]. CONCLUSION: Low self-reported stability is associated with worse symptoms, and worse self-reported and performance-based function. Further research is required to determine the causation relation of self-reported knee stability to knee symptoms and function in individuals with knee osteoarthritis after ACLR.

Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.

Pediatric post-transplant hepatic kaposi sarcoma due to donor-derived human herpesvirus 8.

In areas of the world where human herpesvirus 8 (HHV-8) is endemic, Kaposi sarcoma (KS) is a common SOT-associated cancer. In the United States, where the virus is not prevalent, PTKS is rare, and there is little literature on pediatric PTKS. We present a North American female who underwent deceased donor, left lateral segment liver transplant for biliary atresia at age 11 months. The donor was a male with no known history of KS, originally from an HHV-8-endemic country. Three months after transplantation, the patient developed liver nodules and portal vein thrombosis. Analysis of needle biopsy established the diagnosis of KS and confirmed that the transformed cells were donor-derived. HHV-8 viremia was detected, and ganciclovir dosing (which had been started prophylactically) was increased. Immunosuppression was changed from tacrolimus to sirolimus. After further disease progression, 8 cycles of paclitaxel were administered. Under this treatment, her nodules regressed, HHV-8 viremia resolved, and she had marked clinic improvement. Notably, the adult recipient of the right liver lobe from the same donor also developed PTKS. This is one of few pediatric PTKS cases described in the literature. It contributes to the mechanistic understanding of PTKS development, illustrating the risk posed by donors from HHV-8-endemic countries, as well as the potential for strong PTKS correlation between multiple recipients of organs from a single shared donor.

The patellofemoral pain and osteoarthritis subscale of the KOOS (KOOS-PF): development and validation using the COSMIN checklist.

BACKGROUND: Patellofemoral pain and osteoarthritis are prevalent and associated with substantial pain and functional impairments. Patient-reported outcome measures (PROMs) are recommended for research and clinical use, but no PROMs are specific for patellofemoral osteoarthritis, and existing PROMs for patellofemoral pain have methodological limitations. This study aimed to develop a new subscale of the Knee injury and Osteoarthritis Outcome Score for patellofemoral pain and osteoarthritis (KOOS-PF), and evaluate its measurement properties. METHODS: Items were generated using input from 50 patients with patellofemoral pain and/or osteoarthritis and 14 health and medical clinicians. Item reduction was performed using data from patellofemoral cohorts (n=138). We used the COnsesus-based Standards for the selection of health Measurements INstruments guidelines to evaluate reliability, validity, responsiveness and interpretability of the final version of KOOS-PF and other KOOS subscales. RESULTS: From an initial 80 generated items, the final subscale included 11 items. KOOS-PF items loaded predominantly on one factor, pain during activities that load the patellofemoral joint. KOOS-PF had good internal consistency (Cronbach's α 0.86) and adequate test-retest reliability (intraclass correlation coefficient 0.86). Hypothesis testing supported convergent, divergent and known-groups validity. Responsiveness was confirmed, with KOOS-PF demonstrating a moderate correlation with Global Rating of Change scores (r 0.52) and large effect size (Cohen's d 0.89). Minimal detectable change was 2.3 (groups) and 16 (individuals), while minimal important change was 16.4. There were no floor or ceiling effects. CONCLUSIONS: The 11-item KOOS-PF, developed in consultation with patients and clinicians, demonstrated adequate measurement properties, and is recommended for clinical and research use in patients with patellofemoral pain and osteoarthritis.

2018 Consensus statement on exercise therapy and physical interventions (orthoses, taping and manual therapy) to treat patellofemoral pain: recommendations from the 5th International Patellofemoral Pain Research Retreat, Gold Coast, Australia, 2017.

Patellofemoral pain affects a large proportion of the population, from adolescents to older adults, and carries a substantial personal and societal burden. An international group of scientists and clinicians meets biennially at the International Patellofemoral Research Retreat to share research findings related to patellofemoral pain conditions and develop consensus statements using best practice methods. This consensus statement, from the 5th International Patellofemoral Research Retreat held in Australia in July 2017, focuses on exercise therapy and physical interventions (eg, orthoses, taping and manual therapy) for patellofemoral pain. Literature searches were conducted to identify new systematic reviews and randomised controlled trials (RCTs) published since the 2016 Consensus Statement. The methodological quality of included systematic reviews and RCTs was graded using AMSTAR and PEDro, respectively. Evidence-based statements were developed from included papers and presented to a panel of 41 patellofemoral pain experts for consensus discussion and voting. Recommendations from the expert panel support the use of exercise therapy (especially the combination of hip-focused and knee-focused exercises), combined interventions and foot orthoses to improve pain and/or function in people with patellofemoral pain. The use of patellofemoral, knee or lumbar mobilisations in isolation, or electrophysical agents, is not recommended. There is uncertainty regarding the use of patellar taping/bracing, acupuncture/dry needling, manual soft tissue techniques, blood flow restriction training and gait retraining in patients with patellofemoral pain. In 2017, we launched the International Patellofemoral Research Network (www.ipfrn.org) to consolidate and grow our patellofemoral research community, facilitate collaboration and disseminate patellofemoral pain knowledge to clinicians and the general public. The 6th International Patellofemoral Research Retreat will be held in Milwaukee, Wisconsin, USA, in October 2019.

Athletes Rated as Poor Single-Leg Squat Performers Display Measurable Differences in Single-Leg Squat Biomechanics Compared With Good Performers.

CONTEXT: It is important to validate single-leg squat visual rating criteria used in clinical practice and research. Foot orthoses may improve single-leg squat performance in those who demonstrate biomechanics associated with increased risk of lower limb injury. OBJECTIVE: Validate visual rating criteria proposed by Crossley et al, by determining whether athletes rated as poor single-leg squat performers display different single-leg squat biomechanics than good performers; and evaluate immediate effects of foot orthoses on single-leg squat biomechanics in poor performers. DESIGN: Comparative cross-sectional study. SETTING: University laboratory. PARTICIPANTS: 79 asymptomatic athletes underwent video classification of single-leg squat performance based on established visual rating criteria (overall impression, trunk posture, pelvis "in space," hip movement, and knee movement), and were rated as good (n = 23), fair (n = 41), or poor (n = 15) performers. INTERVENTION: A subset of good (n = 16) and poor (n = 12) performers underwent biomechanical assessment, completing 5 continuous single-leg squats on their dominant limb while 3-dimensional motion analysis and ground reaction force data were recorded. Poor performers repeated the task standing on prefabricated foot orthoses. MAIN OUTCOME MEASURES: Peak external knee adduction moment (KAM) and peak angles for the trunk, hip, knee, and ankle. RESULTS: Compared with good performers, poor performers had a significantly lower peak KAM (mean difference = 0.11 Nm/kg, 95% confidence interval = 0.02 to 0.2 Nm/kg), higher peak hip adduction angle (-4.3°, -7.6° to -0.9°), and higher peak trunk axial rotation toward their stance limb (3.8°, 0.4° to 7.2°). Foot orthoses significantly increased the peak KAM in poor performers (-0.06 Nm/kg, -0.1 to -0.01 Nm/kg), with values approximating those observed in good performers. CONCLUSIONS: Findings validate Crossley et al's visual rating criteria for single-leg squat performance in asymptomatic athletes, and suggest that "off-the-shelf" foot orthoses may be a simple intervention for poor performers to normalize the magnitude of the external KAM during single-leg squat.

The psychological features of patellofemoral pain: a systematic review.

BACKGROUND: Patellofemoral pain (PFP) is prevalent in adolescence and adulthood and often persists. In contrast to other persistent musculoskeletal conditions, for which non-physical, psychological features are implicated, PFP remains largely conceptualised in mechanical terms. AIMS: To (1) identify whether the psychological characteristics of individuals with PFP differs from asymptomatic controls and (2) evaluate the correlations between psychological characteristics and PFP severity. STUDY DESIGN: Systematic review METHODS: A systematic review of the literature was conducted according to PRISMA guidelines. The Epidemiological Appraisal Instrument was used to evaluate quality. Studies measuring psychological constructs with patient-reported measures were included. Standardised mean differences were calculated and supported by narrative synthesis. RESULTS: Twenty-five studies were eligible. Quality results ranged from 28.3% to 61.7%. Psychological constructs were reported under four groupings: mental health, cognitive factors, behavioural factors and other factors. There is limited evidence of mental health and cognitive differences in some individuals with PFP. Features demonstrating linear correlations with pain and physical function included anxiety/depression, catastrophising, praying and hoping and pain-related fear. CONCLUSIONS: Anxiety, depression, catastrophising and fear of movement may be elevated in individuals with PFP and correlate with pain and reduced physical function. These results derive from a limited number of studies. Future research should aim to evaluate if and how psychological factors contribute to PFP. CLINICAL RELEVANCE: Patients are likely to benefit from clinician vigilance to the presence of psychological factors.

Knee kinematics and joint moments during gait following anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

BACKGROUND: Abnormal gait after anterior cruciate ligament reconstruction (ACLR) may contribute to development and/or progression of knee osteoarthritis. OBJECTIVE: To conduct a systematic review and meta-analysis of knee kinematics and joint moments during walking after ACLR. METHODS: We searched seven electronic databases and reference lists of relevant papers, for cross-sectional, human-based observational studies comparing knee joint kinematics and moments during level walking in individuals with ACLR, with the uninjured contralateral knee or healthy individuals as a control. Two independent reviewers appraised methodological quality (modified Downs and Black scale). Where possible, data were pooled by time post-ACLR (RevMan), otherwise narrative synthesis was undertaken. RESULTS: Thirty-four studies were included. Meta-analysis revealed significant sagittal plane deficits in ACLR knees. We found greater knee flexion angles (standardised mean difference: 1.06; 95% CI 0.39 to 1.74) and joint moments (1.61; 0.87 to 2.35) <6 months post-ACLR, compared to healthy controls. However, lower peak knee flexion angles were identified 1-3 years (-2.21; -3.16 to -1.26) and ≥3 years post-ACLR (-1.38, -2.14 to -0.62), and lower knee flexion moment 6-12 months post-ACLR (-0.76; -1.40 to -0.12). Pooled data provided strong evidence of no difference in peak knee adduction moment >3 years after ACLR (vs healthy controls) (0.09; -0.63 to 0.81). No transverse plane conclusions could be drawn. CONCLUSIONS: Sagittal plane biomechanics, rather than the knee adduction moment, appear to be more relevant post-ACLR. Better understanding of sagittal plane biomechanics is necessary for optimal post-operative recovery, and to potentially prevent early onset and progression of knee OA after ACLR. TRIAL REGISTRATION NUMBER: PROSPERO systematic review protocol registration number CRD4201400882 2.