UPF1 regulates mRNA stability by sensing poorly translated coding sequences.

Post-transcriptional mRNA regulation shapes gene expression, yet how cis-elements and mRNA translation interface to regulate mRNA stability is poorly understood. We find that the strength of translation initiation, upstream open reading frame (uORF) content, codon optimality, AU-rich elements, microRNA binding sites, and open reading frame (ORF) length function combinatorially to regulate mRNA stability. Machine-learning analysis identifies ORF length as the most important conserved feature regulating mRNA decay. We find that Upf1 binds poorly translated and untranslated ORFs, which are associated with a higher decay rate, including mRNAs with uORFs and those with exposed ORFs after stop codons. Our study emphasizes Upf1's converging role in surveilling mRNAs with exposed ORFs that are poorly translated, such as mRNAs with long ORFs, ORF-like 3' UTRs, and mRNAs containing uORFs. We propose that Upf1 regulation of poorly/untranslated ORFs provides a unifying mechanism of surveillance in regulating mRNA stability and homeostasis in an exon-junction complex (EJC)-independent nonsense-mediated decay (NMD) pathway that we term ORF-mediated decay (OMD).

Current Concepts in Management of Acromioclavicular Joint Injury.

Background: The management of acromioclavicular joint injuries requires a thorough understanding of the anatomy and biomechanics of the joint, as well as knowledge of the pertinent physical exam findings and classification to determine an appropriate treatment approach, whether operative or nonoperative. In this article, we present a narrative review of the current state of understanding surrounding these issues. Although there are a large number of options for operative intervention, we additionally present our experience with anatomic coracoclavicular ligament reconstruction (ACCR) with imbrication of the deltoid fascia. Methods: A retrospective review of prospectively collected data on a total of 45 patients who had undergone ACCR between 2003 and 2016 were collected. Results: We found that improvements were seen in American Shoulder and Elbow Surgeons Score (ASES) (53 ± 19 to 81 ± 23), Simple Shoulder Test (SST) (6 ± 3 to 12 ± 13), Constant-Murley (CM) (60 ± 18 to 92 ± 8), and Rowe (67 ± 14 to 89 ± 11) and the mean post-operative SANE score was 86 ± 17. Conclusions: ACCR has the advantage of addressing both horizontal and vertical stability with good outcomes.

A retrospective analysis of mortality risk and immunosuppressive therapy for Stevens-Johnson Syndrome and toxic epidermal necrolysis syndrome using the TriNetX research network.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) exist on a spectrum of autoimmune conditions which cause epidermal detachment and keratinocyte necrosis. Due to the rare incidence of these conditions, a dramatic heterogeneity in treatment algorithms exists. To better appreciate pharmacologic immunosuppressive therapies' impact on survival, the authors queried a multi-institutional data network. Data for this study was extracted from TriNetX Research Network, a platform that contains ICD-9/ICD-10 coding data from a consortium of international healthcare organizations. Seventy-one institutions were queried to identify adult patients diagnosed with SJS, TEN or SJS-TEN Overlap. Cohorts were created based on the therapy received: systemic steroids (SS), diphenhydramine (DH), cyclosporine (CS), intravenous immunoglobulin (IVIG), tumor necrosis factor alpha inhibitors (TNFαi), or a combination of treatments. Cohorts were then propensity matched with patients who received supportive care. Patients who only received one of the above treatments showed no significant reduction in 90-day mortality. Patients who received CS or IVIG as part of their multitherapy showed a significantly increased risk of death when compared to supportive care (CS: RR = 1.583, 95% CI [1.119, 2.240]; IVIG: RR = 2.132, 95% CI [1.485, 3.059]). Despite their frequent utilization, this study's analysis suggests that none of these therapies confer significant 90-day mortality survival over supportive care alone. These results highlight the heterogeneity of therapies and emphasize the need for critical prospective appraisal of their outcomes in SJS and TEN.

Colleges and Crime-Comparing Homicide and Suicide Rates Among College Towns and Their Counterparts.

INTRODUCTION: To investigate differences in homicide and suicide rates across college town status and determine whether college towns were predisposed to changes in rates over time. METHODS: We analyzed county-level homicide and suicide rates (total and by firearm) across college town status using 2015-2019 CDC death certificate data and data from the American Communities Project. RESULTS: Population-level homicide rates were similar across college town status, but younger age groups were at increased risk for firearm homicide and total homicide in college towns. College town status was associated with lower population-level firearm suicide rates, but individuals aged less than 18 y were at increased risk for total and firearm suicide. Finally, college towns were not classified as outliers for changes in either firearm homicide or suicide rates over time. CONCLUSIONS: College towns had similar homicide rates and significantly lower firearm suicide rates than other counties; however, individuals aged less than 18 y were at increased risk for both outcomes. The distinctive demographic, social, economic, and cultural features of college towns may contribute to differing risk profiles among certain age groups, thus may also be amenable to focused prevention efforts.

Paradigm shift towards emergency cholecystectomy: one site experience of the Chole-QuiC process.

INTRODUCTION: Substantial evidence exists for the superiority of emergency over delayed cholecystectomy for gallstone disease during primary admission. Despite this, emergency surgery rates in the UK remain low compared with other developed countries, with great variation in care across the nation. We aimed to describe the local paradigm shift towards emergency surgery and investigate outcomes. METHODS: This is a prospective observational study examining patients enrolled onto an emergency cholecystectomy pathway, following the hospital's subscription to the Royal College of Surgeons of England's Cholecystectomy Quality Improvement Collaborative (Chole-QuIC), between 1 December 2021 and 31 January 2023. Multivariate logistical regression models were used to identify patient and hospital factors associated with postoperative outcomes. RESULTS: Of the 307 suitable acute admissions, 261 (85%) had an emergency cholecystectomy, compared with 5% preceding the Chole-QuIC interventions. Waiting time dropped from 67 to 5 days. A total of 208 (79.7%) patients were primary presentations, 92 (35.2%) were classed Tokyo grade 2 and 142 (54.4%) were obese. A total of 23 (8.8%) patients underwent preoperative endoscopic retrograde cholangiopancreatography, and 26 (10%) patients had a subtotal cholecystectomy. Favourable outcomes (Clavien Dindo ≥3) were observed in first presentations (odds ratio (OR) 0.35; p=0.042) and for operation times within 7 days (OR 0.32; p=0.037), with worse outcomes in BMI ≥35 (OR 3.32; p=0.005) and operation time >7 days (OR 3.11; p=0.037). CONCLUSION: A paradigm shift towards emergency cholecystectomy benefits both the patient and the service. Positive outcomes are apparent for early operation in patients presenting for the first time and recurrent attendees, with early operation (<7 days) providing the most favourable outcome in a select patient group.

Development and implementation of an Enhanced Recovery After Cranial Surgery pathway following supratentorial tumor resection at a tertiary care center.

OBJECTIVE: Controlling length of stay (LOS) reduces rates of nosocomial infections and falls, facilitates earlier return to daily activities, and decreases strain on the healthcare system. Complications following supratentorial tumor resection present early in the postoperative period, thereby enhancing the prospect of safe, early discharge. Here, the authors describe their initial experience with the development and implementation of an Enhanced Recovery After Cranial Surgery (ERACS) pathway following resection of supratentorial tumors in select patients. METHODS: This was a nonrandomized, ambispective quality improvement study of patients undergoing elective craniotomy for supratentorial tumor resection at New York University Langone Health between November 17, 2020, and May 19, 2022. Eligible patients were prospectively enrolled in either the ERACS pathway or the standard pathway. These prospective cohorts were compared to a retrospective cohort of patients who met eligibility criteria for the pathway. Patients in the ERACS pathway cohort were targeted for discharge on postoperative day 2. The primary outcome metric was hospital LOS. Secondary outcome metrics included duration of intensive care unit (ICU) care and rates of 30-day emergency department visits, readmissions, and complications. RESULTS: Over the study period, 188 of 317 patients (59.3%) who underwent supratentorial tumor resection met inclusion criteria for ERACS pathway enrollment. Sixty-three patients were enrolled in the ERACS pathway, and 125 patients completed the standard pathway. The historical cohort consisted of 332 patients who would have been eligible for ERACS enrollment. Patients in the ERACS pathway cohort had a median LOS of 1.93 days compared with 2.92 and 2.88 days for patients in the standard pathway and historical cohort, respectively (p < 0.001). There was a significant reduction in ICU utilization in ERACS pathway patients (16.0 ± 6.53 vs 29.5 ± 53.0 vs 21.8 ± 18.2 hours, p = 0.005). There were no differences in the rates of 30-day emergency department visits (12.7% vs 9.6% vs 10.9%, p = 0.809) and readmissions (4.8% vs 4.0% vs 7.8%, p = 0.279) between groups. CONCLUSIONS: Patients in the ERACS pathway cohort experienced reduced LOS and ICU utilization, with similar rates of adverse outcomes compared to standard pathway patients. The authors' initial experience suggests that an accelerated recovery pathway can be safely implemented following supratentorial tumor resection in select patients.

Observational and model evidence together support wide-spread exposure to noncompensable heat under continued global warming.

As our planet warms, a critical research question is when and where temperatures will exceed the limits of what the human body can tolerate. Past modeling efforts have investigated the 35°C wet-bulb threshold, proposed as a theoretical upper limit to survivability taking into account physiological and behavioral adaptation. Here, we conduct an extreme value theory analysis of weather station observations and climate model projections to investigate the emergence of an empirically supported heat compensability limit. We show that the hottest parts of the world already experience these heat extremes on a limited basis and that under moderate continued warming parts of every continent, except Antarctica, will see a rapid increase in their extent and frequency. To conclude, we discuss the consequences of the emergence of this noncompensable heat and the need for incorporating different critical thermal limits into heat adaptation planning.

Lymphoma recurrence presenting as vocal cord fixation.

Lymphomas of the larynx are a rare finding. Those with lymphoma of the larynx often present with symptoms such as vocal hoarseness, throat pain, dysphagia, and weight loss. This is a case of a 74-year-old man who presents with new onset of hoarseness and dysphagia. He has a previous history of diffuse large B-cell lymphoma (DLBCL) but was thought to be in remission at the time of presentation. On nasolaryngoscopy, there was a large, right sided, sub-mucosal mass with right vocal cord fixation. Physical exam and computed topography of the neck did not identify any adenopathy. Biopsy confirmed the recurrence of DLBCL isolated to the larynx at the time of diagnosis. The patient was treated with chemotherapy and fully recovered his vocal cord motion with resolution of his hoarseness and dysphagia. Physicians should consider lymphoma in patients presenting with laryngeal complaints especially in patients with a history of lymphoma.

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP. QUESTIONS/PURPOSES: (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture? METHODS: We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician-author and senior author for radiographic criteria of fracture healing and HO. RESULTS: Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis). CONCLUSION: Most fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines ( https://www.iccfop.org ). LEVEL OF EVIDENCE: Level IV, therapeutic study.

Frontiers in the Application of RF Vacuum Electronics.

The application of radio frequency (RF) vacuum electronics for the betterment of the human condition began soon after the invention of the first vacuum tubes in the 1920s and has not stopped since. Today, microwave vacuum devices are powering important applications in health treatment, material and biological science, wireless communication-terrestrial and space, Earth environment remote sensing, and the promise of safe, reliable, and inexhaustible energy. This article highlights some of the exciting application frontiers of vacuum electronics.

Massive Trauma and Resuscitation Strategies.

Massive trauma remains the leading cause of mortality among people aged younger than 45 years. In this review, we discuss the initial care and diagnosis of trauma patients followed by a comparison of resuscitation strategies. We discuss various strategies including use of whole blood and component therapy, examine viscoelastic techniques for management of coagulopathy, and consider the benefits and limitations of the resuscitation strategies and consider a series of questions that will be important for researchers to answer to provide the best and most cost-effective therapy for severely injured patients.

Next generation high resolution perovskite direct conversion detector: Monte Carlo design optimisation and virtual clinical trial.

We implement virtual clinical integration of next-generation perovskite detectors into common x-ray imaging devices. This was achieved by performing Monte Carlo (MC) optimisation of the design and benchmarking of low cost, high spatial resolution, direct conversion perovskite crystal x-ray flat panel imagers for a next generation of breast-, MV-, and kV-cone beam CT detectors. Semiconductor methylammonium lead bromide perovskite crystals energy deposition efficiencies calculated in TOPAS were benchmarked against four common detector materials for twelve detector crystal thicknesses between 40 to 15 mm and ten beam energies ranging from 20 keV to 6 MeV. Based on these simulations, Koning's dedicated breast CT, and Varian's Truebeam kV- and MV-cone beam CT systems were designated as suitable applications for perovskite detectors. System specific Fastcat hybrid MC cone beam CT image simulation was subsequently used to optimise the perovskite detector design and conduct virtual clinical trials. Device-specific optimal perovskite crystal thicknesses were calculated to be 0.30, 0.86, and 1.99 mm for Koning breast CT and Truebeam kV- and MV-cone beam CT systems, respectively. Replacing the current detectors on these machines with low cost perovskite crystal detectors could be advantageous as it would simultaneously yield 12.1%, 9.5% and 86.1% improvements in detective quantum efficiency as well as increases in contrast to noise ratio in brain, lung, and bone tissues.

Evaluating education innovations rapidly with build-measure-learn: Applying lean startup to health professions education.

PURPOSE: The Lean Startup approach allows innovators (including innovative educators) to rapidly identify and refine promising ideas into models that actually work. Our aim is to outline key principles of Lean Startup, apply these to health professions education, and illustrate these using personal experience. METHODS AND RESULTS: All innovations are grounded in numerous assumptions; these assumptions should be explicitly identified, prioritized, and empirically tested ('validated learning'). To identify and test assumptions, innovators need to get out of the office and interact with customers (learners, teachers, administrators, etc). Assumptions are tested using multiple quick cycles of Build (a 'minimal viable product' [MVP]), Measure (using metrics that relate meaningfully to the assumption), and Learn (interpret data and decide to persevere with further refinements, or pivot to a new direction). The MVP is a product version that allows testing of one or more key assumptions with the least effort. We describe a novel 'Lean Education Canvas' that synopsizes an innovation and its business model on one page, to help identify assumptions and monitor progress. We illustrate these principles using three cases from health professions education. CONCLUSIONS: Lean Startup has tremendous potential for rapid, robust innovation and evaluation in education.[Box: see text].

Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors.

Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of specific target antigens and severe, potentially fatal, toxicities caused by on-target off-tumor toxicities constitute major hurdles. Furthermore, the tumor microenvironment is usually characterized by chronic inflammation, the presence of immunosuppressive molecules, and immune cells that can reduce CAR T cell efficacy and facilitate antigen escape. Nonetheless, solid tumors are under investigation as possible targets despite their complexity, which represents a significant challenge. In preclinical mouse models, CAR T cells are able to efficiently recognize and kill several tumor xenografts. Overall, in the next few years, there will be intensive research into optimizing novel cell therapies to improve their effector functions and keep untoward effects in check. In this review, we provide an update on the state-of-the-art CAR T cell therapies in solid tumors, focusing on the preclinical studies and preliminary clinical findings aimed at developing optimal strategies to reduce toxicity and improve efficacy.

A Narrative Review of the History of Burn-Related Depression and Stress Reactions.

While the roots of burn care date back several millennia, recognition and treatment of psychiatric trauma has had a more contemporary journey. Our understanding of burn care has evolved largely separately from our understanding of psychiatry; however, proper care of the burn patient relies on the comprehension of both disciplines. Historically, high burn mortality rates have caused clinicians to focus on the physiological causes of burn mortality. As burn care improved in the 20th century, providers began to focus on the long-term health outcomes of burn patients, including mitigating mental health consequences of trauma. This shift coincided with advances in our understanding of psychological sequelae of trauma. Subsequently, an association between burn trauma and mental illness began to emerge. The current standard of care is the result of thousands of years of evolving practices and theories, yet our understanding of the pathophysiology of depression among survivors of severe burn injury is far from complete. By taking measure of the past, we aim to provide context and evidence for our current standards and emphasize areas for future lines of research.

Evaluating the Impact of Cardiopulmonary Bypass Priming Fluids on Bleeding After Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVES: Cardiopulmonary bypass (CPB) predisposes young children to coagulopathy. The authors evaluated possible effects of CPB priming fluids on perioperative bleeding in pediatric cardiac surgery. DESIGN: Meta-analysis and systematic review of previously published studies. SETTING: Each study was conducted in a surgical center or intensive care unit. PARTICIPANTS: Studies investigating patients <18 years without underlying hematologic disorders were included. INTERVENTIONS: The authors evaluated randomized controlled trials (RCTs) published between 1980 and 2020 on MEDLINE, EMBASE, PubMed, and CENTRAL databases. The primary outcome was postoperative bleeding; secondary endpoints included blood product transfusion, mortality, and safety. MEASUREMENTS AND MAIN RESULTS: Twenty eligible RCTs were analyzed, with a total of 1,550 patients and a median of 66 patients per study (range 20-200). The most frequently assessed intervention was adding fresh frozen plasma (FFP) to the prime (8/20), followed by albumin (5/20), artificial colloids (5/20), and blood-based priming solutions (3/20). Ten studies with 771 patients evaluated blood loss at 24 hours in mL/kg and were included in a meta-analysis. Most of them investigated the addition of FFP to the priming fluid (7/10). No significant difference was found between intervention and control groups, with a mean difference of -0.13 (-2.61 to 2.34), p = 0.92, I2 = 69%. Further study endpoints were described but their reporting was too heterogeneous to be quantitatively analyzed. CONCLUSIONS: This systematic review of current evidence did not show an effect of different CPB priming solutions on 24-hour blood loss. The analysis was limited by heterogeneity within the dataset regarding population, type of intervention, dosing, and the chosen comparator, compromising any conclusions.

Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

Intra-operative neurophysiological mapping to identify distorted functional anatomy of the 4th ventricle in a 5-month-old infant.

BACKGROUND: Neurophysiological brainstem mapping techniques facilitate the intra-operative localisation of cranial nerve nuclei amidst distorted anatomy. Neurophysiological recording in young infants can be limited due to immature myelination and synaptogenesis, as well as an increased sensitivity to anaesthetic agents. CASE REPORT: A 5-month-old boy was diagnosed with a cystic brainstem lesion located dorsally within the pons and upper medulla. An open surgical biopsy was undertaken via a posterior fossa craniotomy, revealing a grossly distorted fourth ventricular floor. Intra-operative neurophysiological mapping produced oculomotor, facial, glossopharyngeal and vagal muscle responses allowing a deviated functional midline to be identified. Direct stimulation was used to identify an area in the floor of the fourth ventricle eliciting no cranial nerve responses and allow safe entry into the tumour cavity and biopsy. Transcranial motor evoked responses (TcMEPs), short-latency somatosensory evoked potentials (SSEPs) and brainstem auditory evoked potentials (BAEPs) were all successfully recorded throughout the procedure, despite the use of halogenated gaseous anaesthesia. CONCLUSIONS: We describe the use of brainstem mapping techniques for identification of a distorted midline on the floor of the 4th ventricle in an infant, with reproducible recordings of intra-operative TcMEPs, SSEPs and BAEPs.

Synovial tissue perivascular edema is associated with altered gait patterns in patients with knee osteoarthritis.

OBJECTIVE: To explore mechanisms of mechanoinflammation, we investigated the association between the presence of knee synovial perivascular edema and gait biomechanics that serve as surrogate measures of knee load in patients with knee osteoarthritis (OA). DESIGN: Patients with symptomatic, radiographic knee OA and neutral to varus alignment undergoing total knee arthroplasty or high tibial osteotomy participated in this cross-sectional analysis. All participants underwent 3D gait analysis prior to surgery. Synovial biopsies were obtained during surgery for histopathological assessment. The association between the presence of synovial perivascular edema (predictor) and the external knee moment (outcome) in each orthogonal plane was analyzed using multivariate linear regression and polynomial mixed effects regression models, while adjusting for age, sex, BMI, and gait speed. RESULTS: Ninety-two patients with complete gait and histopathological data were included. When fitted over 100% of stance, regression models indicated substantial differences between patients with and without synovial perivascular edema for knee moments in frontal, sagittal and transverse planes. The knee adduction moment was higher in patients with edema from 16 to 74% of stance, with the largest difference at 33% of stance (ß = 6.87 Nm [95%CI 3.02, 10.72]); whereas the knee flexion-extension moment differed from 15 to 92% of stance, with the largest difference in extension at 60% of stance (ß = -10.80 Nm [95%CI -16.20, -5.40]). CONCLUSIONS: In patients with knee OA, the presence of synovial perivascular edema identified by histopathology is associated with aberrant patterns of knee loading throughout stance, supporting the link between biomechanics and synovial inflammation.