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BACKGROUND The orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study. PATIENT AND METHODS We performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom. RESULTS A total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR

In modern radiotherapy, imaging is an important component in the treatment process where it is used for planning the doses to be delivered and for verifying and monitoring the position of the target during treatments. Recent developments in imaging have contributed to advancing radiotherapy techniques’ such as image-guided radiotherapy (IGRT) for intrafraction motion management and adaptive radiation therapy (ART). This is has resulted in the ability to deliver highly conformal radiation doses with increased precision, which has enabled the safe increase in the dose that can be delivered to the tumour, resulting in improvements in clinical outcomes and the implementation of hypofractionated radiotherapy regimens. Although x-ray imaging has predominantly been used in radiotherapy for many years, more complex radiotherapy such as ART, demands an imaging modality with greater soft tissue contrast so radiotherapy targets can be imaged directly. A requirement that has led to the recent introduction of the MR-linac. Ultrasound also offers soft tissue contrast and may have advantages in terms of imaging rates, we therefore considered it pertinent to consider the role of ultrasound imaging in future radiotherapy treatments. In this timely debate, Emma Harris and Davide Fontanarosa discuss whether ultrasound guidance in radiotherapy will become a clinical standard in the future.

Management of inflammatory bowel disease (IBD) has changed considerably over recent years, which has coincided with increased subspecialisation amongst general surgeons. This study evaluated the demographics and outcomes of patients with IBD undergoing bowel resection and assessed for the potential impact of surgical subspecialisation. Patient demographic, operative and outcome data were collected for patients undergoing a bowel resection secondary to IBD, admitted acutely to NHS trusts in the North of England between 2002 and 2016. The primary outcome of interest was 30-day post-operative mortality, with secondary outcomes: length of stay, stoma and anastomosis rates. A total of 913 patients were included in the study cohort. A reduction in the number of resections was noted over time (2002–2006: 361 vs. 2012–2016: 262). No change was observed for 30-day mortality over the study period (3.9%, p = 0.233). Length of stay was also unchanged (p = 0.949). Laparoscopic surgery was increasingly utilised (0.6% vs. 17.2%, p

BackgroundAlthough carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.Methods and resultsWe report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co‐segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%–3.4%, pFBN2 variants in patient alleles compared with controls.ConclusionThe identification of a novel FBN2 variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact FBN2 variants in patients with sporadic CTS, strongly suggest a role of FBN2 in the pathogenesis of CTS.

Little is known about the long-term skeletal impact of bariatric procedures, particularly the increasingly commonly performed gastric sleeve surgery (GS). We examined bone density (BMD) change following three types of bariatric surgery Roux-en-Y gastric bypass (RYGB), GS and laparoscopic adjustable gastric banding (LAGB), compared with diet, over 36 months. Non-randomized, prospective study of participants with severe obesity (n = 52), undergoing weight-loss interventions: RYGB (n = 7), GS (n = 21), LAGB (n = 11) and diet (n = 13). Measurements of calciotropic indices, gut hormones (fasting and post prandial) peptide YY (PYY), glucagon-like peptide 1 (GLP1) and adiponectin together with dual-X-ray absorptiometry and quantitative computed tomography scans were performed thorough the study. All groups lost weight during the first 12 months. Despite weight stability from 12 to 36 months and supplementation of calcium and vitamin D, there was progressive bone loss at the total hip (TH) over 36 months in RYGB −14% (95% CI: −12, −17) and GS −9% (95% CI: −7, −10). In RYGB forearm BMD also declined over 36 months −9% (95% CI: −6, −12) and LS BMD declined over the first 12 months −7% (95% CI: −3, −12). RYGB and GS groups experienced significantly greater bone loss until 36 months than LAGB and diet groups, which experienced no significant BMD loss. These bone losses remained significant after adjustment for weight loss and age. RYGB and GS procedures resulted in elevated postprandial PYY, adiponectin and bone turnover markers up to 36 months without such changes among LAGB and diet participants. RYGB and GS but not LAGB resulted in ongoing TH bone loss for three postoperative years. For RYGB, bone loss was also observed at LS and non-weight-bearing forearms. These BMD changes were independent of weight and age differences. We, therefore, recommend close monitoring of bone health following RYGB and GS surgeries.

Emergency laparotomy is associated with high morbidity and mortality. Current trends suggest improvements have been made in recent years, with increased survival and shorter lengths of stay in hospital. The National Emergency Laparotomy Audit (NELA) has evaluated participating hospitals in England and Wales and their individual outcomes since 2013. This study aims to establish temporal trends for patients undergoing emergency laparotomy and evaluate the influence of NELA.Data for emergency laparotomies admitted to NHS hospitals in the Northern Deanery between 2001 and 2016 were collected, including demographics, co-morbidities, diagnoses, operations undertaken and outcomes. The primary outcome of interest was in-hospital death within 30 days of admission. Cox-regression analysis was undertaken with adjustment for covariates.There were 2828 in-hospital deaths from 24,291 laparotomies within 30 days of admission (11.6%). Overall 30-day mortality significantly reduced during the 15-year period studied from 16.3% (2001-04), to 8.1% during 2013-16 (p 0.001). After multivariate adjustment, laparotomies undertaken in more recent years were associated with a lower mortality risk compared to earlier years (2013-16: HR 0.73, p 0.001). There was a significant improvement in 30-day postoperative mortality year-on-year during the NELA period (from 9.1 to 7.1%, p = 0.039). However, there was no difference in postoperative mortality for patients who underwent laparotomy during NELA (2013-16) compared with the preceding three years (both 8.1%, p = 0.526).30 day postoperative mortality for emergency laparotomy has improved over the past 15-years, with significantly reduced mortality risk in recent years. However, it is unclear if NELA has yet had a measurable effect on 30-day post-operative mortality.

Aim The coronavirus disease 2019 (COVID-19) pandemic presents significant challenges to healthcare systems globally. Orthopaedic surgeons are at risk of contracting COVID-19 due to their close contact with patients in both outpatient and theatre environments. The aim of this review was to perform a literature review, including articles of other coronaviruses, to formulate guidelines for orthopaedic healthcare staff. Methods A search of Medline, EMBASE, the Cochrane Library, World Health Organization (WHO), and Centers for Disease Control and Prevention (CDC) databases was performed encompassing a variety of terms including ‘coronavirus’, ‘covid-19’, ‘orthopaedic’, ‘personal protective environment’ and ‘PPE’. Online database searches identified 354 articles. Articles were included if they studied any of the other coronaviruses or if the basic science could potentially applied to COVID-19 (i.e. use of an inactivated virus with a similar diameter to COVID-19). Two reviewers independently identified and screened articles based on the titles and abstracts. 274 were subsequently excluded, with 80 full-text articles retrieved and assessed for eligibility. Of these, 66 were excluded as they compared personal protection equipment to no personal protection equipment or referred to prevention measures in the context of bacterial infections. Results There is a paucity of high quality evidence surrounding COVID-19. This review collates evidence from previous coronavirus outbreaks to put forward recommendations for orthopaedic surgeons during the COVID-19 pandemic. The key findings have been summarized and interpreted for application to the orthopaedic operative setting. Conclusion For COVID-19 positive patients, minimum suggested PPE includes N95 respirator, goggles, face shield, gown, double gloves, and surgical balaclava. Space suits not advised. Be trained in the correct technique of donning and doffing PPE. Use negative pressure theatres if available. Minimize aerosolization and its effects (smoke evacuation and no pulse lavage). Minimize further unnecessary patient-staff contact (dissolvable sutures, clear dressings, split casts).

Maintaining energy balance is important to ensure a healthy organism. However, energy partitioning, coordinating the distribution of sufficient energy to different organs and tissues is equally important, but the control of this process is largely unknown. In obesity, an increase in fat mass necessitates the production of additional bone mass to cope with the increase in bodyweight and processes need to be in place to communicate this new weight bearing demand. Here, we investigate the interaction between leptin and NPY, two factors critically involved in the regulation of both energy metabolism and bone mass, in this process. We assessed the co-localization of leptin receptors on NPY neurons using RNAScope followed by a systematic examination of body composition and energy metabolism profiling in male and female mice lacking leptin receptors specifically in NPY neurons (Leprlox/lox;NPYCre/+). The effect of short-term switching between chow and high-fat diet was also examined in these mice. We uncovered that leptin receptor expression is greater on a subpopulation of NPY neurons in the arcuate that do not express AgRP. We further show that Leprlox/lox;NPYCre/+ mice exhibit significantly increased adiposity while bone mass is diminished. These body composition changes occur in the absence of alterations in food intake or energy expenditure, demonstrating a prominent role for leptin signaling in NPY neurons in the control of energy partitioning. Importantly however, when fed a high-fat diet, these mice display a switch in energy partitioning whereby they exhibit a significantly enhanced ability to increase their bone mass to match the increased bodyweight caused by higher caloric intake concurrent with attenuated adiposity. Taken together, these results demonstrate that leptin signaling in NPY neurons is critical for coordinating energy partitioning between fat and bone mass especially during situations of changes in energy balance.

Motorcycle riders have a high risk of serious injury if they crash. To assist with identification of countermeasures, the present study examined records from the Royal Adelaide Hospital (RAH) in South Australia for 763 motorcyclists (including scooter riders) admitted between January 2008 and November 2010 and between April 2014 and December 2016. Records were linked with police-reported crash data and results of forensic blood tests for alcohol and drugs. When compared with 1617 car drivers admitted to the RAH over the same periods, motorcyclists were younger, were more commonly male, more likely to hold a learner permit, less likely to hold a provisional licence, less likely to be over the legal alcohol limit and less likely to be at-fault in multiple vehicle crashes. Their crashes were more likely to be single vehicle crashes (specifically roll over, left road – out of control and hit object/animal/pedestrian on road crashes) and were more common on weekends, during the afternoon, on sloping roads, on curved roads, on roads with speed limits of 50 and 80 km/h, during daylight hours, in dry weather and on dry roads. They had a higher severity of injury than car drivers, spent longer in hospital, and were more likely to sustain injuries to multiple body regions. Linear regression showed that older age, higher blood alcohol concentration and higher speed limit increased injury severity for motorcyclists. Based on present findings, motorcycling safety can be improved through countermeasures related to Graduated Licensing Systems, infrastructure, motorcycle technology and protective clothing.

Introduction In recent years, several management options have been used in the management of perforated diverticulitis, ranging from conservative treatment to laparotomy. General surgery has also become increasingly specialised over time. This retrospective cohort study investigated changes in patient outcomes following perforated diverticulitis, management approach and the influence of consultant subspecialisation over time. Materials and methods Data was collected on patients admitted with perforated diverticulitis in the North of England between 2002 and 2016. Subspecialisation was categorised as colorectal or other general subspecialties. The primary outcome of interest was overall 30-day mortality; secondary outcomes included surgical approach, stoma and anastomosis rate. Results A total of 3394 cases of perforated diverticulitis were analysed (colorectal, n = 1290 and other subspecialists, n = 2104) with a 30-day mortality of 11.6%. There was a significant reduction in mortality over time (2002–2006: 18.6% to 2012–2016: 6.8, P < 0.001). There was a significant reduction in open surgery (60% to 25.3%, P < 0.001) with increased conservative management (37.4% to 63.5%, P < 0.001), laparoscopic resection (0.1% to 4.9%, P < 0.001) and laparoscopic washout (0.1% to 5.7%, P < 0.001). Patients admitted under colorectal surgeons had lower mortality than other subspecialists (9.9% vs 12.4%, P = 0.027), which remained significant following multivariate adjustment (hazard ratio 1.44, P = 0.039). These patients had fewer stomas (13.9% vs. 21.0%, P = 0.001) and higher anastomosis rates (22.1% vs 15.8%, P = 0.004). Conclusion This study demonstrated considerable improvements in the management of perforated diverticulitis alongside the positive impact of subspecialisation on patient outcomes.

Background: Insufficient physical activity is one of four primary risk factors for non‐communicable diseases such as stroke, heart disease, type 2 diabetes, cancer and chronic lung disease. As few as one in five children aged 5 to 17 years have the physical activity recommended for health benefits. The outside‐school hours period contributes around 30% of children's daily physical activity and presents a key opportunity for children to increase their physical activity. Testing the effects of interventions in outside‐school hours childcare settings is required to assess the potential to increase physical activity and reduce disease burden. Objectives: To assess the effectiveness, cost‐effectiveness and associated adverse events of interventions designed to increase physical activity in children aged 4 to 12 years in outside‐school hours childcare settings. Search methods: We searched CENTRAL, MEDLINE, Embase, ERIC and SportsDISCUS to identify eligible trials on 18 August 2020. We searched two databases, three trial registries, reference lists of included trials and handsearched two physical activity journals in August 2020. We contacted first and senior authors on articles identified for inclusion for ongoing or unpublished potentially relevant trials in August 2020. Selection criteria: We included randomised controlled trials, including cluster‐randomised controlled trials, of any intervention primarily aimed at increasing physical activity in children aged 4 to 12 years in outside‐school hours childcare settings compared to usual care. To be eligible, the interventions must have been delivered in the context of an existing outside‐school hours childcare setting (i.e. childcare that was available consistently throughout the school week/year), and not set up in the after‐school period for the purpose of research. Two review authors independently screened titles and abstracts of identified papers with discrepancies resolved via a consensus discussion. A third review author was not required to resolve disagreements. Data collection and analysis: Two review authors independently extracted data and assessed the risk of bias of included trials with discrepancies resolved via a consensus discussion; a third review author was not required to resolve disagreements. For continuous measures of physical activity, we reported the mean difference (MD) with 95% confidence intervals (CIs) in random‐effects models using the generic inverse variance method for each outcome. For continuous measures, when studies used different scales to measure the same outcome, we used standardised mean differences (SMDs). We conducted assessments of risk of bias of all outcomes and evaluated the certainty of evidence (GRADE approach) using standard Cochrane procedures. Main results:We included nine trials with 4458 participants. Five trials examined the effectiveness of staff‐based interventions to change practice in the outside‐school hours childcare setting (e.g. change in programming, activities offered by staff, staff facilitation/training). Two trials examined the effectiveness of staff‐ and parent‐based interventions (e.g. parent newsletters/telephone calls/messages or parent tool‐kits in addition to staff‐based interventions), one trial assessed staff‐ and child‐based intervention (e.g. children had home activities to emphasise physical activity education learnt during outside‐school hours childcare sessions in addition to staff‐based interventions) and one trial assessed child‐only based intervention (i.e. only children were targeted). We judged two trials as free from high risk of bias across all domains. Of those studies at high risk of bias, it was across domains of randomisation process, missing outcome data and measurement of the outcome.There was low‐certainty evidence that physical activity interventions may have little to no effect on total daily moderate‐to‐vigorous physical activity compared to no intervention (MD 1.7 minutes, 95% CI –0.42 to 3.82; P = 0.12; 6 trials; 3042 children). We were unable to pool data on proportion of the OSHC session spent in moderate‐to‐vigorous physical activity in a meta‐analysis. Both trials showed an increase in proportion of session spent in moderate‐to‐vigorous physical activity (moderate‐certainty evidence) from 4% to 7.3% of session time; however, only one trial was statistically significant. There was low‐certainty evidence that physical activity interventions may lead to little to no reduction in body mass index (BMI) as a measure of cardiovascular health, compared to no intervention (SMD –0.17, 95% CI –0.44 to 0.10; P = 0.22; 4 trials, 1684 children). Physical activity interventions that were delivered online were more cost‐effective than in person. Combined results suggest that staff‐and‐parent and staff‐and‐child‐based interventions may lead to a small increase in overall daily physical activity and a small reduction or no difference in BMI. Process evaluation was assessed differently by four of the included studies, with two studies reporting improvements in physical activity practices, one reporting high programme satisfaction and one high programme fidelity. The certainty of the evidence for these outcomes was low to moderate. Finally, there was very low‐certainty evidence that physical activity interventions in outside‐school hours childcare settings may increase cardiovascular fitness.No trials reported on quality of life or adverse outcomes. Trials reported funding from local government health grants or charitable funds; no trials reported industry funding. Authors' conclusions: Although the review included nine trials, the evidence for how to increase children's physical activity in outside‐school hours care settings remains limited, both in terms of certainty of evidence and magnitude of the effect. Of the types of interventions identified, when assessed using GRADE there was low‐certainty evidence that multi‐component interventions, with a specific physical activity goal may have a small increase in daily moderate‐to‐vigorous physical activity and a slight reduction in BMI. There was very low‐certainty evidence that interventions increase cardiovascular fitness. By contrast there was moderate‐certainty evidence that interventions were effective for increasing proportion of time spent in moderate‐to‐vigorous physical activity, and online training is cost‐effective. Refereed/Peer-reviewed

In recent years, artificial intelligence (AI) has increased its prevalence in society with the potential to transform many aspects of our lives. AI is considered to be not just one but a number of technologies. Based on a combination of machine learning, neural networks, deep learning and natural language processing, AI has been demonstrated to perform better than humans in certain circumstances. With the increase in size and complexity of available data, the application of AI and related technologies specifically to medicine and healthcare provides possibilities for contributing to significant improvements in patient outcomes with regards to diagnosis and treatments. Questions remain however as to the extent to which human beings will be replaced by AI. With its potential to be transformation in medicine and healthcare, in this topical debate Lois Holloway and Eva Bezak debate the important evolving field of AI. Refereed/Peer-reviewed

Introduction Junior doctor changeover has been perceived as a period of increased risk to patients. However, there is a paucity of contemporary evidence into this ‘Changeover Effect’. The aim of this study was to evaluate the presence of an adverse patient effect during periods of junior doctor changeover. Method Data were requested on all patients aged 18 years or older admitted acutely under General Surgery in the North England between 2005-16. This included patient characteristics, diagnoses, co-morbidities, procedure codes, mortality and length of stay. Patients were included in the study if they were admitted during the ‘changeover week’; defined as the first day of the changeover followed by the six subsequent days. For junior trainees (FY1-CT2), this is the first Wednesday of August, December and April each year. For higher surgical trainees (ST3-8) the first Wednesday and October. Another week, four weeks prior, was chosen as a historical comparator. Results 61714 patients were included in this study. Patient characteristics did not vary between the cohorts. There was no difference in 30-day mortality between changeover and non-changeover groups (2.5% vs. 2.6%, p = 0.280) or length of stay (5.3 vs 5.2, p = 0.613). Changeover week was not a predictor of increased mortality (OR 1.06, p = 0.302) following multivariate adjustment. Further analysis of the first junior and higher specialty trainee periods, August and October respectively, showed no significant difference for measured outcomes. Conclusions This retrospective cohort study provides contemporary evidence that the ‘changeover effect’ does not exist in acute general surgical admissions in the UK.

Introduction Junior doctor changeover has been perceived as a period of increased risk to patients. However, there is a paucity of contemporary evidence of this ‘changeover effect’. The aim of this study was to evaluate the presence of an adverse patient effect during periods of junior doctor changeover. Methods Data were requested on all patients aged 18 years or older admitted acutely under General Surgery in the North of England between 2005 and 2016. This included patient characteristics, diagnoses, comorbidities, procedure codes, mortality and length of stay. Patients were included in the study if they were admitted during the ‘changeover week’; defined as the first day of the changeover followed by the six subsequent days. For junior trainees (FY1-CT2), this is the first Wednesday of August, December and April each year. For higher surgical trainees (ST3–ST8), it is the first Wednesday in October. Another week, four weeks prior, was chosen as a historical comparator. Results In total, 61,714 patients were included in this study. Patient characteristics did not vary between the cohorts. There was no difference in 30-day mortality between changeover and non-changeover groups (2.5% vs 2.6%, p = 0.280) or length of stay (5.3 vs 5.2, p = 0.613). Changeover week was not a predictor of increased mortality (OR 1.06, p = 0.302) following multivariable adjustment. Further analysis of the first junior and higher specialty trainee periods, August and October, respectively, showed no significant difference for measured outcomes. Conclusions This retrospective cohort study provides contemporary evidence that the ‘changeover effect’ does not exist in acute general surgical admissions in the UK.

Chronic pain and restricted knee motion is a significant problem following the total knee arthroplasty (TKA). The molecular pathogenesis of pain post‐TKA is not known and no targeted therapeutic intervention is available. The aim of this study was to investigate whether pro‐inflammatory mediators are elevated in revision knee patients, indicating an active, ongoing inflammatory process that may contribute to pain. Twelve key markers (pro‐inflammatory cytokines granulocyte‐macrophage colony‐stimulating factor [GM‐CSF], interleukin 5 [IL‐5], IL‐8 and IL‐10, chemokines CCL2, CCL3, CCL4, and CCL13, mediators of angiogenesis Flt‐1, vascular endothelial growth factor, and cell migration vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) were measured in knee tissue and synovial fluid (SF) from primary TKA (n = 29) and revision patients (n = 32). Indications for surgery were osteoarthritis (OA) for primary TKA, and component loosening (n = 11), stiffness (n = 11), laxity pattern (n = 8), or progression of OA in patella resurfacing (n = 3) for revision surgery. Pain levels (WOMAC score) were higher in revision than primary patients (p ≤ 0.05). Time from primary to revision ranged from 8 months to 30 years (median 10 years). All markers were elevated in revision TKA; there was no trend toward decreasing levels with greater time from primary surgery for any marker studied in SF. Similar results were seen in knee tissue. We found no differences comparing indications for revision surgery (p ≥ 0.05). The elevation of inflammatory mediators in painful post‐TKA knees requiring revision suggests active, chronic inflammation. Characterization of upregulated markers provides rationale for targeted therapy, even many years from the primary surgery. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2316–2324, 2019

BACKGROUND: Whole-body MRI (WB-MRI) could be an alternative to multimodality staging of colorectal cancer, but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in colorectal cancer.METHODS: The Streamline C trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed colorectal cancer. Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or polyp cancer. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs), and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN43958015, and is complete.FINDINGS: Between March 26, 2013, and Aug 19, 2016, 1020 patients were screened for eligibility. 370 patients were recruited, 299 of whom completed the trial; 68 (23%) had metastasis at baseline. Pathway sensitivity was 67% (95% CI 56 to 78) for WB-MRI and 63% (51 to 74) for standard pathways, a difference in sensitivity of 4% (-5 to 13, p=0·51). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (95% [95% CI 92-97]) and standard pathways (93% [90-96], p=0·48). Agreement with the multidisciplinary team's final treatment decision was 96% for WB-MRI and 95% for the standard pathway. Time to complete staging was shorter for WB-MRI (median, 8 days [IQR 6-9]) than for the standard pathway (13 days [11-15]); a 5-day (3-7) difference. WB-MRI required fewer tests (median, one [95% CI 1 to 1]) than did standard pathways (two [2 to 2]), a difference of one (1 to 1). Mean per-patient staging costs were £216 (95% CI 211-221) for WB-MRI and £285 (260-310) for standard pathways.INTERPRETATION: WB-MRI staging pathways have similar accuracy to standard pathways and reduce the number of tests needed, staging time, and cost.FUNDING: UK National Institute for Health Research.

Excess caloric intake results in increased fat accumulation and an increase in energy expenditure via diet-induced adaptive thermogenesis; however, the underlying mechanisms controlling these processes are unclear. Here we identify the neuropeptide FF receptor-2 (NPFFR2) as a critical regulator of diet-induced thermogenesis and bone homoeostasis. Npffr2−/− mice exhibit a stronger bone phenotype and when fed a HFD display exacerbated obesity associated with a failure in activating brown adipose tissue (BAT) thermogenic response to energy excess, whereas the activation of cold-induced BAT thermogenesis is unaffected. NPFFR2 signalling is required to maintain basal arcuate nucleus NPY mRNA expression. Lack of NPFFR2 signalling leads to a decrease in BAT thermogenesis under HFD conditions with significantly lower UCP-1 and PGC-1α levels in the BAT. Together, these data demonstrate that NPFFR2 signalling promotes diet-induced thermogenesis via a novel hypothalamic NPY-dependent circuitry thereby coupling energy homoeostasis with energy partitioning to adipose and bone tissue., Excess caloric intake leads to increased thermogenesis in brown adipose tissue, to limit weight gain. Here, the authors show that neuropeptide FF receptor-2 signalling promotes thermogenesis via control of NPY expression in the arcuate nucleus, and that it absence in mice leads to a failure of activation of diet-induced thermogenesis and the development of exacerbated obesity.

Background/Aims Sport and Exercise Medicine (SEM) can play a key role to help manage the increasing demands on NHS Rheumatology and Musculoskeletal services. The ‘Complex MSK clinic’ has been developed as a combined consultant-led service staffed by Rheumatologists and Sport and Exercise Medicine (SEM) physicians at the Oxford University Hospitals. Patients referred from primary care to the rheumatology services were allocated to this clinic via an internal triage process. The aim of this project was to identify the spectrum of diagnoses and the epidemiological characteristics of patients seen in the clinic to help develop patient pathways, optimise patient care, and to showcase this collaborative approach Methods A retrospective analysis of the electronic patient record (EPR) of 194 consecutive patients attending the Complex MSK Clinic between 1 October and 30 November 2019 was performed. Patient age, reason for referral, length of time to appointment, prior investigations and treatment were all recorded, as were the primary/secondary diagnoses made, investigations requested, treatment provided and follow up arrangements. 16 patients had missing data or did not attend their appointment, leaving 178 patients that were included in the analysis. Results Mean age at appointment was 49 (range 17-90). 86.5% of all referrals were made by Oxfordshire GPs , with the main reason for referral being diagnostic uncertainty (78%). Almost 1 in 4 patients were given a primary diagnosis of osteoarthritis (23.6%), of which 64.3% involved the hands. Other prominent diagnoses included chronic pain syndrome/fibromyalgia (20.2%), mechanical pain (15.7%), and inflammatory arthritis or spondyloarthritis (14.0%). The most common further management was referral to physiotherapy services (46.1%), with 23.6% of patients offered additional medication and 11.2% a therapeutic injection. 104 (58%) patients were discharged after their first appointment, with 52 (29%) followed up in the complex MSK service and only 22 (12%) referred to another specialist clinic. Conclusion This report illustrates the spectrum of diagnoses seen within this unique service, highlighting a role for both Rheumatology and SEM within the same clinic. The low onward referral rate demonstrates appropriate triage and an efficient approach that is appropriate for this cohort of patients. It could reduce overall costs and patient journeys. Further work is required to streamline patient pathways, evaluate patient satisfaction and to determine whether the clinic is cost-effective and improves patient pathways. Disclosure J.A. Navarajasegaran: None. J. Betts: None. J. Baldock: None. A. Soni: None. R. Smith: None.

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance. In osteoblasts (OBs), insulin signaling plays a crucial role in the control of systemic glucose homeostasis. We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states. Compared to the controls, chow-fed Rptorob−/− mice had substantially less fat mass and exhibited adipocyte hyperplasia. Remarkably, upon feeding with high-fat diet, mice with pre- and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels, increased glucose tolerance and insulin sensitivity. This leanness and resistance to weight gain was not attributable to changes in food intake, physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility. RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways, which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptor-knockout osteoblasts. Collectively, these findings point to a critical role for the mTORC1 complex in the skeletal regulation of whole-body glucose metabolism and the skeletal development of insulin resistance.

Background: Perceptions of neighbourhood attributes such as proximity of food retailers that are discordant with objective measures of the same are associated with poor health behaviours and weight gain. Factors associated with discordant perceptions are likely relevant to planning more effective interventions to improve health. Purpose: Analysis of cross-sectional relationships between individual and neighbourhood factors and overestimations of walking distances to local fruit/vegetable retailers (FVR). Methods: Perceived walking times, converted to distances, between participant residences and FVR were compared with objectively-assessed road network distances calculated with a Geographic Information System for n = 1305 adults residing in Adelaide, South Australia. Differences between perceived and objective distances were expressed as &lsquo, overestimated&rsquo, distances and were analysed relative to perceptions consistent with objective distances. Cross-sectional associations were evaluated between individual socio-demographic, health, and area-level characteristics and overestimated distances to FVR using multilevel logistic regression. Results: Agreement between objective and perceived distances between participants&rsquo, residence and the nearest FVR was only fair (weighted kappa = 0.22). Overestimated distances to FVR were positively associated with mental well-being, and were negatively associated with household income, physical functioning, sense of community, and objective distances to greengrocers. Conclusions: Individual characteristics and features of neighbourhoods were related to overestimated distances to FVR. Sense of connectivity and shared identity may shape more accurate understandings of local resource access, and offer a focal point for tailored public health initiatives that bring people together to achieve improved health behaviour.

Chronic pain is highly prevalent and more common in people with chronic obstructive pulmonary disease (COPD) than people of similar age/sex in the general population. This systematic review aimed to describe how frequently and in which contexts pain is considered in the clinical practice guidelines (CPGs) for the broad management of COPD. Databases (Medline, Scopus, CiNAHL, EMbase, and clinical guideline) and websites were searched to identify current versions of COPD CPGs published in any language since 2006. Data on the frequency, context, and specific recommendations or strategies for the assessment or management of pain were extracted, collated, and reported descriptively. Of the 41 CPGs (English n = 20) reviewed, 16 (39%) did not mention pain. Within the remaining 25 CPGs, pain was mentioned 67 times (ranging from 1 to 10 mentions in a single CPG). The most frequent contexts for mentioning pain were as a potential side effect of specific pharmacotherapies (22 mentions in 13 CPGs), as part of differential diagnosis (14 mentions in 10 CPGs), and end of life or palliative care management (7 mentions in 6 CPGs). In people with COPD, chronic pain is common; adversely impacts quality of life, mood, breathlessness, and participation in activities of daily living; and warrants consideration within CPGs for COPD. Refereed/Peer-reviewed

Medical physics can be one of the most rewarding applications of physics in day-to-day society's life. Hence, translational research in this particular field attracts a lot of interest given its potential impact on the delivery of patient care. The credibility of scientific discoveries and research outcomes reported in the scientific literature is driven by confidence in the integrity of scientists performing this research. However, scientific misconduct often blackens the image of scientific research and negatively impacts the faith society has in science.

BackgroundPaediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is common (prevalence 1%–2%). Two-thirds of children experience moderate or severe pain, which is associated with increased fatigue and poorer physical function. However, we do not know if treatment for CFS/ME improves pain.ObjectiveIdentify whether specialist treatment of paediatric CFS/ME improves pain.MethodsWe conducted a detailed search in MEDLINE, EMBASE, PsycINFO and the Cochrane Library. Two researchers independently screened texts published between 1994 and 24 January 2019 with no language restrictions. Inclusion criteria were (1) randomised controlled trials and observational studies; (2) participants aged ResultsOf 1898 papers screened, 26 studies investigated treatment for paediatric CFS/ME, 19 of which did not measure pain at any time point. Only five treatment studies measured pain at baseline and follow-up and were included in this review. None of the interventions were specifically targeted at treating pain. Of the included studies, two showed no improvement in pain scores, one suggested an improvement in one subgroup and two studies identified improvements in pain measures in ‘recovered’ patients compared with ‘non-recovered’ patients.ConclusionsDespite the prevalence and impact of pain in children with CFS/ME surprisingly few treatment studies measured pain. In those that did measure pain, the treatments used focused on overall management of CFS/ME and we identified no treatments that were targeted specifically at managing pain. There is limited evidence that treatment helps improve pain scores. However, patients who recover appear to have less pain than those who do not recover. More studies are needed to determine if pain in paediatric CFS/ME requires a specific treatment approach, with a particular focus on patients who do not recover following initial treatment.PROSPERO registration numberCRD42019117540.

The maintenance of whole body energy homeostasis is critical to survival and mechanisms exist whereby an organism can adapt to its environment and the stresses placed upon it. Environmental temperature and thermogenesis are key components known to affect energy balance. However, little is known about how these processes are balanced against the overall energy balance. We show that even mild cold exposure has a significant effect on energy expenditure and UCP-1 levels which increase by 43% and 400%, respectively, when wild-type (WT) mice at thermoneutral (29 °C) were compared to mice at room temperature (22 °C) conditions. Interestingly, bone mass was lower in cold-stressed WT mice with significant reductions in femoral bone mineral content (− 19%) and bone volume (− 13%). Importantly, these cold-induced skeletal changes were absent in mice lacking NPY, one of the main controllers of energy homeostasis, highlighting the critical role of NPY in this process. However, energy expenditure was significantly greater in cold-exposed NPY null mice, indicating that suppression of non-thermogenic tissues, like bone, contributes to the adaptive responses to cold exposure. Altogether, this work identifies NPY as being crucial in coordinating energy and bone homeostasis where it suppresses energy expenditure, UCP-1 levels and lowers bone mass under conditions of cold exposure.

To determine whether age and neuropeptide Y (NPY) were involved in the skeletal response to extended periods of diet-induced obesity. Male wild-type (WT) and NPY null (NPYKO) mice were fed a mild (23% fat) high-fat diet for 10 weeks from 6 or 16 weeks of age. Metabolism and bone density were assessed during feeding. Skeletal changes were assessed by microCT and histomorphometry. High-fat feeding in 6-week-old WT mice led to significantly increased body weight, adiposity and serum leptin levels, accompanied with markedly suppressed cortical bone accrual. NPYKO mice were less susceptible to fat accrual but, importantly, displayed a complete lack of suppression of bone accrual or cortical bone loss. In contrast, when skeletally mature (16 week old) mice underwent 10 weeks of fat feeding, the metabolic response to HFD was similar to younger mice, however bone mass was not affected in either WT or NPYKO. Thus, growing mice are particularly susceptible to the detrimental effects of HFD on bone mass, through suppression of bone accrual involving NPY signalling. This study provides new insights into the relationship between the opposing processes of a positive weight/bone relationship and the negative ‘metabolic’ effect of obesity on bone mass. This negative effect is particularly active in growing skeletons, which have heightened sensitivity to changes in obesity. In addition, NPY is identified as a fundamental driver of this negative ‘metabolic’ pathway to bone.

Background: Cortical bone is a significant determinant of bone strength and its deterioration contributes to bone fragility. Thin cortices and increased cortical porosity have been noted in patients with chronic kidney disease (CKD), but the “Turnover Mineralization Volume” classification of renal osteodystrophy does not emphasize cortical bone as a key parameter. We aimed to assess trabecular and cortical bone microarchitecture by histomorphometry and micro-CT in patients with CKD G5 and 5D (dialysis). Methods: Transiliac bone biopsies were performed in 14 patients undergoing kidney transplantation (n = 12) and parathyroidectomy (n = 2). Structural parameters were analysed by histomorphometry and micro-CT including trabecular bone volume, thickness (TbTh), number (TbN) and separation and cortical thickness (CtTh) and porosity (CtPo). Indices of bone remodelling and mineralisation were obtained and relationships to bone biomarkers examined. Associations were determined by Spearman’s or Pearson’s rank correlation coefficients. Results: By micro-CT, trabecular parameters were within normal ranges in most patients, but all patients showed very low CtTh (127 ± 44 µm) and high CtPo (60.3 ± 22.5%). CtPo was inversely related to TbN (r = –0.56; p = 0.03) by micro-CT and to TbTh (r = –0.60; p = 0.024) by histomorphometry and correlated to parathyroid hormone values (r = 0.62; p = 0.021). By histomorphometry, bone turnover was high in 50%, low in 21% and normal in 29%, while 36% showed abnormal patterns of mineralization. Significant positive associations were observed between osteoblast surface, osteoclast surface, mineralization surface and bone turnover markers. Conclusions: Deterioration of cortical ­microarchitecture despite predominantly normal trabecular parameters reinforces the importance of comprehensive cortical evaluation in patients with CKD.

Brown adipose tissue (BAT), largely controlled by the sympathetic nervous system (SNS), has the ability to dissipate energy in the form of heat through the actions of uncoupling protein-1 (UCP-1), thereby critically influencing energy expenditure. Besides BAT, the SNS also strongly influences bone, and recent studies have demonstrated a positive correlation between BAT activity and bone mass, albeit the interactions between BAT and bone remain unclear. Here we show that UCP-1 is critical for protecting bone mass in mice under conditions of permanent mild cold stress for this species (22°C). UCP-1-/- mice housed at 22°C showed significantly lower cancellous bone mass, with lower trabecular number and thickness, a lower bone formation rate and mineralising surface, but unaltered osteoclast number, compared to wild type mice housed at the same temperature. UCP-1-/- mice also displayed shorter femurs than wild types, with smaller cortical periosteal and endocortical perimeters. Importantly, these altered bone phenotypes were not observed when UCP-1-/- and wild type mice were housed in thermo-neutral conditions (29°C), indicating a UCP-1 dependent support of bone mass and bone formation at the lower temperature. Furthermore, at 22°C UCP-1-/- mice showed elevated hypothalamic expression of neuropeptide Y (NPY) relative to wild type, which is consistent with the lower bone formation and mass of UCP-1-/- mice at 22°C caused by the catabolic effects of hypothalamic NPY-induced SNS modulation. The results from this study suggest that during mild cold stress, when BAT-dependent thermogenesis is required, UCP-1 activity exerts a protective effect on bone mass possibly through alterations in central NPY pathways known to regulate SNS activity.

Wnt antagonist Dkk1 is a negative regulator of bone formation and Dkk1 +/− heterozygous mice display a high bone mass phenotype. Complete loss of Dkk1 function disrupts embryonic head development. Homozygous Dkk1 −/− mice that were heterozygous for Wnt3 loss of function mutation (termed Dkk1 KO) are viable and allowed studying the effects of homozygous inactivation of Dkk1 on bone formation. Dkk1 KO mice showed a high bone mass phenotype exceeding that of heterozygous mice as well as a high incidence of polydactyly and kinky tails. Whole body bone density was increased in the Dkk1 KO mice as shown by longitudinal dual-energy X-ray absorptiometry. MicroCT analysis of the distal femur revealed up to 3-fold increases in trabecular bone volume and up to 2-fold increases in the vertebrae, compared to wild type controls. Cortical bone was increased in both the tibiae and vertebrae, which correlated with increased strength in tibial 4-point bending and vertebral compression tests. Dynamic histomorphometry identified increased bone formation as the mechanism underlying the high bone mass phenotype in Dkk1 KO mice, with no changes in bone resorption. Mice featuring only Wnt3 heterozygosity showed no evident bone phenotype. Our findings highlight a critical role for Dkk1 in the regulation of bone formation and a gene dose-dependent response to loss of DKK1 function. Targeting Dkk1 to enhance bone formation offers therapeutic potential for osteoporosis.

Purpose: The main goal in treating knee osteoarthritis (OA) is providing symptom relief, with a continued focus on easing joint pain and enabling mobility, in order for patients to go about daily activity. With the COVID-19 pandemic having impacted healthcare systems and regimes globally, the aim of this study is to understand how treatment management of knee OA patients and prescribing behavior across US healthcare professionals (HCPs) was affected, and how they adapt towards a potential ‘new norm’ in treating this condition. Methods: A cross-sectional chart review survey was conducted in both Q2 2019 and Q2 2020 among US board-certified rheumatologists (rheums), orthopedic surgeons (orthos), primary care physicians with a focus in sports medicine (SM PCPs), and pain specialists, all practicing across hospital and private practices. Recruited from a large access panel, physicians were screened for duration of practice in their specialty (3-50 years) and caseload (35 or more knee OA patients personally managed, at least 10 of which must be classified as moderate-severe). Participants were asked to complete a 3-part online survey: (1) a doctor demographic questionnaire, (2) a perceptual questionnaire, assessing perception of available and upcoming OA therapies, and (3) patient record charts for the next 5 knee OA patients seen following receipt of the survey, capturing demographics and treatment history. Data were analyzed using descriptive statistics. Results: The total number of sampled physicians recruited in this survey with their reported patient totals are stated in Table 1. [Formula presented] When focusing on the current prescription medication reported patients are receiving, oral medications, particularly NSAIDs, are widely used, regardless of the physician specialty. Here we see a directional increase in the proportion of reported patients deriving from sampled primary care SM PCPs from pre-COVID (Q219) to during COVID (Q220) (not statistically significantly different), whilst the same is not true for the other three secondary care sampled specialties, namely rheums, orthos and pain specialists (not statistically significantly different) - see Fig. 1. [Formula presented] [Formula presented] [Formula presented] Conclusions: From the sample surveyed, it appears that primary care SM PCPs adopted their treatment adjustment during COVID-19 pandemic differently, by prescribing more orals while other secondary care physicians (rheums, orthos, pain specialists) focused on injection treatment for longer pain relief. Considering movement restrictions and limited elective surgeries during the pandemic, the lack of targeted treatment options for knee OA has been made more apparent. With a burgeoning pipeline, many of which are targeted therapies, it is hopeful that knee OA treaters will be less reliant on symptom remedies and can readily offer patients’ longer-acting pain relief or disease modifying options to combat joint deterioration.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed &gt, 1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p &lt, 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.

Importance: The focus of occupational therapy is often on personal care, life skills, and daily living. Sport, as a type of leisure activity, can also provide benefits to health and well-being. Occupational therapy practitioners should therefore promote the role of sport in the lives of clients. Objective: To investigate the extent, range, and nature of peer-reviewed occupational therapy literature investigating sport as a leisure occupation. Data Sources: The following databases were searched: Embase, MEDLINE, OTseeker, PsycINFO, PubMed, and SPORTDiscus. Study Selection and Data Collection: We identified published studies investigating competitive sport in occupational therapy research or practice. Included studies investigated adult participants (age ≥18 yr) participating in sport, had a clear occupational therapy input, and were written in the English language. Findings: Six studies met the inclusion criteria. Only 2 of the 6 studies identified through the search strategy were conducted after 2004, diagnosis and outcome measures varied widely, and sport as a leisure occupation was found to have positive individual outcomes. Conclusions and Relevance: Opportunities exist to investigate sport as a leisure occupation and its involvement in occupational therapy practice. Future research may contribute to positive outcomes and experiences for clients who receive occupational therapy. What This Article Adds: This scoping review describes literature about sport as an occupation and highlights the opportunities for practitioners and researchers to incorporate sport as a leisure occupation.

Much research has considered the relationship between neighbourhood crime and physical activity, but few studies have assessed clinical outcomes consequent to behaviour, such as cardiometabolic risk. Fewer still have simultaneously assessed perceived and objective measures of crime. Perceptions of crime and actual victimisation vary according to gender;thus, this study sought to assess: 1) correspondence between perceived and objective neighbourhood crime; and 2) gender-specific associations between perceived and reported crime and metabolic syndrome, representing cardiometabolic risk. The indirect effect of neighbourhood crime on metabolic syndrome via walking was additionally evaluated. An Australian population-based biomedical cohort study (2004±2007) collected biomedical, socio-demographic, and neighbourhood perceptions data from n = 1,172 urban-dwelling,adults. Area-level reported crime rates were standardised and linked to individual databased on participants' residential location. Correspondence between actual and perceived crime measures was assessed using Pearson correlation coefficients. Cross-sectional associations between crime and metabolic syndrome were analysed using generalised estimating equations regression models accounting for socio-demographic factors and area level income. Correspondence between perceived and objective crime was small to medium among men and women (r = 0.17 to 0.33). Among men, metabolic syndrome was related to rates of violent (OR = 1.21, 95% CI 1.08±1.35) and total crime (OR = 1.17, 95% CI 1.04±1.32), after accounting for perceived crime. Among women, metabolic syndrome was related to perceived crime (OR = 1.35, 95% CI 1.14±1.60) after accounting for total reported crime. Among women, there were indirect effects of perceived crime and property crime on metabolic syndrome through walking. Results indicate that crime, an adverse social exposure,is linked to clinical health status. Crime rates, and perceptions of crime and safety, differentially impact upon cardiometabolic health according to gender. Social policy and public health strategies targeting crime reduction, as well as strategies to increase perceptions of safety, have potential to contribute to improved cardiometabolic outcomes. Refereed/Peer-reviewed

Background:Though the pathogenesis of knee osteoarthritis (OA) is complex, patients with OA frequently have other comorbidities, including hypertension, which eludes to other considerations needed when deciding appropriate treatment management.Objectives:This study aims to examine the profiles of knee OA patients with hypertension vs. those without any comorbidities, and to elucidate key differences between these patient groups as potential areas of consideration.Methods:A multi-center, online medical chart review study of patients with OA was conducted between May – July 2020 among US rheumatologists (rheums), orthopedic surgeons (orthos), primary care physicians with a focus in sports medicine (SM PCPs), and pain specialists. Physicians recruited were screened for duration of practice in their specialty (3-50 years) and caseload (>=35 knee OA patients personally managed, at least 10 being moderate-severe). Patient charts were recorded for the next 5 eligible patients seen during the screening period. Respondents abstracted patient demographics and treatments used. Descriptive statistics were used to analyse the data.Results:260 physicians were recruited and collectively reported 796 knee OA patients; 559 were reported to experience hypertension whilst 237 were reported as not experiencing any comorbidities.Reported hypertension patients were significantly older (mean 67 vs 59 years old, respectively; p≤0.01) and weighed more (mean 82kg vs 77kg, respectively; p≤0.01) than patients without comorbidities; they were also significantly more likely to be previous smokers compared to those without comorbidities (23% vs 8%, respectively; p≤0.01). With regards to current knee OA severity, both orthos and SM PCPs reported a significantly higher proportion of hypertension patients that were deemed ‘severe’ (physician opinion) vs patients without comorbidities (orthos: 50% vs 32%, respectively; SM PCPs: 42% vs 23%, respectively; p≤0.01).Rheums and pain specialists reported greater mild opioid usage amongst hypertension patients compared to those without comorbidities (rheums: 28% vs 10%, respectively (p≤0.05); pain specialists: 40% vs 9%, respectively; (p≤0.01)); orthos and SM PCPs stated significantly greater use of corticosteroid injections amongst their reported hypertension patients vs those without comorbidities (orthos: 60% vs 41%, respectively; SM PCPs: 40% vs 19%, respectively; p≤0.01). Hypertension patients reported by orthos and SM PCPs are more likely to be considered for total knee replacement (TKR) surgery compared to those without comorbidities (orthos: 59% vs 32%, respectively; SM PCPs: 37% vs 19%, respectively; p≤0.01). Conversely, hypertension patients reported by rheums are less likely to be considered for TKR vs those without comorbidities (41% vs 18%, respectively; p≤0.05).Reported hypertension patients had a significantly higher mean Visual Analogue Scale for Pain (VAS) score than patients without comorbidities (6.6 vs 5.9, respectively; p≤0.01). A significantly higher proportion of patients with hypertension demonstrate radiographic evidence of bone erosion compared to those without comorbidities (69% vs 56%, respectively; p≤0.01).Conclusion:From the sample surveyed, knee OA patients with hypertension may require a more specific and holistic treatment approach that takes into account their CV status and managing physician specialty. Further investigation using comparator cohort is warranted.References:[1]Ipsos Osteoarthritis Therapy Monitor (May – July 2020, 260 specialists reporting on 769 knee OA patients seen in consultation, data collected online. Participating physicians were primary treaters and saw a minimum number of 35 knee OA patients). Data © Ipsos 2021, all rights reserved.[2]Ipsos Osteoarthritis Therapy Monitor (May – July 2020, 260 specialists reporting on 769 knee OA patients seen in consultation, data collected online. Participating physicians were primary treaters and saw a minimum number of 35 knee OA patients). Data © Ipsos 2021, all rights reserved.Disclosure of Interests:None declared.

Background:Knee Osteoarthritis (OA) treatment aims to provide symptom relief, easing joint pain and enabling mobility. The COVID-19 pandemic affected healthcare systems globally, including ways OA patients were treated.Objectives:This study is to understand how treatment management of knee OA patients and prescribing behavior across US healthcare professionals (HCPs) was affected when COVID-19 impacted healthcare systems and regimes globallyMethods:A multi-center online medical chart review study of patients with OA was conducted between May – July 2019 & 2020 among US rheumatologists (rheums), orthopedic surgeons (orthos), primary care physicians with a focus in sports medicine (SM PCPs), and pain specialists, practicing across hospital and private practices. Recruited from a large access panel, physicians were screened for duration of practice in their specialty (3-50 years) and caseload (35 or more knee OA patients personally managed, at least 10 of which must be classified as moderate-severe). Patient charts were recorded for the next 5 eligible patients seen during the screening period. Respondents abstracted patient demographics and treatment regimes used. Descriptive statistics were used to analyse the dataResults:275 physicians were recruited and collectively reported 1375 patients between May-Jul 2019; 260 physicians were recruited and collectively reported 1300 patients between May-Jul 2020.Looking at treatments patients were receiving at time of reporting, oral medications, particularly NSAIDs, were widely used, regardless of the physician specialty. A directional increase of 6% in the proportion of reported patients deriving from sampled primary care SM PCPs from pre-COVID (Q219) to during COVID (Q220), whilst the same is not true for rheums, orthos, and pain specialists.Figure 1.Medication usage in reported knee OA patients across all sampled specialties - Q2 2019 vs Q2 2020With regards to the usage of injectable therapy, the opposite pattern is seen - higher proportions of reported patients deriving from sampled rheums, orthos & pain specialists receiving injectables vs those deriving from sampled SM PCPs. While focusing on orthos, the proportion of reported patients deriving from them who receive injectables grew by 5% in Q220 (during COVID) vs Q219 (pre-COVID) – directionally more so than other specialties. This is possibly due to limited elective surgeries during the pandemic.Looking deeper into injectable usage amongst reported patients deriving from sampled rheums and orthos, the proportion of the total reported patient set receiving this treatment type is relatively similar across both specialties, prior to, and during the COVID-19 pandemic. However, among reported patients who received surgery, a directionally higher proportion of this reported patient cohort deriving from orthos are noted to receive injectables vs those from rheums – this is true both pre- and during the pandemic.Conclusion:From the sample surveyed, it appears that primary care SM PCPs adopted their treatment adjustment during COVID-19 pandemic differently, by prescribing more orals, while other secondary care physicians (rheums, orthos, pain specialists) focused on injection treatment for longer pain relief. Considering movement restrictions and limited elective surgeries during the pandemic, the lack of targeted treatment options for knee OA has been made more apparent. With a burgeoning pipeline, many of which are targeted therapies, it is hopeful that knee OA treaters will be less reliant on symptom remedies and can readily offer patients’ longer-acting pain relief or disease modifying options to combat joint deteriorationReferences:[1]Ipsos Osteoarthritis Therapy Monitor (May – July 2019, 275 specialists reporting on 1375 OA patients seen in consultation; May – July 2020, 260 specialists reporting on 1300 OA patients seen in consultation, data collected online. Participating physicians were primary treaters and saw a minimum number of 35 knee OA patients). Data © Ipsos 2021, all rights reserved.Disclosure of Interests:None declared.

Objectives Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla. Methods To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis. Results By specifically targeting the insulin receptor in both fly and mouse NPY expressing neurons, we found NPY-specific insulin signaling controls food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype. Additionally, the lack of insulin signaling in NPY neurons leads to a dysregulation of GH/IGF-1 axis and to altered insulin sensitivity. Conclusions Taken together, these results suggest that insulin actions in NPY neurons is critical for maintaining energy balance and an impairment of this pathway may be causally linked to the development of metabolic diseases., Graphical abstract Image 1, Highlights • Insulin controls feeding via non-AgRP expressing NPY-neurons in flies and mice. • Energy expenditure is regulated by insulin responsive NPY neurons. • Insulin signaling in NPY neurons is required for maintaining whole body glucose homeostasis and insulin sensitivity. • Central insulin-NPY pathways regulate bone mass and growth development.

The autopsy files at Forensic Science South Australia were searched over an 11-year period from January 2008 to December 2018 for all cases of motorcycle fatalities in which there had been lower-limb amputations. Six cases were identified, consisting of five male riders and one female pillion passenger. The age range was 48–67 years (average 59 years), which was significantly older than the control group (40.6 years; p 2 (average 34.9 kg/m2), which again was significantly greater than the control group (28.8 kg/m2; p

AIM To evaluate the association between the image quality of cancer staging whole-body magnetic resonance imaging (WB-MRI) and patient demographics, distress, and perceived scan burden. MATERIALS AND METHODS A sample of patients recruited prospectively to multicentre trials comparing WB-MRI with standard scans for staging lung and colorectal cancer were invited to complete two questionnaires. The baseline questionnaire, administered at recruitment, collated data on demographics, distress and co-morbidity. The follow-up questionnaire, completed after staging investigations, measured perceived WB-MRI scan burden (scored 1 low to 7 high). WB-MRI anatomical coverage, and technical quality was graded by a radiographic technician and grading combined to categorise the scan as “optimal”, “sub-optimal” or “degraded”. A radiologist categorised 30 scans to test interobserver agreement. Data were analysed using the chi-square, Fisher's exact, t-tests, and multinomial regression. RESULTS One hundred and fourteen patients were included in the study (53 lung, 61 colorectal; average age 65.3 years, SD=11.8; 66 men [57.9%]). Overall, 45.6% (n=52), scans were classified as “optimal” quality, 39.5% (n=45) “sub-optimal”, and 14.9% (n=17) as “degraded”. In adjusted analyses, greater deprivation level and higher patient-reported scan burden were both associated with a higher likelihood of having a sub-optimal versus an optimal scan (odds ratio [OR]: 4.465, 95% confidence interval [CI]: 1.454 to 13.709, p=0.009; OR: 1.987, CI: 1.153 to 3.425, p=0.013, respectively). None of the variables predicted the likelihood of having a degraded scan. CONCLUSIONS Deprivation and patients' perceived experience of the WB-MRI are related to image quality. Tailored protocols and individualised patient management before and during WB-MRI may improve image quality.

Background: Following LOE for the originator brand of etanercept in 2016 and the subsequent launch of its first biosimilar version, several other biosimilars have arrived in the rheumatoid arthritis treatment space. Due to their potential for reducing healthcare spend and their supposed equivalence, biosimilars are expected to be of rising relevance and impact in the following years. 12 biosimilar brands of biologic originator treatments are now available in Europe to treat rheumatoid arthritis; it will be crucial to understand physician perceptions of biosimilars relative to branded products and the impact such views have on potential prescribing decisions. Objectives: The objective of the study was to assess perceptions of efficacy and safety for biosimilars relative to branded biologic originator products among treating Rheumatologists in the EU5 countries (United Kingdom (UK), France (FR), Italy (IT), Spain (SP) and Germany (DE)). Methods: A cross-sectional survey was conducted in Q3 2018 in the EU5 among national, regional and hospital physicians who had been practicing between 3-30 years. Respondents completed a Physician Perceptual Questionnaire online, which assessed the overall perception of biologic brands and anti-TNF biosimilars, important attributes for treatments, and specific barriers to prescribing them. Data were analyzed using descriptive statistics. Results: A total of 261 rheumatologists in the EU5 were recruited as part of the study (with almost equal numbers of rheumatologists representing each EU5 country). Treating rheumatologists were practicing for an average of 17.4 years, mainly in teaching hospitals (50.2%) and urban hospitals (20.7%)1. Physicians consistently expressed greater satisfaction for branded products, with 73.9% (range: 63.5% DE to 90.6% FR) of physicians having rated satisfaction with the originator brand of etanercept as a 6 or 7 (on a 7-point scale where 7 corresponded to highest satisfaction), compared to only 37.5% for biosimilar etanercept (range: 28.6% IT to 51.9% DE)1. When asked about specific attributes related to RA treatments, 64.4% of our sampled rheumatologists associated the originator brand of rituximab with ‘Inhibition of radiographic progression’ (range: 55.1% IT to 81.1% FR) – versus 47.5% association for biosimilar rituximab (range: 32.7% IT to 62.3% FR)1. 73.2% of physicians associated the originator brand of infliximab with ‘helps maintain or improve physical function’ (range: 55.8% DE to 87.0% ES) compared to 58.6% of biosimilar infliximab (range: 44.9% IT to 67.9% FR)1. For ‘reduction in morning stiffness’, 78.5% of our rheumatologists associated it with originator etanercept (range: 65.4% DE to 88.7% FR) versus only 66.7% for biosimilar etanercept (range: 55.1% IT to 81.1% FR)1. Conclusion: Biosimilars score lower on overall satisfaction and are less frequently associated with specific efficacy attributes relative to branded products. This is possibly due to their relatively short time in clinical practice, and the resulting lack of experience and supporting data compared to the older branded equivalents. Proof of concept may be essential to close the perceptual gap that still exists between branded products and biosimilars. References: [1] Ipsos RA Therapy Monitor (261 sampled rheumatologists reporting on RA patients in EU5 in Q32018) Disclosure of Interests: None declared

Objective To evaluate the incidence of undiagnosed celiac disease (CD) in patients presenting with bone stress injuries (BSI) to a NHS Sport and Exercise Medicine (SEM) clinic. Design Retrospective cohort study. Setting Single tertiary-level SEM clinic. Patient/participants One hundred consecutive patients with radiologically proven BSIs. Interventions Laboratory blood tests (LBT) can unmask underlying metabolic bone disorders. Anti-tissue transglutaminase antibody (TTG) testing has a high sensitivity and specificity for CD. In this SEM clinic, clinicians were encouraged to perform LBT including TTG, at time of diagnosis of BSI. A retrospective analysis of age, sex, fracture site, co-morbidities, TTG result, and subsequent investigations was performed. Main outcome measures The primary outcome was the number and percentage of patients with BSIs and either positive TTG (CD seropositivity) or a diagnosis of CD. Results Of the 100 patients with radiologically proven BSIs, 70% were female, and the mean age was 37 years (range 16-69). Eighty-five percent had the appropriate LBTs, of which 70% (60/85) were female, and the mean age was 37(16-69). Metatarsal (35%) and tibial (21%) were the most common BSIs. Anti-tissue transglutaminase antibody was performed in 85 patients. Two patients (2/85) had pre-existing CD and were excluded from incidence calculations. Five patients [5/83 (6%), mean age 38 years (28-57), 80% female] had a positive TTG, of whom 3 have subsequently had CD confirmed by endoscopic biopsy. Four patients with a positive TTG underwent dual-energy X-ray absorptiometry with osteopenia found in 3 (75%) cases. Conclusions In this cohort, the incidence of CD seropositivity was 6%, and the prevalence of biopsy-confirmed CD was 5%, approximately 5-fold higher than UK population estimates. Anti-tissue transglutaminase antibody screening for CD should be considered in all patients presenting with BSIs.

Introduction Stress fractures, fatigue-induced bone fractures caused by repetitive mechanical stress, are often multifactorial in nature and are associated with a number of metabolic bone disorders. Whilst the association between coeliac disease (CD) and osteoporosis is well-recognised, it is unclear whether an association between CD and stress fractures exists, with only rare case reports in the literature. This study aimed to examine the incidence of CD in a prospective cohort of patients presenting with stress fractures to a specialist NHS Sport and Exercise Medicine (SEM) clinic. Methods An analysis of a prospective cohort of 100 consecutive patients with radiologically-proven stress fractures who presented to a single tertiary UK SEM clinic was performed. Electronic health records were used to examine fracture site, comorbidities, tissue transglutaminase (TTG) result, biochemistry, haematinics, dual energy x-ray absorptiometry, and endoscopy findings. Results Seventy patients in the cohort were female (70%) and the mean age was 37 years (range 18–69). Two patients had pre-existing coeliac disease (2%). Coeliac serology was performed for 85 patients (85%), with 5 additional patients found to have a positive TTG (5% of cohort, 6% of those tested). CD was confirmed by endoscopic biopsy in three patients, with two not undergoing endoscopy locally due to their geographic location, giving a prevalence of CD in this cohort of 5–7%. The most common site of fracture was the metatarsals (5/7, 71%), with hallux sesamoid and fibula fractures detected in one patient each respectively. Six patients with possible or confirmed CD underwent DEXA. No patients had osteoporosis, with osteopenia (T-Score between -1.0 and -2.5) found in three patients (3/6, 50%). Coexistent vitamin and mineral deficiency were common in the CD patients (iron, 2/6 (33%); vitamin B12, 2/5 (40%); folate, 1/4 (25%); vitamin D, 2/6 (33%)). Conclusions In this cohort of patients with stress fractures, the prevalence of CD was between 5% and 7%, approximately 5-fold higher than general UK population estimates. Screening for CD with serological testing should be considered in all patients presenting with stress fractures. Stress fractures were not associated with osteoporosis in the patients with CD, and only 50% had osteopenia, suggesting that coeliac disease and the associated malabsorption leads to stress fracture via mechanisms separate from reduced bone density.

Fractures are a common injury among motorcycle riders and can have serious health implications. Impact protection (IP) has been designed to help prevent fractures, yet there are conflicting opinions as to whether this IP does in fact help prevent fractures in real-world crashes. This work aimed to (1) use simulated dummy impacts to examine whether existing types of IP could reduce the force transferred to the underlying bone to below fracture tolerance levels and (2) investigate whether current European Standard (EN 1621-1) test procedures for impact protectors designed for motorcyclists are sufficient to ensure fracture protection.Twenty-three shoulder and 7 knee IP specimens were tested using a 23-kg impactor contacting axially along the clavicle and femur of an anthropomorphic test device (ATD) at an energy level corresponding to the fracture tolerance of these bones. Sixteen IP specimens were the same as those worn by motorcycle riders involved in crashes where injury outcome was known (knee: n = 3; shoulder: n = 13) and the IP had been previously tested to EN 1621-1. Other IP tested represented a wide range of IP available for purchase at a motorcycle accessory store. Double and triple layers of IP were also tested. Energy attenuated during the dummy impacts was compared to energy attenuated when tested to EN 1621-1.Of the 23 shoulder IP tested, the average percentage reduction of transferred force to the shoulder from the baseline test was 7.6 ± 4.8%. The percentage reduction of transferred force to the knee from the baseline was 43.9 ± 7.5%. The entire group of knee IP tested reduced the transferred force to the knee to below the 10-kN injury threshold for the femur. There was a positive but nonsignificant correlation between the ATD test and the EN 1621-1 impact test performance, suggesting that the European standard test method likely provides a good indication of IP performance. However, given the low correlation coefficient, the relationship between IP performance in the European standard test method and injury protection remains unclear.Though the energy attenuation test method in the European standard may be an appropriate approach, distinct differences in injury protection performance observed between knee and shoulder IP indicate that there may be a need for different performance criteria for IP designated to protect different body regions.

The endocrine system plays a crucial role in regulating the activity of cells and organs among vertebrates, including the class Chondrichthyes. Accordingly, Chondrichthyan endocrinology publications have been steadily increasing in the global literature. However, while interest in South American Chondrichthyan research has been growing over the last 50 years, the field of endocrinology related to Chondrichthyans has been limited. Understanding the trajectory of a scientific discipline assists researchers and stakeholders in making decisions regarding which research areas require further attention. Further, visualisation techniques based on bibliometric analysis of scientific publications assist in understanding fluctuations in the trends of specific research fields over time. In this study, Chondrichthyan research publications over time were analysed by creating visualisation maps using VOSviewer bibliometric software. Trends in South America Chondrichthyan research with an emphasis on endocrinology were explored over a 50-year period (1967–2016). These trends were compared with Chondrichthyans research worldwide for the more recent 15-year period (2002–2016). The number of South America Chondrichthyan scientific publications increased from six during the 1967–1981 period to 112 in 2016. However, only eight papers were found published in the area of Chondrichthyan endocrinology research. Fisheries, reproduction and taxonomy were the dominate research areas in South America over the 50 years. For the more recent 15 years, South American publications comprised 11% of the total literature published globally. While South America research outputs fluctuated closely with global research trends, differences appeared when comparing areas of growth. This study describes the trends in Chondrichthyan research literature globally and more specifically in South America. Although South American countries may never contribute to the same scale as the wider international scientific community, the future of Chondrichthyans would strongly benefit from the contributions of the many diverse research groups around the world. Fil: Awruch, Cynthia Andrea. University of Tasmania; Australia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina Fil: Somoza, Gustavo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Baldock, Clive. University of Tasmania; Australia