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Objective: The aim of this study was to apply sequence analysis (SA) to phenotype healthcare patterns of adult patients with musculoskeletal (MSK) conditions using primary care electronic health records and to investigate the association between these healthcare patterns and post-consultation patient's self-reported outcome., Methods: Data from the Multi-level Integrated Data for musculoskeletal health intelligence and ActionS (MIDAS) programme conducted in North Staffordshire and Stoke-on-Trent, UK was utilised. The study included patients aged ≥18 years who consulted primary care for MSK conditions between September 2021 and July 2022. SA was employed to categorise patients with similar healthcare patterns in primary care in the five years prior to their index consultation in respect to consultations, analgesic prescriptions, imaging, physiotherapy, and secondary care referrals. Association of socio-demographic characteristics and self-reported outcome with clusters were determined., Results: In total, 1,875 patients consulting primary care for MSK conditions were available for analysis. SA identified five clusters of prior healthcare patterns among patients with MSK conditions, including "increasing consultation and analgesia" (5.60%), "low consultation and healthcare use" (57.39%), "high consultation and healthcare use" (8.32%), "low consultation but high analgesia" (13.01%), and "low consultation but moderate healthcare use" (15.68%). Patients in the "high consultation and healthcare use" group were predominantly female, older, obese, had more comorbidities and lived in the most deprived areas compared to those in the "low consultation and healthcare use" group. Additionally, self-reported outcome varied significantly between clusters, with patients in the "high consultation and healthcare use" group reporting worse self- reported outcome., Conclusion: This analysis identified five distinct clusters of healthcare patterns for patients with MSK conditions in primary care and observed substantial variations in patient's self-reported outcome and socio-demographic profiles across these different groups of patients., (This article is protected by copyright. All rights reserved.)

Background: Abbreviation use in clinical and academic cardiology is widespread, yet there are few guidelines regulating the creation and utilization of abbreviations. Inconsistent abbreviations can introduce ambiguity and pose challenges to practice and research., Objectives: The authors aimed to analyze how abbreviations are created and utilized in general cardiology and cardiac imaging society guidelines in order to assess whether ambiguities and discrepancies exist between societies., Methods: Abbreviation data were collected from 7 national and international societies of general cardiology and cardiac imaging over a 6-year span (2018-2023). Data were linguistically coded for abbreviation type, unique occurrence, meaning or sense count, and frequency of discrepancy between societies., Results: Among a total of 5,394 abbreviation tokens, there were 1,782 unique entries. Among the unique entries, 227 (12.7%) had 2 or more associated meanings (senses), and thus were potentially ambiguous. Cardiac societies differed from each other, and also internally, in their use of abbreviations, with the European Society of Cardiology representing the highest frequency of discrepant abbreviation usage (14.5%)., Conclusions: More than 12.7% of abbreviations in cardiology society guidelines had 2 or more corresponding meanings, potentially increasing the risks of miscommunication and misrepresentation. We call on cardiology and cardiac imaging societies to define and publish best practices regarding abbreviation creation and utilization., Competing Interests: This research did not receive any specific grant funding from any public or private sources. Dr Hill is a consultant for Philips Healthcare. Dr Mitchell reports author textbook chapters with Elsevier and contracted research grants from W. L. Gore & Associates to University of Wisconsin-Madison, consulting Acoustic Range Estimates. Dr Rigolin owns stock ownership in Amgen, Edwards, Intuitive Surgical, Organon, Rednivia, Regeneron, AstraZeneca, Bristol Myers Squibb, Merck/Schering-Plough, Pfizer, and Viatris. Dr Strom received research grants from the National Heart, Lung, and Blood Institute (1R01HL169517) and National Institute of Aging (1R01AG063937), Anumana, Philips Healthcare, EVERSANA Lifesciences, and Bracco Diagnostics; reports consulting for Bracco Diagnostics, Edwards Lifesciences, Philips Healthcare, General Electric Healthcare, and EVERSANA, and is a scientific advisory board member for Ultromics, HeartSciences, Bristol Myers Squibb, and EchoIQ. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the official views of the NHLBI, NIH, or the United States Department of Health and Human Services., (© 2025 The Authors.)

Introduction: This study evaluated the hypothesis that vascular aging (VA) reduces ventricular contractile function and mechanical efficiency (ME) using the left ventricular pressure-volume (PV) construct., Methods: A previously published in-silico computational model (CM) was modified to evaluate the hypothesis in two phases. In phase I, the CM included five settings of aortic compliance ( C A ) from normal to stiff, studied at a heart rate of 80 bpm, and phase II included the normal to stiff C A settings evaluated at 60, 100, and 140 bpm. The PV construct provided steady-state and transient data through a simulated vena caval occlusion (VCO). The steady-state data included left ventricular volumes (EDV and ESV), stroke work (SW), and VCO provided the PV area (PVA) data in addition to the three measures of contractile state (CS): end-systolic pressure-volume relationship (ESPVR), dP/dt max -EDV and preload recruitable stroke work (PRSW). Finally, ME was calculated with the SW/PVA parameter., Results: In phase I, EDV and ESV increased, as did SW and PVA. The impact on the CS parameters demonstrated a small decrease in ESPVR, no change in dP/dt max -EDV, and a large increase in PRSW. ME decreased from 71.5 to 60.8%, respectively. In phase II, at the normal and stiff C A settings, across the heart rates studied, EDV and ESV decreased, ESPVR and dP/dt max -EDV increased and PRSW decreased. ME decreased from 76.4 to 62.6% at the normal C A and 65.8 to 53.2% at the stiff C A ., Discussion: The CM generated new insights regarding how the VA process impacts the contractile state of the myocardium and ME., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Mulligan, Thrash, Mitrev, Folk, Exarchakis, Ewert and Hill.)

Objectives: To explore the acceptability of an optimised physiotherapy (OPTimisE) intervention for people with lateral elbow tendinopathy (LET) and feasibility of comparing it to usual care in a randomised controlled trial., Design: Semistructured interviews, analysed using thematic analysis and mapped onto the COM-B model of behaviour change., Setting: Conducted as part of the OPTimisE Pilot & Feasibility randomised controlled trial within physiotherapy departments in the United Kingdom National Health Service., Participants: 17 patients with LET (purposively sampled to provide representativeness based on age, sex, ethnicity, deprivation index and treatment allocation) and all 8 physiotherapists involved as treating clinicians or site principal investigators., Results: Four themes were identified. First, participants reported the OPTimisE intervention as acceptable. Second, differences between the OPTimisE intervention and usual care were identified, including the use of an orthosis, holistic advice/education including modifiable risk factors, forearm stretches, general upper body strengthening and a more prescriptive exercise-dosing regimen. Third, participants provided feedback related to the trial resources, which were viewed positively, but identified language translation as a need. Fourth, feedback related to trial processes identified the need for changes to outcome collection and reduction of administrative burden. From the perspective of adopting the OPTimisE intervention, we found evidence that participants were able to change their behaviour. Considering the findings through the lens of the COM-B model, the intervention is likely to be deliverable in practice and the trial can be delivered at scale with some additional support for physiotherapists., Conclusions: Overall, the OPTimisE intervention was found to be different to usual care and acceptable to patients and physiotherapists. The study highlighted the need to refine trial processes and resources prior to a full-scale trial, to reduce administrative burden, increase support for physiotherapists, improve return rate of outcome questionnaires and provide language translation., Trial Registration Number: ISRCTN database 19 July 2021. https://www.isrctn.com/ISRCTN64444585., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Mean arterial pressure and cardiac output provide insufficient guidance for the management of intraoperative hypotension (IOH). In silico models offer additional insights into acute changes in hemodynamic parameters that may be encountered during IOH. A computational model (CM) generated parameters quantifying ventricular-vascular coupling, and pressure-volume construct across levels of aortic compliance (C A ). We studied how a loss from normal-to-stiff C A impacts critical care metrics of hemodynamics during vascular occlusion. Pulse pressure (PP), end-systolic pressure (P es ), arterial compliance (Art-ca), arterial elastance (Art-ea), and dynamic arterial elastance (Eadyn), along mechanical efficiency (ME) were measured at five levels of C A . A loss in C A impacted all variables. During steady-state conditions, PP, P es , and stroke work increased significantly as C A decreased. Art-ca decreased and Art-ea increased similarly; Eadyn increased and ME decreased. During a decrease in preload across all C A levels, arterial dynamics measures remained linear. The CM demonstrated that a loss in C A impacts measures of arterial dynamics during steady-state and transient conditions and the model demonstrates that critical care metrics are sensitive to changes in C A . While Art-ca and Art-ea were sensitive to changes in preload, Eadyn did not change., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER-localized eukaryotic glycoprotein secretion checkpoint, UDP-glucose glycoprotein glucosyl-transferase (UGGT). The enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re-glucosylating one of its N-linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT-mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity ("responsive mutant"). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop-2-Q118E, E227K and L186P mutants, which cause gelatinous drop-like corneal dystrophy (GDLD). Compared with the wild-type Trop-2, which is correctly localized at the plasma membrane, these Trop-2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop-2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9-mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop-2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1 -/- cells. UGGT1 also efficiently reglucosylated Trop-2-Q118E-EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad-spectrum rescue-of-secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants., (© 2024 The Authors. Traffic published by John Wiley & Sons Ltd.)

Objective: The purpose of this study was to develop and externally validate multivariable prediction models for future pain intensity outcomes to inform targeted interventions for patients with neck or low back pain in primary care settings., Methods: Model development data were obtained from a group of 679 adults with neck or low back pain who consulted a participating United Kingdom general practice. Predictors included self-report items regarding pain severity and impact from the STarT MSK Tool. Pain intensity at 2 and 6 months was modeled separately for continuous and dichotomized outcomes using linear and logistic regression, respectively. External validation of all models was conducted in a separate group of 586 patients recruited from a similar population with patients' predictor information collected both at point of consultation and 2 to 4 weeks later using self-report questionnaires. Calibration and discrimination of the models were assessed separately using STarT MSK Tool data from both time points to assess differences in predictive performance., Results: Pain intensity and patients reporting their condition would last a long time contributed most to predictions of future pain intensity conditional on other variables. On external validation, models were reasonably well calibrated on average when using tool measurements taken 2 to 4 weeks after consultation (calibration slope = 0.848 [95% CI = 0.767 to 0.928] for 2-month pain intensity score), but performance was poor using point-of-consultation tool data (calibration slope for 2-month pain intensity score of 0.650 [95% CI = 0.549 to 0.750])., Conclusion: Model predictive accuracy was good when predictors were measured 2 to 4 weeks after primary care consultation, but poor when measured at the point of consultation. Future research will explore whether additional, nonmodifiable predictors improve point-of-consultation predictive performance., Impact: External validation demonstrated that these individualized prediction models were not sufficiently accurate to recommend their use in clinical practice. Further research is required to improve performance through inclusion of additional nonmodifiable risk factors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association.)

Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a Ct UGGT GT24 "WY" conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for Ct UGGT GT24 in vitro as measured by ligand-enhanced fluorescence. In cellula , 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to Ct UGGT GT24 appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Objectives: To explore the lived experience of people with lateral elbow tendinopathy (LET) and its impact on everyday life., Design: Qualitative semi-structured interviews, analysed using thematic analysis., Setting: Conducted as part of the mixed-methods OPTimisE pilot and feasibility randomised controlled trial of outpatient physiotherapy patients in the UK., Participants: 17 participants with LET, purposively sampled from the trial to provide representativeness based on age, sex, ethnicity, deprivation index and treatment allocation., Results: Four themes were identified from the participants' responses: (1) cause of onset-typically symptoms were attributed to: sudden changes in activity, repetitive work or compensating for other musculoskeletal conditions; (2) impact on everyday life-which included substantial impacts on quality-of-life, particularly due to pain disturbing sleep and difficulties performing daily tasks (related to work and hobbies) due to pain, although most reported being able to persevere with work; (3) self-help and understanding of the condition-with uncertainty about the appropriateness and potential harm of online advice and confusion from the diagnostic term 'Tennis Elbow' that non-sporting individuals struggled to relate to; (4) healthcare experiences-the treatments received were highly variable and often perceived as ineffectual., Conclusions: For the first time, the lived experience of people from a range of backgrounds suffering from LET has been explored. Findings suggest that people frequently related the cause to a specific activity. They reported substantial impacts on daily tasks, sleep, work and hobbies. People also reported hesitancy to trust online information without formal healthcare advice, were confused by the common label of 'Tennis Elbow', and perceived the wide array of healthcare treatment options they had received to offer false hope and be largely ineffective. This study provides stimulus for clinicians to consider the advice and treatment provided, and whether the messages conveyed reflect the favourable natural history of the condition., Trial Registration Number: ISRCTN64444585., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Musculoskeletal disorders (MSDs) are a common reason for seeking primary health care. The STarT Musculoskeletal (MSK) tool is designed to stratify patients suffering from MSDs to risk groups, based on prognostic factors., Aim: The aim was to translate and cross-culturally adapt the STarT MSK tool in a Swedish primary health care context through testing of reliability and construct validity., Methods: We included consecutive patients with MSDs seeking primary care (n = 99). The STarT MSK was translated using international recommendations. Construct validity was investigated by correlation analysis (Spearmans Rho) with the following reference instruments: the Örebro Musculoskeletal Pain Questionnaire (ÖMPQ), the EuroQol 5-dimension (EQ-5D) and the Musculoskeletal Health Questionnaire (MSKHQ). Reliability was tested using test-retest (Intra Class Correlation, ICC 2.1 ) (n = 31). Known-groups validity was calculated with a difference of 10% between risk groups based on how the participants had answered., Results: The STarT MSK was successfully translated into Swedish. The participants were grouped into low risk (n = 28), medium risk (n = 60) and high risk (n = 11). The construct validity showed a moderate to high correlation with the ÖMPQ (r = .61), EQ-5D (r = .59) and MSK-HQ (r = .56). All separate items except item 2 and 9 correlated according to predefined hypotheses. Test-retest demonstrated an excellent reliability for the total score (ICC 2.1 0.85) (n = 31). The STarT MSK tool was able to differentiate by 10% between the risk groups, based on how the participants had answered., Conclusion: The STarT MSK has been successfully translated and adapted into Swedish and shows acceptable measurement properties regarding test-retest reliability and aspects of validity and seems to be able to discriminate between the proposed risk groups. The tool can therefore be useful in a Swedish primary health care context. A future study needs to determine the tools predictive validity and to investigate if stratification to risk groups leads to a faster recovery and to lower health care costs., (© 2023. The Author(s).)

Background: Video and computer games are popular activities, with 72% of adolescents aged 13 to 17 years reporting video game use on either a computer, game console, or portable device. Despite high levels of video and computer game use in adolescence, relatively little scientific literature exists examining the association and effects of video and computer games on adolescents., Objective: The objective of this study was to examine the prevalence of video and computer game use among US adolescents and rates of positive screens for obesity, diabetes, high blood pressure (BP), and high cholesterol., Methods: A secondary data analysis was conducted using the National Longitudinal Study of Adolescent to Adult Health (Add Health) data, including adolescents aged 12 to 19 years between 1994 and 2018., Results: Respondents (n=4190) who played the most video and computer games had a significantly (P=.02) higher BMI and were more likely to self-report having at least one of the evaluated metabolic disorders: obesity (BMI >30 kg/m 2 ), diabetes, high BP (BP >140/90), and high cholesterol (>240). With increased video or computer game use, there was a statistically significant increase in high BP rates in each quartile, with those with more frequent use also having higher rates of high BP. A similar trend was observed for diabetes, though the association did not reach statistical significance. No significant association was observed between video or computer game use and diagnoses of dyslipidemia, eating disorders, or depression., Conclusions: Frequency of video and computer game use is associated with obesity, diabetes, high BP, and high cholesterol in adolescents aged 12 to 19 years. Adolescents who play the most video and computer games have a significantly higher BMI. They are more likely to have at least one of the evaluated metabolic disorders: diabetes, high BP, or high cholesterol. Public health interventions designed to target modifiable disease states through health promotion and self-management may support the health of adolescents aged 12 to 19 years. Video and computer games can integrate health promotion interventions in gameplay. This is an important area for future research as video and computer games are integrated into the lives of adolescents., (©Stephanie R Lebby, Sangeetha Shyam, Amutha Ramadas, Andrew R Bohm, Julia C Hill, Karen L Fortuna, Stephanie R Zoltick. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 06.07.2023.)

Objectives: The aim of this study was to describe and compare health economic outcomes [health-care utilization and costs, work outcomes, and health-related quality of life (EQ-5D-5L)] in patients classified into different levels-of-risk subgroups by the Keele STarT MSK Tool., Methods: Data on health-care utilization, costs and EQ-5D-5L were collected from a health-care perspective within a primary care prospective observational cohort study. Patients presenting with one (or more) of the five most common musculoskeletal pain presentations were included: back, neck, shoulder, knee or multi-site pain. Participants at low, medium and high risk of persistent disabling pain were compared in relation to mean health-care utilization and costs, health-related quality of life, and employment status. Regression analysis was used to estimate costs., Results: Over 6 months, the mean (s.d.) total health-care (National Health Service and private) costs associated with the low, medium, and high-risk subgroups were £132.92 (167.88), £279.32 (462.98) and £476.07 (716.44), respectively. Mean health-related quality of life over the 6-month period was lower and more people changed their employment status in the high-risk subgroup compared with the medium- and low-risk subgroups., Conclusions: This study demonstrates that subgroups of people with different levels of risk for poor musculoskeletal pain outcomes also have different levels of health-care utilization, health-care costs, health-related quality of life, and work outcomes. The findings show that the STarT MSK Tool not only identifies those at risk of a poorer outcome, but also those who will have more health-care visits and incur higher costs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Endoplasmic reticulum (ER) retention of mis-folded glycoproteins is mediated by the ERlocalised eukaryotic glycoprotein secretion checkpoint, UDP-glucose glycoprotein glucosyl-transferase (UGGT). The enzyme recognises a mis-folded glycoprotein and flags it for ER retention by reglucosylating one of its N-linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT-mediated ER retention can cause rare disease even if the mutant glycoprotein retains activity ("responsive mutant"). Here, we investigated the subcellular localisation of the human Trop-2 Q118E variant, which causes gelatinous droplike corneal dystrophy (GDLD). Compared with the wild type Trop-2, which is correctly localised at the plasma membrane, the Trop-2-Q118E variant is found to be heavily retained in the ER. Using Trop-2-Q118E, we tested UGGT modulation as a rescue-of-secretion therapeutic strategy for congenital rare disease caused by responsive mutations in genes encoding secreted glycoproteins. We investigated secretion of a EYFP-fusion of Trop-2-Q118E by confocal laser scanning microscopy. As a limiting case of UGGT inhibition, mammalian cells harbouring CRISPR/Cas9-mediated inhibition of the UGGT1 and/or UGGT2 gene expressions were used. The membrane localisation of the Trop-2-Q118E-EYFP mutant was successfully rescued in UGGT1 -/- and UGGT1/2 -/- cells. UGGT1 also efficiently reglucosylated Trop-2-Q118E-EYFP in cellula . The study supports the hypothesis that UGGT1 modulation constitutes a novel therapeutic strategy for the treatment of Trop-2-Q118E associated GDLD, and it encourages the testing of modulators of ER glycoprotein folding Quality Control (ERQC) as broad-spectrum rescueof-secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.

Background: Musculoskeletal disorders represented 149 million years lived with disability world-wide in 2019 and are the main cause of years lived with disability worldwide. Current treatment recommendations are based on "one-size fits all" principle, which does not take into account the large degree of biopsychosocial heterogeneity in this group of patients. To compensate for this, we developed a stratified care computerized clinical decision support system for general practice based on patient biopsychosocial phenotypes; furthermore, we added personalized treatment recommendations based on specific patient factors to the system. In this study protocol, we describe the randomized controlled trial for evaluating the effectiveness of computerized clinical decision support system for stratified care for patients with common musculoskeletal pain complaints in general practice. The aim of this study is to test the effect of a computerized clinical decision support system for stratified care in general practice on subjective patient outcome variables compared to current care., Methods: We will perform a cluster-randomized controlled trial with 44 general practitioners including 748 patients seeking their general practitioner due to pain in the neck, back, shoulder, hip, knee, or multisite. The intervention group will use the computerized clinical decision support system, while the control group will provide current care for their patients. The primary outcomes assessed at 3 months are global perceived effect and clinically important improvement in function measured by the Patient-Specific Function Scale (PSFS), while secondary outcomes include change in pain intensity measured by the Numeric Rating Scale (0-10), health-related quality of life (EQ-5D), general musculoskeletal health (MSK-HQ), number of treatments, use of painkillers, sick-leave grading and duration, referral to secondary care, and use of imaging., Discussion: The use of biopsychosocial profile to stratify patients and implement it in a computerized clinical decision support system for general practitioners is a novel method of providing decision support for this patient group. The study aim to recruit patients from May 2022 to March 2023, and the first results from the study will be available late 2023., Trial Registration: The trial is registered in ISRCTN 11th of May 2022: 14,067,965., (© 2023. The Author(s).)

Complex astrophysical systems often exhibit low-scatter relations between observable properties (e.g., luminosity, velocity dispersion, oscillation period). These scaling relations illuminate the underlying physics, and can provide observational tools for estimating masses and distances. Machine learning can provide a fast and systematic way to search for new scaling relations (or for simple extensions to existing relations) in abstract high-dimensional parameter spaces. We use a machine learning tool called symbolic regression (SR), which models patterns in a dataset in the form of analytic equations. We focus on the Sunyaev-Zeldovich flux-cluster mass relation ( Y SZ - M ), the scatter in which affects inference of cosmological parameters from cluster abundance data. Using SR on the data from the IllustrisTNG hydrodynamical simulation, we find a new proxy for cluster mass which combines Y SZ and concentration of ionized gas ( c gas ): M ∝ Y conc 3/5 ≡ Y SZ 3/5 (1 - A c gas ). Y conc reduces the scatter in the predicted M by ∼20 - 30% for large clusters ( M ≳ 10 14 h -1 M ⊙ ), as compared to using just Y SZ . We show that the dependence on c gas is linked to cores of clusters exhibiting larger scatter than their outskirts. Finally, we test Y conc on clusters from CAMELS simulations and show that Y conc is robust against variations in cosmology, subgrid physics, and cosmic variance. Our results and methodology can be useful for accurate multiwavelength cluster mass estimation from upcoming CMB and X-ray surveys like ACT, SO, eROSITA and CMB-S4.

Background: The STarT MSK cluster randomised controlled trial (RCT) investigated the clinical- and cost-effectiveness of risk-based stratified primary care versus usual care for patients with back, neck, shoulder, knee or multi-site pain. Trial quantitative results showed risk-based stratified care was not superior to usual care for patients' clinical outcomes, but the intervention led to some changes in GP clinical decision-making. This paper reports a linked qualitative study exploring how risk-based stratified care was perceived and used in the trial, from the perspectives of clinicians and patients., Methods: Semi-structured interviews were conducted with 27 patients, and focus groups and interviews with 20 clinicians (GPs and physiotherapists) in the intervention arm of the trial. Data were analysed thematically and findings explored using Normalisation Process Theory (NPT) and the COM-B model., Main Findings: Risk-based stratified care (subgrouping and matching treatments) was found to have 'coherence' (i.e. made sense) to several clinicians and patients, in that it was well-integrated in practice, and supported clinical decision-making. However, for some GPs stratified care was less 'meaningful', as the risk-stratification tool did not fit with usual ways of consulting and added to already time-pressured consultations. GPs reported giving more patients written information/advice due to easier access to electronic information leaflets through the trial template and were motivated to refer patients to physiotherapy as they believed the trial resulted in faster physiotherapy access (although this was not the case). Patients and clinicians reported that risk-based stratified care influenced conversations in the consultation, prompting greater attention to psychosocial factors, and facilitating negotiation of treatment options. Physiotherapists saw benefits in receiving information about patients' risk subgroup on referral forms., Conclusion: These findings provide context for interpreting some of the trial outcomes, particularly in relation to changes in clinical decision-making when risk-based stratified care was used. Findings also indicate potential reasons for lack of GP engagement with risk-based stratified care. Positive outcomes were identified that were not captured in the quantitative data, specifically that risk-based stratified care positively influenced some GP-patient conversations and facilitated negotiation of treatment options., Trial Registration: ISRCTN15366334 (26/04/2016)., (© 2022. The Author(s).)

High-power, narrow-linewidth light sources in the visible and UV spectra are in growing demand, particularly as quantum information and sensing research proliferates. Vertical external-cavity surface-emitting lasers (VECSELs) with intra-cavity frequency conversion are emerging as an attractive platform to fill these needs. Using such a device, we demonstrate 3.5 MHz full-width half-maximum Rydberg-state spectroscopy via electromagnetically induced transparency (EIT). The laser's 690 mW of output power at a wavelength of 475 nm enables large Rabi frequencies and strong signal-to-noise ratio in shorter measurement times. In addition, we characterize the frequency stability of the VECSEL using the delayed self-heterodyne technique and direct comparison with a commercial external-cavity diode laser (ECDL). We measure the pre-doubled light's Lorentzian linewidth to be 2π × 5.3(2) kHz, and the total linewidth to be 2π × 23(2) kHz. These measurements provide evidence that intra-cavity frequency-doubled VECSELs can perform precision spectroscopy at and below the MHz level, and are a promising tool for contemporary, and future, quantum technologies.

Objectives: We hypothesized that expression and activity of nitric oxide synthase-3 enzyme (Nos3) in bicuspid aortic valve (BAV) aortopathy are related to tissue layer and Nos3 genotype., Methods: Gene expression of Nos3 and platelet and endothelial cell adhesion molecule-1 (Pecam1) and NOS activity were measured in intima-containing media and adventitial specimens of ascending aortic tissue. The presence of 2 Nos3 single-nucleotide polymorphisms (SNPs; -786T/C and 894G/T) was determined for non-aneurysmal (NA) and aneurysmal patients with BAV (n = 40, 89, respectively); patients with tricuspid aortic valve (TAV) and aneurysm (n = 151); and NA patients with TAV (n = 100)., Results: Elevated Nos3 relative to Pecam1 and reduced Pecam1 relative to a housekeeping gene were observed within intima-containing aortic specimens from BAV patients when compared with TAV patients. Lower Nos3 in the adventitia of aneurysmal specimens was noted when compared with specimens of NA aorta, independent of valve morphology. NOS activity was similar among cohorts in media/intima and decreased in the diseased adventitia, relative to control patients. Aneurysmal BAV patients exhibited an under-representation of the wild-type genotype for -786 SNP. No differences in genotype distribution were noted for 894 SNP. Primary intimal endothelial cells from patients with at least 1 C allele at -786 SNP exhibited lower Nos3 when compared with wild-type cells., Conclusions: These findings of differential Nos3 in media/intima versus adventitia depending on valve morphology or aneurysm reveal new information regarding aneurysmal pathophysiology and support our ongoing assertion that there are distinct mechanisms giving rise to ascending aortopathy in BAV and TAV patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Physiotherapy is recommended for people with tennis elbow, but whilst a wide array of treatments is available, the optimal approach remains uncertain. We have therefore recently developed an optimised physiotherapy treatment package for tennis elbow based on a synthesis of the evidence, patient input and clinical consensus. It consists of detailed advice and education, a structured progressive exercise programme and provision of a counter-force elbow brace. Here, we report the protocol for our multicentre pilot and feasibility randomised controlled trial (RCT) designed to (a) examine the feasibility of our optimised physiotherapy treatment package and (b) to pilot trial processes for a future fully powered RCT to test clinical and cost-effectiveness compared with usual physiotherapy treatment., Methods: A multicentre pilot and feasibility RCT will be conducted across three sites in England, recruiting up to 50 patients (or for a maximum of 12 months). Participants with tennis elbow, identified from physiotherapy clinic waiting lists and general practice surgeries, will be randomly allocated to receive the optimised physiotherapy treatment package or usual physiotherapy care. Analysis will focus on feasibility measures including consent rate, intervention fidelity, follow-up rate and outcome completion rate. A nested qualitative study will explore the acceptability of the study processes and patient and physiotherapist experiences of the new optimised intervention., Discussion: This study will determine the feasibility of a new optimised physiotherapy treatment package for people with tennis elbow and pilot the processes for a future fully powered RCT. In the longer term, this treatment package may provide superior clinical outcomes for patients, in terms of pain and quality of life, and be more cost-effective for the health service., Trial Registration: Registered with the ISRCTN database 19/7/2021, https://www.isrctn.com/ISRCTN64444585., (© 2022. The Author(s).)

Background: Low back pain (LBP) is one of the most common reasons for primary care visits and is the leading contributor to years lived with disability worldwide. The purpose of this study was to understand the perspectives of patients and primary care team members related to their experiences with a new physiotherapist-led primary care model for LBP., Methods: We conducted an interpretive description qualitative study. Data were collected using a combination of semi-structured interviews and focus group discussions and analyzed using thematic analysis. Participants included adults (> 18 years of age) with LBP and primary care team members who participated in a physiotherapist-led primary care model for LBP in Kingston, Ontario, Canada., Results: We conducted 18 semi-structured interviews with patients with LBP (10 women; median age of 52) as well as three focus group discussions with a total of 20 primary care team members representing three teams. Four themes (each with sub-themes) were constructed: 1) enhanced primary care delivery for LBP (improved access and engagement in physiotherapy care, improved communication and care integration between the physiotherapist and primary care team, less inappropriate use of healthcare resources); 2) positive patient experiences and perceived outcomes with the new model of care (physiotherapist built therapeutic alliance, physiotherapist provided comprehensive care, improved confidence in managing LBP, decreased impact of pain on daily life); 3) positive primary care team experiences with the new model of care (physiotherapist fit well within the primary care team, physiotherapist provided expertise on LBP for the primary care team, satisfaction in being able to offer a needed service for patients); and 4) challenges implementing the new model of care (challenges with prompt access to physiotherapy care, challenges making the physiotherapist the first contact for LBP, and opportunities to optimize communication between the physiotherapist and primary care team)., Conclusions: A new physiotherapist-led primary care model for LBP was described by patients and primary care team members as contributing to positive experiences and perceived outcomes for patients, primary care team members, and potentially the health system more broadly. Results suggest that this model of care may be a viable approach to support integrated and guideline adherent management of LBP in primary care settings., (© 2022. The Author(s).)

Aims: Tranexamic acid (TXA) is now commonly used in major surgical operations including orthopaedics. The TRAC-24 randomized control trial (RCT) aimed to assess if an additional 24 hours of TXA postoperatively in primary total hip (THA) and total knee arthroplasty (TKA) reduced blood loss. Contrary to other orthopaedic studies to date, this trial included high-risk patients. This paper presents the results of a cost analysis undertaken alongside this RCT., Methods: TRAC-24 was a prospective RCT on patients undergoing TKA and THA. Three groups were included: Group 1 received 1 g intravenous (IV) TXA perioperatively and an additional 24-hour postoperative oral regime, Group 2 received only the perioperative dose, and Group 3 did not receive TXA. Cost analysis was performed out to day 90., Results: Group 1 was associated with the lowest mean total costs, followed by Group 2 and then Group 3. The differences between Groups 1 and 3 (-£797.77 (95% confidence interval -1,478.22 to -117.32) were statistically significant. Extended oral dosing reduced costs for patients undergoing THA but not TKA. The reduced costs in Groups 1 and 2 resulted from reduced length of stay, readmission rates, emergency department attendances, and blood transfusions., Conclusion: This study demonstrated significant cost savings when using TXA in primary THA or TKA. Extended oral dosing reduced costs further in THA but not TKA. Cite this article: Bone Jt Open  2022;3(7):536-542.

Background: The STarT-MSK-Tool is an adaptation of the well established STarT-Back-Tool, used to risk-stratify patients with a wider range of musculoskeletal presentations., Objective: To formally translate and cross-culturally adapt the Keele STarT-MSK risk stratification tool into German (STarT-MSKG) and to establish its reliability and validity., Methods: A formal, multi-step, forward and backward translation approach was used. To assess validity patients aged ≥18 years, with acute, subacute or chronic musculoskeletal presentations in the lumbar spine, hip, knee, shoulder, or neck were included. The prospective cohort was used with initial data collected electronically at the point-of-consultation. Retest and 6-month follow-up questionnaires were sent by email. Test-retest reliability, construct validity, discriminative ability, predictive ability and floor or ceiling effects were analysed using intraclass correlation coefficient, and comparisons with a reference standard (Orebro-Musculoskeletal-Pain-Questionnaire: OMPQ) using correlations, ROC-curves and regression models., Results: The participants' (n = 287) mean age was 47 (SD = 15.8) years, 51% were female, with 48.8% at low, 43.6% at medium, and 7.7% at high risk. With ICC = 0.75 (95% CI 0.69; 0.81) test-retest-reliability was good. Construct validity was good with correlations for the STarT-MSKG-Tool against the OMPQ-Tool of rs = 0.74 (95% CI 0.68, 0.79). The ability of the tool [comparison OMPQ] to predict 6-month pain and disability was acceptable with AUC = 0.77 (95% CI 0.71, 0.83) [OMPQ = 0.74] and 0.76 (95% CI 0.69, 0.82) [OMPQ = 0.72] respectively. However, the explained variance (linear/logistic regression) for predicting 6-month pain (21% [OMPQ = 17%]/logistic = 29%) and disability (linear = 20%:[OMPQ = 19%]/logistic = 26%), whilst being comparable to the existing OMPQ reference standard, fell short of the a priori target of ≥30%., Conclusions: The German version of the STarT-MSK-Tool is a valid instrument for use across multiple musculoskeletal conditions and is availabe for use in clinical practice. Comparison with the OMPQ suggests it is a good alternative., Competing Interests: The authors have declared that no competing interests exist.

Purpose Musculoskeletal (MSK) pain is a common cause of work absence. The recent SWAP (Study of Work And Pain) randomised controlled trial (RCT) found that a brief vocational advice service for primary care patients with MSK pain led to fewer days' work absence and provided good return-on-investment. The I-SWAP (Implementation of the Study of Work And Pain) initiative aimed to deliver an implementation test-bed of the SWAP vocational advice intervention with First Contact Practitioners (FCP). This entailed adapting the SWAP vocational advice training to fit the FCP role. This qualitative investigation explored the implementation potential of FCPs delivering vocational advice for patients with MSK pain. Methods Semi-structured interviews and focus groups were conducted with 10 FCPs and 5 GPs. Data were analysed thematically and findings explored using Normalisation Process Theory (NPT). Results I-SWAP achieved a degree of 'coherence' (i.e. made sense), with both FCPs and GPs feeling FCPs were well-placed to discuss work issues with these patients. However, for many of the FCPs, addressing or modifying psychosocial and occupational barriers to return-to-work was not considered feasible within FCP consultations, and improving physical function was prioritised. Concerns were also raised that employers would not act on FCPs' recommendations regarding return-to-work. Conclusion FCPs appear well-placed to discuss work issues with MSK patients, and signpost/refer to other services; however, because they often only see patients once they are less suited to deliver other aspects of vocational advice. Future research is needed to explore how best to provide vocational advice in primary care settings., (© 2021. The Author(s).)

Objectives: There are a wide range of physiotherapy treatment options for people with lateral elbow tendinopathy (LET); however, previous studies have reported inconsistent approaches to treatment and a lack of evidence demonstrating clinical effectiveness. This study aimed to combine the best available research evidence with stakeholder perspectives to develop key components of an optimised physiotherapist-led treatment protocol for testing in a future randomised controlled trial (RCT)., Design: Online consensus groups using nominal group technique (NGT), a systematic approach to building consensus using structured multistage meetings., Setting: UK National Health Service (NHS)., Participants: 10 physiotherapists with special interest in LET, 2 physiotherapy service managers and 3 patients who had experienced LET., Interventions: Two consensus groups were conducted; the first meeting focused on agreeing the types of interventions to be included in the optimised treatment protocol; the second meeting focused on specific details of intervention delivery. Participants were sent an evidence summary of available treatments for LET prior to the first meeting. All treatment options were discussed before anonymous voting and ranking of priority. Consensus for inclusion of each treatment option was set at ≥70% based on OMERACT guidelines. Options with 30%-69% agreement were discussed again, and a second vote was held, allowing for a change of opinion., Results: The optimised physiotherapist-led treatment package included: advice and education, exercise therapy and orthotics. Specific components for each of these interventions were also agreed such as: condition-specific advice, health-promotion advice, exercise types, exercise into 'acceptable' levels of pain, exercise dosage and type of orthoses. Other treatment options including electrotherapy, acupuncture and manual therapy were excluded., Conclusion: An optimised physiotherapist-led treatment protocol for people with LET was successfully developed using an online NGT consensus approach. This intervention is now ready for testing in a future pilot/feasibility RCT to contribute much needed evidence about the treatment of LET., Trial Registration Number: This is the pre-cursor to the OPTimisE Pilot and Feasibility Randomised Controlled Trial. Registration: https://www.isrctn.com/ISRCTN64444585., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Aims: The aim of this study is to assess the impact of a pilot enhanced recovery after surgery (ERAS) programme on length of stay (LOS) and post-discharge resource usage via service evaluation and cost analysis., Methods: Between May and December 2019, 100 patients requiring hip or knee arthroplasty were enrolled with the intention that each would have a preadmission discharge plan, a preoperative education class with nominated helper, a day of surgery admission and mobilization, a day one discharge, and access to a 24/7 dedicated helpline. Each was matched with a patient under the pre-existing pathway from the previous year., Results: Mean LOS for ERAS patients was 1.59 days (95% confidence interval (CI) 1.14 to 2.04), significantly less than that of the matched cohort (3.01 days; 95% CI 2.56 to 3.46). There were no significant differences in readmission rates for ERAS patients at both 30 and 90 days (six vs four readmissions at 30 days, and nine vs four at 90 days). Despite matching, there were significantly more American Society of Anesthesiologists (ASA) grade 3 patients in the ERAS cohort. There was a mean cost saving of £757.26 (95% CI £-1,200.96 to £-313.56) per patient. This is despite small increases in postoperative resource usage in the ERAS patients., Conclusion: ERAS represents a safe and effective means of reducing LOS in primary joint arthroplasty patients. Implementation of ERAS principles has potential financial savings and could increase patient throughput without compromising care. In elective care, a preadmission discharge plan is key. Cite this article: Bone Jt Open  2021;2(11):966-973.

Background: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA ( n = 21) to those with RA ( n = 27) and normal knees ( n = 3)., Methods: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device. RA patients were categorized as active ( n = 20) or controlled ( n = 7) based upon SF white blood cell counts (> or <300 cells/mm 3 ). Samples were cryopreserved and analyzed by multiplex fluorescent bead assays (Luminex). Between-group differences of 16 separate biomarker proteins were identified using ANOVA on log10-transformed concentrations with p values adjusted for multiple testing., Results: Only six biomarkers were significantly higher in SF from active RA compared to OA-TNF-α, IL-1-β IL-7, MMP-1, MMP-2, and MMP-3. Only MMP-8 levels in RA patients correlated with SF WBC counts ( p < 0.0001). Among OA patients, simultaneous SF IL-4, IL-6, IL-8, and IL-15 levels were higher than serum levels, whereas MMP-8, MMP-9, and IL-18 levels were higher in serum ( p < 0.05)., Conclusion: These results support the growing evidence that OA patients have a pro-inflammatory/catabolic SF environment. SF biomarker analysis using multiplex testing and US guidance may distinguish OA phenotypes and identify treatment options based upon targeted inflammatory pathways similar to patients with RA.

Cycle threshold (C T ) values are correlated with the amount of viral nucleic acid in a sample and may be obtained from some qualitative real-time polymerase chain reaction tests used for diagnosis of most patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, C T values cannot be directly compared across assays, and they must be interpreted with caution as they are influenced by sample type, timing of sample collection, and assay design. Presently, the correlation between C T values and clinical outcomes is not well understood. We conducted a systematic review and meta-analysis of published studies through April 19, 2021, that reported an association between C T values and hospitalization, disease severity, and mortality in patients ≥18 years old with SARS-CoV-2. A meta-analysis of 7 studies showed no significant difference in mean C T values between hospitalized and nonhospitalized patients. Among hospitalized patients, those with C T values <25 had a high risk of more severe disease and mortality than patients with C T values >30 (odds ratio [OR], 2.31; 95% CI, 1.70 to 3.13; and OR, 2.95; 95% CI, 2.19 to 3.96; respectively). The odds of increased disease severity and mortality were less pronounced in patients with C T values of 25-30 compared with >30., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The Musculoskeletal Health Questionnaire (MSK-HQ) is a recently developed generic questionnaire that consists of 14 items assessing health status in people with musculoskeletal disorders. The objective was to translate and cross-culturally adapt the MSK-HQ into Norwegian and to examine its construct validity and reliability in people on sick leave with musculoskeletal disorders., Methods: A prospective cohort study was carried out in Norway on people between 18 and 67 years of age and sick leave due to a musculoskeletal disorder. The participants were recruited through the Norwegian Labour and Welfare Administration during November 2018-January 2019 and responded to the MSK-HQ at inclusion and after four weeks. Internal consistency was assessed by Cronbach's alpha, and structural validity with a factor analysis. Construct validity was assessed by eight "a priori" defined hypotheses regarding correlations between the MSK-HQ and other reference scales. Correlations were analyzed by Spearman's- or Pearson's correlation coefficient and interpreted as high with values ≥ 0.50, moderate between 0.30-0.49, and low < 0.29. Reliability was tested with test-retest, standard error of measurement (SEM) and smallest detectable change (SDC)., Results: A total of 549 patients, mean age (SD) 48.6 (10.7), 309 women (56.3%), were included. The mean (SD) MSK-HQ sum scores (min-max 3-56) were 27.7 (8.2). Internal consistency was 0.86 and a three-factor structure was determined by factor analysis. Construct validity was supported by the confirmation of all hypotheses; high correlation with HRQOL, psychosocial risk profile, and self-perceived health; moderate correlation with physical activity, self-perceived work ability, and work presenteeism; and low correlation with the number of sick days. The test-retest reliability was good with an intraclass correlation coefficient of 0.83 (95% CI, 0.74-0.89), SEM was 2.3 and SDC 6.5., Conclusions: The Norwegian version of the MSK-HQ demonstrated high internal consistency, a three-factor structure, good construct validity and good test-retest reliability when used among people on sick leave due to musculoskeletal disorders., (© 2021. The Author(s).)

Background: Stratified care involves subgrouping patients based on key characteristics, e.g. prognostic risk, and matching these subgroups to early treatment options. The STarT-MSK programme developed and tested a new stratified primary care intervention for patients with common musculoskeletal (MSK) conditions in general practice. Stratified care involves changing General Practitioners' (GPs) behaviour, away from the current 'stepped' care approach to identifying early treatment options matched to patients' risk of persistent pain. Changing healthcare practice is challenging, and to aid the successful delivery of stratified care, education and support for GPs was required. This paper details the iterative development of a clinician support package throughout the lifespan of the programme, to support GPs in delivering the stratified care intervention. We argue that clinician support is a crucial aspect of the intervention itself, which is often overlooked., Methods: Qualitative research with patients and GPs identified barriers and facilitators to the adoption of stratified care, which were mapped onto the Theoretical Domains Framework (TDF). Identified domains were 'translated' into an educational paradigm, and an initial version of the support package developed. This was further refined following a feasibility and pilot RCT, and a finalised support package was developed for the main RCT., Results: The clinician support package comprised face-to-face sessions combining adult-learning principles with behaviour change theory in a multimethod approach, which included group discussion, simulated consultations, patient vignettes and model consultation videos. Structured support for GPs was crucial to facilitate fidelity and, ultimately, a successful trial. Clinician support is a two-way process- the study team can learn from and adapt to specific local factors and issues not previously identified. The support from senior clinicians was required to ensure 'buy in'. Monitoring of GP performance, provision of regular feedback and remedial support are important aspects of effective clinician support., Conclusion: Designing effective clinician support from the onset of trial intervention design, in an evidence-based, theory-informed manner, is crucial to encourage active engagement and intervention fidelity within the trial, enabling the delivery of a robust and reliable proof-of-principle trial. We offer practical recommendations for future general practice interventions., (© 2021. The Author(s).)

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10 -3 ) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10 -6 ) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Aims: We studied the outcomes of hip and knee arthroplasties in a high-volume arthroplasty centre to determine if patients with morbid obesity (BMI ≥ 40 kg/m 2 ) had unacceptably worse outcomes as compared to those with BMI < 40 kg/m 2 ., Methods: In a two-year period, 4,711 patients had either total hip arthroplasty (THA; n = 2,370), total knee arthroplasty (TKA; n = 2,109), or unicompartmental knee arthroplasty (UKA; n = 232). Of these patients, 392 (8.3%) had morbid obesity. We compared duration of operation, anaesthetic time, length of stay (LOS), LOS > three days, out of hours attendance, emergency department attendance, readmission to hospital, return to theatre, and venous thromboembolism up to 90 days. Readmission for wound infection was recorded to one year. Oxford scores were recorded preoperatively and at one year postoperatively., Results: On average, the morbidly obese had longer operating times (63 vs 58 minutes), longer anaesthetic times (31 vs 28 minutes), increased LOS (3.7 vs 3.5 days), and significantly more readmissions for wound infection (1.0% vs 0.3%). There were no statistically significant differences in either suspected or confirmed venous thromboembolism. Improvement in Oxford scores were equivalent., Conclusion: Although morbidly obese patients had less favourable outcomes, we do not feel that the magnitude of difference is clinically significant when applied to an individual, particularly when improvement in Oxford scores were unrelated to BMI. Cite this article: Bone Jt Open  2021;2(7):515-521.

High resolution seafloor mapping shows extraordinary evidence that massive (>300 m thick) icebergs once drifted >5,000 km south along the eastern United States, with >700 iceberg scours now identified south of Cape Hatteras. Here we report on sediment cores collected from several buried scours that show multiple plow marks align with Heinrich Event 3 (H3), ~31,000 years ago. Numerical glacial iceberg simulations indicate that the transport of icebergs to these sites occurs during massive, but short-lived, periods of elevated meltwater discharge. Transport of icebergs to the subtropics, away from deep water formation sites, may explain why H3 was associated with only a modest increase in ice-rafting across the subpolar North Atlantic, and implies a complex relationship between freshwater forcing and climate change. Stratigraphy from subbottom data across the scour marks shows there are additional features that are both older and younger, and may align with other periods of elevated meltwater discharge.

Background: Homelessness is associated with substantial morbidity. Data linkages between homeless and health systems are important to understand unique needs across homeless populations, identify homeless individuals not registered in homeless databases, quantify the impact of housing services on health-system use, and motivate health systems and payers to contribute to housing solutions., Methods: We performed a cross-sectional survey including six health systems and two Homeless Management Information Systems (HMIS) in Cook County, Illinois. We performed privacy-preserving record linkage to identify homelessness through HMIS or ICD-10 codes captured in electronic medical records. We measured the prevalence of health conditions and health-services use across the following typologies: housing-service utilizers stratified by service provided (stable, stable plus unstable, unstable) and non-utilizers (i.e., homelessness identified through diagnosis codes-without receipt of housing services)., Results: Among 11,447 homeless recipients of healthcare, nearly 1 in 5 were identified by ICD10 code alone without recorded homeless services (n = 2177; 19%). Almost half received homeless services that did not include stable housing (n = 5444; 48%), followed by stable housing (n = 3017; 26%), then receipt of both stable and unstable services (n = 809; 7%). Setting stable housing recipients as the referent group, we found a stepwise increase in behavioral-health conditions from stable housing to those known as homeless solely by health systems. Compared to those in stable housing, prevalence rate ratios (PRR) for those without homeless services were as follows: depression (PRR = 2.2; 95% CI 1.9 to 2.5), anxiety (PRR = 2.5; 95% CI 2.1 to 3.0), schizophrenia (PRR = 3.3; 95% CI 2.7 to 4.0), and alcohol-use disorder (PRR = 4.4; 95% CI 3.6 to 5.3). Homeless individuals who had not received housing services relied on emergency departments for healthcare-nearly 3 of 4 visited at least one and many (24%) visited multiple., Conclusions: Differences in behavioral-health conditions and health-system use across homeless typologies highlight the particularly high burden among homeless who are disconnected from homeless services. Fragmented and high use of emergency departments for care should motivate health systems and payers to promote housing solutions, especially those that incorporate substance use and mental health treatment.

UDP-glucose:glycoprotein glucosyltransferase (UGGT) flags misfolded glycoproteins for ER retention. We report crystal structures of full-length Chaetomium thermophilum UGGT (CtUGGT), two CtUGGT double-cysteine mutants, and its TRXL2 domain truncation (CtUGGT-ΔTRXL2). CtUGGT molecular dynamics (MD) simulations capture extended conformations and reveal clamping, bending, and twisting inter-domain movements. We name "Parodi limit" the maximum distance on the same glycoprotein between a site of misfolding and an N-linked glycan that can be reglucosylated by monomeric UGGT in vitro, in response to recognition of misfold at that site. Based on the MD simulations, we estimate the Parodi limit as around 70-80 Å. Frequency distributions of distances between glycoprotein residues and their closest N-linked glycosylation sites in glycoprotein crystal structures suggests relevance of the Parodi limit to UGGT activity in vivo. Our data support a "one-size-fits-all adjustable spanner" UGGT substrate recognition model, with an essential role for the UGGT TRXL2 domain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Sciatica has a substantial impact on patients and society. Current care is 'stepped', comprising an initial period of simple measures of advice and analgesia, for most patients, commonly followed by physiotherapy, and then by more intensive interventions if symptoms fail to resolve. No study has yet tested a model of stratified care in which patients are subgrouped and matched to different care pathways based on their prognosis and clinical characteristics., Objectives: The objectives were to investigate the clinical effectiveness and cost-effectiveness of a stratified care model compared with usual, non-stratified care., Design: This was a two-parallel group, multicentre, pragmatic, 1 : 1 randomised controlled trial., Setting: Participants were recruited from primary care (42 general practices) in North Staffordshire, North Shropshire/Wales and Cheshire in the UK., Participants: Eligible patients were aged ≥ 18 years, had suspected sciatica, had access to a mobile phone/landline, were not pregnant, were not receiving treatment for the same problem and had not had previous spinal surgery., Interventions: In stratified care, a combination of prognostic and clinical criteria associated with referral to spinal specialist services was used to allocate patients to one of three groups for matched care pathways. Group 1 received advice and up to two sessions of physiotherapy, group 2 received up to six sessions of physiotherapy, and group 3 was fast-tracked to magnetic resonance imaging and spinal specialist opinion. Usual care was based on the stepped-care approach without the use of any stratification tools/algorithms. Patients were randomised using a remote web-based randomisation service., Main Outcome Measures: The primary outcome was time to first resolution of sciatica symptoms (six point ordinal scale, collected via text messages). Secondary outcomes (at 4 and 12 months) included pain, function, psychological health, days lost from work, work productivity, satisfaction with care and health-care use. A cost-utility analysis was undertaken over 12 months. A qualitative study explored patients' and clinicians' views of the fast-track care pathway to a spinal specialist., Results: A total of 476 patients were randomised (238 in each arm). For the primary outcome, the overall response rate was 89.3% (88.3% and 90.3% in the stratified and usual care arms, respectively). Relief from symptoms was slightly faster (2 weeks median difference) in the stratified care arm, but this difference was not statistically significant (hazard ratio 1.14, 95% confidence interval 0.89 to 1.46; p  = 0.288). On average, participants in both arms reported good improvement from baseline, on most outcomes, over time. Following the assessment at the research clinic, most participants in the usual care arm were referred to physiotherapy., Conclusions: The stratified care model tested in this trial was not more clinically effective than usual care, and was not likely to be a cost-effective option. The fast-track pathway was felt to be acceptable to both patients and clinicians; however, clinicians expressed reluctance to consider invasive procedures if symptoms were of short duration., Limitations: Participants in the usual care arm, on average, reported good outcomes, making it challenging to demonstrate superiority of stratified care. The performance of the algorithm used to allocate patients to treatment pathways may have influenced results., Future Work: Other approaches to stratified care may provide superior outcomes for sciatica., Trial Registration: Current Controlled Trials ISRCTN75449581., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 49. See the NIHR Journals Library website for further project information., Competing Interests: Sue Jowett is (from 2016 to present) a member of the National Institute for Health Research Health Technology Assessment Clinical Trials Committee and reports personal fees as an independent advisor at the Pfizer (Pfizer Inc., New York, NY, USA) chronic pain advisory board meeting in November 2018, outside the submitted work. Kate M Dunn reports grants from the Wellcome Trust (London, UK), during the conduct of the study.

The overall quality of care for musculoskeletal pain conditions is suboptimal, partly due to a considerable evidence-practice gap. In osteoarthritis and low back pain, structured models of care exist to help overcome that challenge. In osteoarthritis, focus is on stepped care models, where treatment decisions are guided by response to treatment, and increasingly comprehensive interventions are only offered to people with inadequate response to more simple care. In low back pain, the most widely known approach is based on risk stratification, where patients with higher predicted risk of poor outcome are offered more comprehensive care. For both conditions, the recommended interventions and models of care share many commonalities and there is no evidence that one model of care is more effective than the other. Limitations of existing models of care include a lack of integrated information on social factors, comorbid conditions, and previous treatment experience, and they do not support an interplay between health care, self-management, and community-based activities. Moving forwards, a common model across musculoskeletal conditions seems realistic, which points to an opportunity for reducing the complexity of implementation. We foresee this development will use big data sources and machine-learning methods to combine stepped and risk-stratified care and to integrate self-management support and patient-centred care to a greater extent in future models of care., Competing Interests: The authors declare there are no conflicts of interest. A. Kongsted's position at the University of Southern Denmark is partly financed by an unrestricted grant from the Foundation for Chiropractic Research and Postgraduate Education. J.C. Hill, S.T. Skou, and A. Kongsted are, respectively, part of the groups that developed the STarT Back Screening Tool, the GLA:D program for knee/hip, and the GLA:D program for LBP. A. Kongsted is an associate editor of the BMC Chiropractic and Manual Therapy journal. S.T. Skou is an associate editor of the Journal of Orthopaedic & Sports Physical Therapy, and has received grants from The Lundbeck Foundation and personal fees from Munksgaard, all of which are outside the submitted work. S.T. Skou is currently funded by grants from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 801790) and from Region Zealand (Exercise First), both unrelated to the current study. J.G. Quicke is partly funded by a NIHR Clinical Research Network West Midlands, Research Scholar Fellowship, and is a member of the NICE OA guideline committee. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care, or NICE.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Severe cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO 2 /FiO 2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Objective: We explored patients' experiences of using Internet-based self-management support for low back pain (LBP) in primary care, with and without physiotherapist telephone guidance., Design: Exploratory descriptive qualitative study using thematic analysis, nested within a randomized feasibility trial., Methods: Patients with LBP who participated in a feasibility trial of the SupportBack Internet intervention (ISRCTN: 31034004) were invited to take part in semistructured telephone interviews after the three-month intervention period (a convenience sample from within the trial population). Fifteen participants took part (age range = 36-87 years, 66.7% female, characteristics representative of the trial population). Data were analyzed thematically., Results: Analysis resulted in the development of six themes (subthemes in parentheses): Perceptions of SupportBack's design (Clarity and ease of use, Variety and range of information provided, Need for specificity and flexibility), Engaging with the SupportBack intervention, Promoting positive thought processes (Reassurance, Awareness of self-management), Managing behavior with SupportBack (Motivation and goal setting, Using activity as a pain management strategy, Preferences for walking or gentle back exercises), Feeling supported by telephone physiotherapists (Provision of reassurances and clarity, Physiotherapists are motivating), Severity and comorbidity as barriers (Preexisting condition or severity acting as a barrier, Less useful for mild low back pain)., Conclusions: The Internet intervention SupportBack appeared to feasibly support self-management of LBP. Reassurance and ongoing support to implement behavioral changes were central to reported benefits. The addition of physiotherapist telephone support further enhanced the patient experience and the potential utility of the intervention., (© 2019 American Academy of Pain Medicine.)

Introduction: The enhanced recovery after surgery (ERAS) concept in arthroplasty surgery has led to a reduction in postoperative length of stay in recent years. Patients with prolonged length of stay (PLOS) add to the burden of a strained NHS. Our aim was to identify the main reasons., Methods: A PLOS was arbitrarily defined as an inpatient hospital stay of four days or longer from admission date. A total of 2,000 consecutive arthroplasty patients between September 2017 and July 2018 were reviewed. Of these, 1,878 patients were included after exclusion criteria were applied. Notes for 524 PLOS patients were audited to determine predominant reasons for PLOS., Results: The mean total length of stay was 4 days (1 to 42). The top three reasons for PLOS were social services, day-before-surgery admission, and slow to mobilize. Social services accounted for 1,224 excess bed days, almost half (49.2%, 1,224/2,489) of the sum of excess bed days., Conclusion: A preadmission discharge plan, plus day of surgery admission and mobilization on the day of surgery, would have the potential to significantly reduce length of stay without compromising patient care.Cite this article: Bone Joint Open 2020;1-8:488-493., (© 2020 Author(s) et al.)

In our paper published in this journal, we present a pilot study application of a novel way to "indirectly assess" skeletal muscle glycogen based on the methodology that we developed though high-frequency skeletal muscle ultrasound [...].

Background: The Musculoskeletal Health Questionnaire (MSK-HQ) has been developed to measure musculoskeletal health status across musculoskeletal conditions and settings. However, the MSK-HQ needs to be further evaluated across settings and different languages., Objective: The objective of the study was to evaluate and compare measurement properties of the MSK-HQ across Danish (DK) and English (UK) cohorts of patients from primary care physiotherapy services with musculoskeletal pain., Methods: MSK-HQ was translated into Danish according to international guidelines. Measurement invariance was assessed by differential item functioning (DIF) analyses. Test-retest reliability, measurement error, responsiveness and minimal clinically important change (MCIC) were evaluated and compared between DK (n = 153) and UK (n = 166) cohorts., Results: The Danish version demonstrated acceptable face and construct validity. Out of the 14 MSK-HQ items, three items showed DIF for language (pain/stiffness at night, understanding condition and confidence in managing symptoms) and three items showed DIF for pain location (walking, washing/dressing and physical activity levels). Intraclass Correlation Coefficients for test-retest were 0.86 (95% CI 0.81 to 0.91) for DK cohort and 0.77 (95% CI 0.49 to 0.90) for the UK cohort. The systematic measurement error was 1.6 and 3.9 points for the DK and UK cohorts respectively, with random measurement error being 8.6 and 9.9 points. Receiver operating characteristic (ROC) curves of the change scores against patients' own judgment at 12 weeks exceeded 0.70 in both cohorts. Absolute and relative MCIC estimates were 8-10 points and 26% for the DK cohort and 6-8 points and 29% for the UK cohort., Conclusions: The measurement properties of MSK-HQ were acceptable across countries, but seem more suited for group than individual level evaluation. Researchers and clinicians should be aware that some discrepancy exits and should take the observed measurement error into account when evaluating change in scores over time.

Skeletal muscle glycogen (SMG) stores in highly glycolytic activities regulate muscle contraction by controlling calcium release and uptake from sarcoplasmic reticulum, which could affect muscle contraction. Historically, the assessment of SMG was performed through invasive and non-practical muscle biopsies. In this study we have utilized a novel methodology to assess SMG through a non-invasive high-frequency ultrasound. Nine MLS professional soccer players (180.4 ± 5.9 cm; 72.4 ± 9.3 kg; 10.4% ± 0.7% body fat) participated. All followed the nutritional protocol 24 h before the official match as well as performing the same practice program the entire week leading to the match. The SMG decreased from 80 ± 8.6 to 63.9 ± 10.2; p = 0.005 on MuscleSound ® score (0-100) representing a 20% ± 10.4% decrease in muscle glycogen after match. Inter-individual differences in both starting glycogen content (65-90) and in percentage decrease in glycogen after the match (between 6.2% and 44.5%). Some players may not start the match with adequate SMG while others' SMG decreased significantly throughout the game. Adequate pre-match SMG should be achieved during half-time and game-play in order to mitigate the decrease in glycogen. Further and more ample studies are needed before the application of this technology.

Background: Musculoskeletal (MSK) pain from the five most common presentations to primary care (back, neck, shoulder, knee or multi-site pain), where the majority of patients are managed, is a costly global health challenge. At present, first-line decision-making is based on clinical reasoning and stratified models of care have only been tested in patients with low back pain. We therefore, examined the feasibility of; a) a future definitive cluster randomised controlled trial (RCT), and b) General Practitioners (GPs) providing stratified care at the point-of-consultation for these five most common MSK pain presentations., Methods: The design was a pragmatic pilot, two parallel-arm (stratified versus non-stratified care), cluster RCT and the setting was 8 UK GP practices (4 intervention, 4 control) with randomisation (stratified by practice size) and blinding of trial statistician and outcome data-collectors. Participants were adult consulters with MSK pain without indicators of serious pathologies, urgent medical needs, or vulnerabilities. Potential participant records were tagged and individuals sent postal invitations using a GP point-of-consultation electronic medical record (EMR) template. The intervention was supported by the EMR template housing the Keele STarT MSK Tool (to stratify into low, medium and high-risk prognostic subgroups of persistent pain and disability) and recommended matched treatment options. Feasibility outcomes included exploration of recruitment and follow-up rates, selection bias, and GP intervention fidelity. To capture recommended outcomes including pain and function, participants completed an initial questionnaire, brief monthly questionnaire (postal or SMS), and 6-month follow-up questionnaire. An anonymised EMR audit described GP decision-making., Results: GPs screened 3063 patients (intervention = 1591, control = 1472), completed the EMR template with 1237 eligible patients (intervention = 513, control = 724) and 524 participants (42%) consented to data collection (intervention = 231, control = 293). Recruitment took 28 weeks (target 12 weeks) with > 90% follow-up retention (target > 75%). We detected no selection bias of concern and no harms identified. GP stratification tool fidelity failed to achieve a-priori success criteria, whilst fidelity to the matched treatments achieved "complete success"., Conclusions: A future definitive cluster RCT of stratified care for MSK pain is feasible and is underway, following key amendments including a clinician-completed version of the stratification tool and refinements to recommended matched treatments., Trial Registration: Name of the registry: ISRCTN., Trial Registration Number: 15366334. Date of registration: 06/04/2016.