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Background: Certain groups are commonly under-served by health research due to exclusionary models of research design/delivery. Working in partnership with under-served groups is key to improving inclusion. This project aimed to explore the use of a knowledge mobilisation approach to start building partnerships with under-served groups based on trust and mutual understanding., Methods: This co-produced public involvement project employed a knowledge mobilisation approach. The project team involved public contributors from four community organisations and staff from two Universities. A series of 'community conversations' were co-produced. These involved open discussions with local people in community settings. The conversations provide an informal space to engage in a multi-directional dialogue about health research and incorporated approaches such as prompt questions, live illustrations, and themed boards. The findings were reviewed collectively. Dissemination/feedback activities and lessons learned for future engagement with community organisations and under-served groups were also co-produced., Results: Over 100 people attended the community conversations. Attendees varied widely in their sociodemographic characteristics (e.g., socioeconomic status and ethnicity) and brought diverse lived experiences (e.g., experiences of homelessness and disability). A strong appetite for change and desire to mobilise public knowledge were evident. Attendees reported wide-ranging barriers to inclusion in health research and suggested ways to address them. Three inter-related take-home messages were identified: ensure relevance, appreciation, and trust; prioritise language and accessibility needs; and maximise flexibility in all research-related activities. Feedback about the community conversations and dissemination activities was largely positive, with all parties planning to continue the partnership building. The lessons learned provide practical suggestions for promoting inclusion in research and highlight the importance of addressing research teams' training/support needs., Conclusions: Knowledge mobilisation was a valuable approach for facilitating multi-directional dialogues and relationship building between local communities and university teams. This approach enabled co-creation of new knowledge related to inclusion and partnership working in health research. The project has provided a firm foundation to build upon. However, creating sustainable, inclusive public partnerships is likely to require systemic changes, such as weighting of fundings schemes to projects that prioritise inclusion of under-served groups throughout the research cycle., Competing Interests: Declarations Ethics approval and consent to participate Ethical approval was not sought because this was a public involvement project. Consent for publication Not applicable. Availability of data and materials No datasets were generated or analysed during the current study. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To identify and synthesise the content of knee bracing interventions in randomised controlled trials (RCTs) of knee osteoarthritis (OA)., Design: In this scoping review, three electronic databases (PubMed, Web of Science, Cochrane) were searched up to 10th June 2024. Nineteen previous systematic reviews of knee bracing for knee OA and four recent international clinical practice guidelines were also hand searched. Identified studies were screened for eligibility by two independent reviewers. Information on bracing interventions was extracted from included RCT reports, informed by Template for Intervention Description and Replication (TIDieR) guidelines. Data were synthesised narratively., Results: Thirty-one RCTs testing 47 different bracing interventions were included. Braces were broadly grouped as valgus/varus, patellofemoral, sleeve, neutral hinged, or control/placebo knee braces. Brace manufacturer and models varied, as did amount of recommended brace use. Only three interventions specifically targeted brace adherence. Information on brace providers, setting, number of treatment sessions, and intervention modification over time was poorly reported. Adherence to brace use was described for 32 (68%) interventions, most commonly via self-report. Several mechanisms of action for knee braces were proposed, broadly grouped as biomechanical, neuromuscular, and psychological., Conclusions: Many different knee brace interventions have been tested for knee OA, with several proposed mechanisms of action, a lack of focus on adherence, and a lack of full reporting. These issues may be contributing to the heterogeneous findings and inconsistent guideline recommendations about the clinical effectiveness of knee bracing for knee OA to date., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Anthraquinones are polycyclic compounds with an unsaturated diketone structure (quinoid moiety). As important secondary metabolites of plants, anthraquinones play an important role in the response of many biological processes and environmental factors. Anthraquinones are common in the human diet and have a variety of biological activities including anticancer, antibacterial, and antioxidant activities that reduce disease risk. The biological activity of anthraquinones depends on the substitution pattern of their hydroxyl groups on the anthraquinone ring structure. However, there is still a lack of systematic summary on the distribution, classification, and biosynthesis of plant anthraquinones. Therefore, this paper systematically reviews the research progress of the distribution, classification, biosynthesis, and regulation of plant anthraquinones. Additionally, we discuss future opportunities in anthraquinone research, including biotechnology, therapeutic products, and dietary anthraquinones., (© 2023 Wiley Periodicals LLC.)

Background: The aim of this project is to evaluate public contributors' experiences of their involvement in qualitative data analysis workshops during an on-going research project titled 'Personalised Primary care for Patients with Multiple long-term conditions'., Methods: Four qualitative data analysis workshops were designed and conducted between August and December 2023. We used the Cube evaluation framework (henceforth referred to as the Cube) to evaluate the workshops. The Cube suggests four domains for successful PPI (voice, agenda, change, contribute).Within Workshops One, Two and Three public contributors had to login to an account to access the Cube; this was modified in Workshop Four following feedback from public contributors., Findings: Across the four workshops the Cube was completed 11 times. Across all four workshops, public contributors thought that their voice was heard, that there were diverse ways to contribute and that they led the agenda. Public contributors thought that researchers responded to their questions and issues, when necessary., Conclusion: This evaluation has shown that public contributors can gain new skills and lead qualitative data analysis discussions., (© 2024. The Author(s).)

Background: Twitter (now X) is a digital social network commonly used by health care professionals. Little is known about whether it helps health care professionals to share, mobilize, and cocreate knowledge or reduce the time between research knowledge being created and used in clinical practice (the evidence-to-practice gap). Musculoskeletal first contact physiotherapists (FCPs) are primary care specialists who diagnose and treat people with musculoskeletal conditions without needing to see their general practitioner (family physician) first. They often work as a sole FCP in practice; hence, they are an ideal health care professional group with whom to explore knowledge mobilization using Twitter., Objective: We aimed to explore how Twitter is and can be used to mobilize knowledge, including research findings, to inform FCPs' clinical practice., Methods: Semistructured interviews of FCPs with experience of working in English primary care were conducted. FCPs were purposively sampled based on employment arrangements and Twitter use. Recruitment was accomplished via known FCP networks and Twitter, supplemented by snowball sampling. Interviews were conducted digitally and used a topic guide exploring FCP's perceptions and experiences of accessing knowledge, via Twitter, for clinical practice. Data were analyzed thematically and informed by the knowledge mobilization mindlines model. Public contributors were involved throughout., Results: In total, 19 FCPs consented to the interview (Twitter users, n=14 and female, n=9). Three themes were identified: (1) How Twitter meets the needs of FCPs, (2) Twitter and a journey of knowledge to support clinical practice, and (3) factors impeding knowledge sharing on Twitter. FCPs described needs relating to isolated working practices, time demands, and role uncertainty. Twitter provided rapid access to succinct knowledge, the opportunity to network, and peer reassurance regarding clinical cases, evidence, and policy. FCPs took a journey of knowledge exchange on Twitter, including scrolling for knowledge, filtering for credibility and adapting knowledge for in-service training and clinical practice. Participants engaged best with images and infographics. FCPs described misinformation, bias, echo chambers, unprofessionalism, hostility, privacy concerns and blurred personal boundaries as factors impeding knowledge sharing on Twitter. Consequently, many did not feel confident enough to actively participate on Twitter., Conclusions: This study explores how Twitter is and can be used to mobilize knowledge to inform FCP clinical practice. Twitter can meet the knowledge needs of FCPs through rapid access to succinct knowledge, networking opportunities, and professional reassurance. The journey of knowledge exchange from Twitter to clinical practice can be explained by considering the mindlines model, which describes how FCPs exchange knowledge in digital and offline contexts. Findings demonstrate that Twitter can be a useful adjunct to FCP practice, although several factors impede knowledge sharing on the platform. We recommend social media training and enhanced governance guidance from professional bodies to support the use of Twitter for knowledge mobilization., (©Laura Campbell, Jonathan Quicke, Kay Stevenson, Zoe Paskins, Krysia Dziedzic, Laura Swaithes. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.07.2024.)

Competing Interests: The authors report no conflict of interest.

An alkali-silica reaction (ASR) is a chemical process that leads to the formation of an expansive gel, potentially causing durability issues in concrete structures. This article investigates the properties and behaviour of ASR products in mortar with the addition of low-purity calcined clay as an additional material. This study includes an evaluation of the expansion and microstructural characteristics of the mortar, as well as an analysis of the formation and behaviour of ASR products with different contents of calcined clay. Expansion tests of the mortar beam specimens were conducted according to ASTM C1567, and a detailed microscopic analysis of the reaction products was performed. Additionally, their mechanical properties were determined using nanoindentation. This study reveals that with an increasing calcined clay content, the amount of the crystalline form of the ASR gel decreases, while the nanohardness increases. The Young's modulus of the amorphous ASR products ranged from 5 to 12 GPa, while the nanohardness ranged from 0.41 to 0.67 GPa. The obtained results contribute to a better understanding of how the incorporation of low-purity calcined clay influences the ASR in mortar, providing valuable insights into developing sustainable and durable building materials for the construction industry.

Objective: Implementing clinical guidelines for osteoarthritis (OA) in primary care is complex. Whilst international guidelines detail what best practice for OA looks like, little is known about how this is best implemented. Limited resources are available to guideline developers, practitioners, researchers, or the public to facilitate implementation. Set in the context of a larger research project which sought to understand the factors that influence knowledge mobilisation (KM) in implementation for OA guidelines, this study reports the development of a toolkit to optimise KM for the implementation of evidence-based OA guidelines in primary care., Design: Triangulation of three qualitative data sets was conducted, followed by a stakeholder consensus exercise. Public contributors were involved in dedicated meetings (n = 3) to inform the content, design, and KM plans for the toolkit., Results: From data triangulation, 53 key findings were identified, which were refined into 30 draft recommendation statements, within six domains: approaches to KM; the knowledge mobiliser role; understanding context; implementation planning; the nature of the intervention; and appealing to a range of priorities. Stakeholder voting (n = 27) demonstrated consensus with the recommendations and informed the wording of the final toolkit., Conclusions: Factors that optimise KM for OA guideline implementation in primary care were identified. Empirical data, practice-based evidence, implementation practice, and stakeholder (including patient and public) engagement have informed a toolkit comprising several overarching principles of KM, which are suitable for use in primary care. Consideration of equitable access when implementing evidence-based OA care among diverse populations is recommended when using the toolkit. Further research is needed to evaluate the toolkit's utility and transferability., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D)., Methods: The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.9 kg/m 2 ) was performed after single (24 subjects, 5-480 mg) and multiple (32 subjects, 60-480 mg) once-daily administration of CPL207280.  The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C-peptide, proinsulin, glucagon levels) observed during the 14-day treatment period., Results: No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (C max ) or area under the plasma concentration-time curve up to 24 h. However, dose-normalized C max decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half-life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed., Conclusions: CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single-daily administration and justifies further development of this therapy for patients with T2D., (© 2024 Celon Pharma. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: This project (named Reinvent) aimed to promote Public Involvement (PI) in health research. Academics worked with a community group, the Eloquent Praise & Empowerment Dance Company, to develop a community partnership with young people from Black African, Asian and Caribbean heritage communities. The goal of this paper is to evaluate the Reinvent project for key learnings on how to engage and build partnerships with young people from Black African, Asian and Caribbean heritage communities., Methods: Reinvent developed a steering group which consisted of five young people, one academic, a Race Equality Ambassador and the Director of Eloquent. The steering group co-produced an agenda for two workshops and the evaluation tools used. The content of the workshops included drama exercises, discussions on physical and mental health, nutrition and school-life, short introductions to the concepts of research and PI, and group work to critique and improve a video currently used to promote PI in health research to young people. The evaluation tools included using the 'Cube' evaluation framework, video-blogging and collecting anonymous feedback. Findings The responses to the 'Cube' evaluation framework were positive across all four domains (agenda, voice, contribute change) in both workshops. A few of the young people described having a better understanding of the meaning and practice of PI in a video-blog. The anonymous feedback suggested that the workshops had increased young people's confidence in sharing their thoughts and opinions about health and PI., Conclusion: Reinvent has shown that academic institutions and young people from an under-served community can partner to co-design workshops and apply evaluation tools. Working with young people in an environment in which they were comfortable, and by researchers joining in with the activities that the young people enjoyed (such as dance), enabled more informal and open conversations to develop. More work is needed to build upon this project so that young people can feel confident and supported to get involved in PI activities relating to research., (© 2024. The Author(s).)

The introduction of Integrated Care Systems (ICS) in England aimed to increase joint planning and delivery of health and social care, and other services, to better meet the needs of local communities. There is an associated duty to undertake collaborative research across ICS partners to inform this new integrated approach, which might be challenging given that organisations span health, local authority, voluntary and community sector, and research. This study aimed to explore the appetite for collaborative Research and Innovation (R&I) across ICSs, potential barriers and solutions. This qualitative study involved semi-structured interviews with 24 stakeholders who held senior positions within organisations across two ICS areas (Staffordshire and Stoke-on-Trent; Shropshire, Telford and Wrekin). Interview transcripts were analysed using inductive and deductive analysis, first mapping to the Theoretical Domains Framework (TDF), then considering key influences on organisational behaviour in terms of Capability, Opportunity and Motivation from the COM-B Behaviour Change Wheel. There were fundamental limitations on organisational opportunities for collaborative R&I: a historical culture of competition (rather than collaboration), a lack of research culture and prioritisation, compounded by a challenging adverse economic environment. However, organisations were motivated to undertake collaborative R&I. They recognised the potential benefits (e.g., skill-sharing, staff development, attracting large studies and funding), the need for collaborative research that mirrors integrated care, and subsequent benefits for care recipients. Related barriers included negative experiences of collaboration, fear of failing and low confidence. Capability varied across organisations in terms of research skills and confidence, which reflected the range of partners (from local authorities to NHS Trusts, primary care, and academic institutions). These findings indicate a need to shift from a culture of competition to collaboration, and to help organisations across ICS to prioritise research, and share resources and skills to mitigate the limiting effects of a constrained economic environment. This could be further explored using a systems change approach, to develop the collaborative research efforts alongside the overarching move towards integrated care., (© 2024. The Author(s).)

Introduction: Osteoarthritis is the commonest form of chronic joint pain, which patients often self-manage before seeking healthcare advice. Patients frequently seek advice from community pharmacies, and a recent policy has recommended integrating community pharmacies into long-term condition pathways. This study explored community pharmacy teams' (CPs) and other healthcare professionals' (HCPs) views on community pharmacies providing an extended role for osteoarthritis management, identifying potential barriers and facilitators to this., Methods: A multi-methods study comprising surveys of CPs and other HCPs, followed by qualitative interviews. Descriptive statistics were used in an exploratory analysis of the survey data. Qualitative data were analysed using reflexive thematic analysis and the identified barriers and facilitators were mapped to the Theoretical Domains Framework., Result: CPs and other HCPs in the surveys and interviews reported that an extended role for osteoarthritis management could include: a subjective assessment, explaining the joint problem and its treatment, medication management and support for self-care. There was less consensus on diagnosing the problem as OA and completing an objective assessment. A key facilitator was training to deliver the role, whilst barriers were high workload and lack of access to General Practitioner medical records., Discussion: Acceptable elements of an extended community pharmacy role for osteoarthritis centre around the provision of information, advice on medication and supported self-management., Conclusion: CPs are well placed to contribute towards evidenced-based osteoarthritis management. Feasibility testing of delivering the extended role is needed and future implementation requires training for CPs and raising public awareness of the extended role., (© 2024 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Introduction: Globally, back pain is the leading cause of years of disability. In the United Kingdom, over 20 million people live with musculoskeletal (MSK) pain, with low back pain being one of the most common causes. National strategies promote self-management and the use of digital technologies to empower populations., Aims: To evaluate the uptake and impact of providing the SelfSTart approach (STarT Back and SelfBACK App) when delivered by a First Contact Physiotherapist (FCP) to people presenting with low back pain in primary care., Methods: Patients presenting with a new episode of low back pain underwent routine assessment and completion of a STarT Back questionnaire. Patients with low/medium scores were offered the SelfBACK App. A control population was provided by the MIDAS-GP study. Patient Experience, outcome measures, healthcare utilisation and retention were captured through the app and clinical systems (EMIS). Interviews with five FCPs explored the experiences of using the SelfSTart approach., Results: SelfSTarT was taken up by almost half (48%) of those to whom it was offered. Compared to MIDAS-GP, users were more likely to be younger, male, in work, and with higher health literacy. SelfSTarT users reported significant improved experiences relating to receiving an agreed care plan and receiving sufficient information. There were no significant differences in treatments offered. FCPs were positive about the app and felt it had value but wanted feedback on patient progress. They recognised that a digital solution would not be suitable for all., Conclusion: This approach offers an opportunity to empower and support self-management, using robustly evaluated digital technology., (© 2024 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Precision manufacturing requirements are the key to ensuring the quality and reliability of biomedical implants. The powder bed fusion (PBF) technique offers a promising solution, enabling the creation of complex, patient-specific implants with a high degree of precision. This technology is revolutionizing the biomedical industry, paving the way for a new era of personalized medicine. This review explores and details powder bed fusion 3D printing and its application in the biomedical field. It begins with an introduction to the powder bed fusion 3D-printing technology and its various classifications. Later, it analyzes the numerous fields in which powder bed fusion 3D printing has been successfully deployed where precision components are required, including the fabrication of personalized implants and scaffolds for tissue engineering. This review also discusses the potential advantages and limitations for using the powder bed fusion 3D-printing technology in terms of precision, customization, and cost effectiveness. In addition, it highlights the current challenges and prospects of the powder bed fusion 3D-printing technology. This work offers valuable insights for researchers engaged in the field, aiming to contribute to the advancement of the powder bed fusion 3D-printing technology in the context of precision manufacturing for biomedical applications.

Background: Osteoarthritis is a common, painful and disabling long-term condition. Delivery of high-quality guideline-informed osteoarthritis care that successfully promotes and maintains supported self-management is imperative. However, osteoarthritis care remains inconsistent, including under use of core non-pharmacological approaches of education, exercise and weight loss. Community pharmacies are an accessible healthcare provider. United Kingdom government initiatives are promoting their involvement in a range of long-term conditions, including musculoskeletal conditions. It is not known what an enhanced community pharmacy role for osteoarthritis care should include, what support is needed to deliver such a role, and whether it would be feasible and acceptable to community pharmacy teams. In this (PharmOA) study, we aim to address these gaps, and co-design and test an evidence-based extended community pharmacy model of service delivery for managing osteoarthritis., Methods: Informed by the Theoretical Domains Framework, Normalisation Process Theory, and the Medical Research Council (MRC) framework for developing complex interventions, we will undertake a multi-methods study involving five phases: 1. Systematic review to summarise currently available evidence on community pharmacy roles in supporting adults with osteoarthritis and other chronic (non-cancer) pain. 2. Cross-sectional surveys and one-to-one qualitative interviews with patients, healthcare professionals and pharmacy staff to explore experiences of current, and potential extended community pharmacy roles, in delivering osteoarthritis care. 3. Stakeholder co-design to: a) agree on the extended role of community pharmacies in osteoarthritis care; b) develop a model of osteoarthritis care within which the extended roles could be delivered (PharmOA model of service delivery); and c) refine existing tools to support community pharmacies to deliver extended osteoarthritis care roles (PharmOA tools). 4. Feasibility study to explore the acceptability and feasibility of the PharmOA model of service delivery and PharmOA tools to community pharmacy teams. 5. Final stakeholder workshop to: a) finalise the PharmOA model of service delivery and PharmOA tools, and b) if applicable, prioritise recommendations for its wider future implementation., Discussion: This novel study paves the way to improving access to and availability of high-quality guideline-informed, consistent care for people with osteoarthritis from within community pharmacies., (© 2024. The Author(s).)

Background: This study examines how the neutrophil-lymphocyte ratio (NLR) predicts coronavirus disease 2019 (COVID-19) hospitalization, severity, length, and mortality in adult patients., Methods: A study was done using a retrospective, single-center, observational design. A total of 400 patients who were admitted to the Ziv Medical Center (Safed, Israel) from April 2020 to December 2021 with a confirmed diagnosis of COVID-19 through RT-PCR testing were included in the analysis. Two complete blood count laboratory tests were conducted for each patient. The first test was administered upon admission to the hospital, while the second test was conducted prior to the patient's discharge from the hospital or a few days before their death., Results: Four hundred patients were included in the study, 206 males (51.5%) and 194 females (48.5%). The mean age was 64.5 ± 17.1 years. In the group of cases, there were 102 deaths, and 296 survivors were recorded, with a fatality rate of 25.5%. The median NLR was 6.9 ± 5.8 at the beginning of hospitalization and 15.1 ± 32.9 at the end of hospitalization (p < 0.001). The median length of hospital stay was 9.4 ± 8.8 days. NLR in the fatality group was 34.0 ± 49.9 compared to 8.4 ± 20.4 in the survivor group (p < 0.001). Comparison between the NLR at the time of admission of the patient and before discharge/death was 6.9 ± 5.8 vs. 15.1 ± 32.9 (p < 0.001)., Conclusions: The analyses conducted revealed a statistically significant correlation between the NLR and the severity, mortality rates, and the duration of hospitalization. The consideration of NLR should commence during the initial phases of the disease when assessing individuals afflicted with COVID-19.

Objective: To assess the quality of care, effectiveness, and cost-effectiveness over 12 months after implementing a structured model of care for hip and knee osteoarthritis (OA) in primary healthcare as compared to usual care., Design: In this pragmatic cluster-randomized, controlled trial with a stepped-wedge cohort design, we recruited 40 general practitioners (GPs), 37 physiotherapists (PTs), and 393 patients with symptomatic hip or knee OA from six municipalities (clusters) in Norway. The model included the delivery of a 3-hour patient education and 8-12 weeks individually tailored exercise programs, and interactive workshops for GPs and PTs. At 12 months, the patient-reported quality of care was assessed by the OsteoArthritis Quality Indicator questionnaire (16 items, pass rate 0-100%, 100%=best). Costs were obtained from patient-reported and national register data. Cost-effectiveness at the healthcare perspective was evaluated using incremental net monetary benefit (INMB)., Results: Of 393 patients, 109 were recruited during the control periods (control group) and 284 were recruited during interventions periods (intervention group). At 12 months the intervention group reported statistically significant higher quality of care compared to the control group (59% vs. 40%; mean difference: 17.6 (95% confidence interval [CI] 11.1, 24.0)). Cost-effectiveness analyses showed that the model of care resulted in quality-adjusted life-years gained and cost-savings compared to usual care with mean INMB €2020 (95% CI 611, 3492) over 12 months., Conclusions: This study showed that implementing the model of care for OA in primary healthcare, improved quality of care and showed cost-effectiveness over 12 months compared to usual care., Trial Registration Number: ClinicalTrials.gov NCT02333656., Competing Interests: Declaration of Competing Interest NØ is part funded by The Research Council of Norway (No. 328657 REMEDY). EAA is part funded by The Research Council of Norway (No. 296114 NORCHER). KD is part funded by the National Institute for Health and Care Research (NIHR) Applied Health Research Collaboration (ARC) West Midlands (NIHR 200165). KD is an NIHR Senior Investigator (ID NIHR 200259). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This final article in the four-part series focuses on the often neglected yet important role of the public in implementing research in General Practice and Primary Care more broadly. Experience in implementation of findings from research with public engagement in Primary Care has highlighted how partnership working with patients and the public is important in transitioning from 'what we know' from the evidence-base to 'what we do' in practice. Factors related to Primary Care research that make public engagement important are highlighted e.g. implementing complex interventions, implementing interventions that increase health equity, implementing interventions in countries with different primary healthcare system strengths. Involvement of patients and public can enhance the development of modelling and simulation included in studies on systems modelling for improving health services. We draw on the emerging evidence base to describe public engagement in implementation and offer some guiding principles for engaging with the public in the implementation in General Practice and Primary Care in general. Illustrative case studies are included to support others wishing to offer meaningful engagement in implementing research evidence.

Objective: The Joint Effort Initiative (JEI) is an international collaboration of clinicians, researchers, and consumer organisations with a shared vision of improving the implementation of osteoarthritis management programs (OAMPs). This study aimed to identify JEI's future priorities and guide direction., Design: A two-part international survey to prioritise topics of importance to our membership and research stakeholders. Survey one presented a list of 40 topics under 5 themes. Consenting participants were asked to choose their top three topics in each theme. A short list of 25 topics was presented in survey two. Participants were asked to rank the importance (100-point NRS scale, 100 ​= ​highest priority). Response frequency (median, IQR) was used to rank the top priorities by theme., Results: Ninety-five participants completed survey one (61% female, 48% clinicians) and 57 completed survey two. The top ranked topic/s were:i. Promotion and advocacy: support training for health professionals (median 85, IQR 24).ii. Education and training: incorporating behaviour change into OAMPs (80, 16), advanced OA skills (80, 30), and integration of OA education into clinical training (80, 36).iii. Improving OAMPs delivery: regular updates on changes to best-evidence OA care (84, 24).iv. Future research: improve uptake of exercise, physical activity, and weight-loss (89, 16).v. Enhancing relationships, alliances, and shared knowledge: promote research collaborations (81, 30), share challenges and opportunities for OAMP implementation (80, 23)., Conclusions: These topics will set the JEI's research and collaboration agenda for the next 5 years and stimulate ideas for others working in the field., Competing Interests: DJH is the co-director of the Sydney Musculoskeletal Health Flagship. In addition, DJH is the editor of the osteoarthritis section for UpToDate, co-Editor in Chief of Osteoarthritis and Cartilage and board member of Osteoarthritis Research Society International. DJH provides consulting advice on scientific advisory boards for Pfizer, Lilly, TLCBio, Novartis, Tissuegene, and Biobone. KLB receives royalties from Wolter Kluwers. The remaining authors declare no conflict of interest., (© 2023 The Author(s).)

Background: Many international clinical guidelines recommend therapeutic exercise as a core treatment for knee and hip osteoarthritis. We aimed to identify individual patient-level moderators of the effect of therapeutic exercise for reducing pain and improving physical function in people with knee osteoarthritis, hip osteoarthritis, or both., Methods: We did a systematic review and individual participant data (IPD) meta-analysis of randomised controlled trials comparing therapeutic exercise with non-exercise controls in people with knee osteoathritis, hip osteoarthritis, or both. We searched ten databases from March 1, 2012, to Feb 25, 2019, for randomised controlled trials comparing the effects of exercise with non-exercise or other exercise controls on pain and physical function outcomes among people with knee osteoarthritis, hip osteoarthritis, or both. IPD were requested from leads of all eligible randomised controlled trials. 12 potential moderators of interest were explored to ascertain whether they were associated with short-term (12 weeks), medium-term (6 months), and long-term (12 months) effects of exercise on self-reported pain and physical function, in comparison with non-exercise controls. Overall intervention effects were also summarised. This study is prospectively registered on PROSPERO (CRD42017054049)., Findings: Of 91 eligible randomised controlled trials that compared exercise with non-exercise controls, IPD from 31 randomised controlled trials (n=4241 participants) were included in the meta-analysis. Randomised controlled trials included participants with knee osteoarthritis (18 [58%] of 31 trials), hip osteoarthritis (six [19%]), or both (seven [23%]) and tested heterogeneous exercise interventions versus heterogeneous non-exercise controls, with variable risk of bias. Summary meta-analysis results showed that, on average, compared with non-exercise controls, therapeutic exercise reduced pain on a standardised 0-100 scale (with 100 corresponding to worst pain), with a difference of -6·36 points (95% CI -8·45 to -4·27, borrowing of strength [BoS] 10·3%, between-study variance [τ 2 ] 21·6) in the short term, -3·77 points (-5·97 to -1·57, BoS 30·0%, τ 2 14·4) in the medium term, and -3·43 points (-5·18 to -1·69, BoS 31·7%, τ 2 4·5) in the long term. Therapeutic exercise also improved physical function on a standardised 0-100 scale (with 100 corresponding to worst physical function), with a difference of -4·46 points in the short term (95% CI -5·95 to -2·98, BoS 10·5%, τ 2 10·1), -2·71 points in the medium term (-4·63 to -0·78, BoS 33·6%, τ 2 11·9), and -3·39 points in the long term (-4·97 to -1·81, BoS 34·1%, τ 2 6·4). Baseline pain and physical function moderated the effect of exercise on pain and physical function outcomes. Those with higher self-reported pain and physical function scores at baseline (ie, poorer physical function) generally benefited more than those with lower self-reported pain and physical function scores at baseline, with the evidence most certain in the short term (12 weeks)., Interpretation: There was evidence of a small, positive overall effect of therapeutic exercise on pain and physical function compared with non-exercise controls. However, this effect is of questionable clinical importance, particularly in the medium and long term. As individuals with higher pain severity and poorer physical function at baseline benefited more than those with lower pain severity and better physical function at baseline, targeting individuals with higher levels of osteoarthritis-related pain and disability for therapeutic exercise might be of merit., Funding: Chartered Society of Physiotherapy Charitable Trust and the National Institute for Health and Care Research., Competing Interests: Declaration of interests RDR receives royalties for two books: Individual Participant Data Meta-analysis: A Handbook for Healthcare Research and Prognosis Research in Healthcare: Concepts, Methods and Impact. SB-Z receives consulting fees from Infirst Healthcare and Pfizer, and payment from Osteoarthritis Cartilage as a deputy editor. DAvdW is a member of PROGRESS Medical Research Council Prognosis Research Strategy (PROGRESS) Partnership (G0902393/99558). JQ was an unpaid member of the UK National Institute for Health and Care Excellence osteoarthritis guideline committee (2019–22). SB-Z, MvM, KD, and MAH are unpaid members of the OA Trial Bank Steering Committee. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Patient and public involvement (PPI) is increasingly seen as essential to health service research. There are strong moral and ethical arguments for good quality PPI. Despite the development of guidance aimed at addressing the inconsistent reporting of PPI activities within research, little progress has been made in documenting the steps taken to undertake PPI and how it influences the direction of a study. Without this information, there are minimal opportunities to share learnings across projects and strengthen future PPI practices. The aim of this paper is to present details on the processes and activities planned to integrate PPI into the qualitative research component of a mixed-methods, multi-site study evaluating the implementation of a smart template to promote personalised primary care for patients with multiple long-term conditions., Methods: This proposal describes the processes and activities planned to integrate PPI into the development and piloting of qualitative data collection tools (topic guides for both practice staff and patients) and a tailored data analysis package developed for PPI members incorporating broad concepts and specific methods of qualitative data analysis., Discussion: Outputs relating to PPI activity may include clear, concise and suitably worded topic guides for qualitative interviews. Piloting of the topic guides via mock interviews will further develop researchers' skills including sensitisation to the experiences of participants being interviewed. Working with PPI members when analysing the qualitative data aims to provide reciprocal learning opportunities and may contribute to improving the overall rigour of the data analysis. The intent of publishing proposed PPI activities within this project is to inform the future delivery of high quality PPI., (© 2023. The Author(s).)

Results of experimental investigation on the mitigation of alkali-silica reaction (ASR) by low-grade calcined clay are presented. Domestic clay with an Al 2 O 3 content equal to 26% and SiO 2 -58% was used. The calcination temperatures were as follows: 650 °C, 750 °C, 850 °C and 950 °C, which were chosen much more widely than presented in previous studies. Pozzolanity of the raw and calcined clay was determined with the Fratini test. The performance of calcined clay to mitigate ASR was evaluated according to ASTM C1567 using reactive aggregates. A control mortar mixture was prepared with 100% Portland cement (Na 2 O eq = 1.12%) as a binder with reactive aggregate, and test mixtures were made with 10% and 20% of calcined clay as a cement replacement. The microstructure of the specimens was observed on the polished sections using scanning electron microscope (SEM) operated in backscattered mode (BSE). The results of expansion of mortar bars with reactive aggregate showed that replacing cement with calcined clay reduced the expansion of the mortar bars. The greater the cement replacement, the better results in terms of ASR mitigation. However, the influence of the calcination temperature was not as clear. The opposite trend was found with the use of 10% or 20% calcined clay.

Objectives: To explore two linked strategies to highlight the best current available evidence for hydrotherapy and to explore the barriers and enablers to mobilizing this evidence into practice., Method: Phase 1: The best published evidence for hydrotherapy was collated using a Critically Appraised Topic (CAT) methodology. The focus was the best available research evidence for hydrotherapy in musculoskeletal conditions (i.e. osteoarthritis (OA), juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and low back pain (LBP)). Once evaluated for quality, a summary of the evidence was produced in a Clinical Bottom Line (CBL). Phase 2: A Focus Group explored the: CBL, the barriers and facilitators of embedding the best evidence for hydrotherapy into practice., Results: Phase 1: The CAT identified seven studies that indicated hydrotherapy had beneficial, although short term, effects for common musculoskeletal conditions. Phase 2: Six participants from primary, secondary care, private practice, and education discussed the evidence identified. They highlighted issues such as: understanding the value of hydrotherapy, an overuse of quantitative methodologies and the quality of existing research as being barriers to this knowledge being actively mobilized into clinical care., Conclusions: These two linked enquiries (CAT and Focus Group) identified the best evidence and the basis for discussion to explore barriers and facilitators of evidence use in practice. This gave an understanding of the reasons for the research to practice gap and thereby allows planning of knowledge mobilization strategies to reduce this.

Objectives: This follow-up study of the INSTinCTS (INjection vs SplinTing in Carpal Tunnel Syndrome) trial compared the effects of corticosteroid injection (CSI) and night splinting (NS) for the initial management of mild-to-moderate CTS on symptoms, resource use and carpal tunnel surgery, over 24 months., Methods: Adults with mild-to-moderate CTS were randomized 1:1 to a local corticosteroid injection or a night splint worn for 6 weeks. Outcomes at 12 and 24 months included the Boston Carpal Tunnel Questionnaire (BCTQ), hand/wrist pain intensity numeric rating scale (NRS), the number of patients referred for and undergoing CTS surgery, and healthcare utilization. A cost-utility analysis was conducted., Results: One hundred and sixteen participants received a CSI and 118 a NS. The response rate at 24 months was 73% in the CSI arm and 71% in the NS arm. By 24 months, a greater proportion of the CSI group had been referred for (28% vs 20%) and undergone (22% vs 16%) CTS surgery compared with the NS group. There were no statistically significant between-group differences in BCTQ score or pain NRS at 12 or 24 months. CSI was more costly [mean difference £68.59 (95% CI: -120.84, 291.24)] with fewer quality-adjusted life-years than NS over 24 months [mean difference -0.022 (95% CI: -0.093, 0.045)]., Conclusion: Over 24 months, surgical intervention rates were low in both groups, but less frequent in the NS group. While there were no differences in the clinical effectiveness of CSI and NS, initial treatment with CSI may not be cost-effective in the long-term compared with NS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Communities of Practice (CoPs) offer a strategy for mobilising knowledge and integrating evidence-based interventions into musculoskeletal practice, yet little is known about their practical application in this context. This study aimed to (i) explore the process of knowledge mobilisation in the context of a CoP to implement evidence-based interventions in musculoskeletal care and (ii) co-develop recommendations to optimise the process of knowledge mobilisation in CoPs., Methods: A qualitative study comprising observation of a CoP and related planning meetings (n = 5), and interviews with CoP stakeholders (including clinicians, lay members, managers, commissioners, academics) (n = 15) was undertaken. Data were analysed using thematic analysis and interpreted considering the Integrated Promoting Action on Research Implementation in Health Services theory. Public contributors were collaboratively involved at key stages of the study., Results: Four themes were identified: identifying and interpreting knowledge, practical implementation of a CoP, culture and relationship building, and responding to the external context. Resource and infrastructure enabled the set-up, delivery and running of the CoP. Support for lay members is recommended to ensure effective participation and equity of power. CoP aims and purpose can develop iteratively, and this may enhance the ability to respond to contextual changes. Several recommendations for the practical application of CoPs are suggested to create the best environment for knowledge exchange and creation, support an equitable platform for participation, and help members to navigate and make sense of the CoP in a flexible way., Conclusion: This study identified how a CoP with diverse membership can promote partnership working at the intersection between knowledge and practice. Several important considerations for preparing for and operationalising the approach in implementation have been identified. Evaluation of the costs, effectiveness and impact of CoPs is needed to better understand the value added by the approach. More broadly, research is needed to explore the practical application of online CoPs and the role of international CoPs in optimising the uptake of innovations and best practice., (© 2023. The Author(s).)

Objective: To explore the acceptability, barriers and enablers of NICE guidelines for osteoarthritis in the Scottish primary care setting using the Joint Implementation of Guidelines for Osteoarthritis in Western Europe (JIGSAW-E) model and investigate the role of Advanced Physiotherapy Practitioners (APPs) in providing evidence-based care., Design: A qualitative case study comprised of semi-structured interviews followed by a workshop with participants., Setting: 10 Scottish primary care practices., Participants: Six general practitioners (GPs) and eight APPs were interviewed. Twenty-three practitioners attended the workshop including 22 physiotherapists and one GP., Results: While both GPs and APPs recognised the need to improve and standardise osteoarthritis care delivery, this study found that APPs were better situated to implement the evidence-based model. Barriers to implementation included lack of time for training, limited appointment time for GPs to consult and discuss medication use with patients, limitation of disease specific guidelines for patients with complex multimorbidity, and system-based barriers such as electronic data collection and high staff turnover. The key enabler was practitioners' motivation to provide optimal, standardised quality care for osteoarthritis. To increase acceptance, ownership and usability for both practitioners and patients, the JIGSAW-E model materials required adaptation to the local context., Conclusion: This study provides evidence that the JIGSAW-E model is acceptable in Scottish primary care. Furthermore, the evolving roles of GPs and APPs within multidisciplinary primary care teams provides a platform to implement the JIGSAW-E model, where APPs are well placed to provide leadership and training in the delivery of evidence-based care for osteoarthritis., (Copyright © 2022 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Yield and grain composition play an important role in food production. The aim of this study was to determine the content of phytosterols, squalene, and tocopherols in four varieties of common buckwheat grains: Kora, Panda, Smuga, and Korona depending on the tillage and nitrogen doses employed. The grains were cultivated at the Experimental Station of the State Research Institute of Soil Science and Plant Cultivation in Osiny, Poland, with plow tillage, without plow tillage cultivation, and with nitrogen fertilizers (0, 50, and 100 kg N 2 ha -1 ). Gas chromatography with a mass spectrometer was used to assess all the parameters studied. The cultivation methods did not affect the levels of phytosterols, tocopherols, and squalene, but the highest levels of phytosterols were seen in the Kora variety with 50 kg N 2 ha -1 (ranging from 1198 μg to 1800 μg·g -1 of sample weight); therefore, the variety was the best source of phytosterols investigated.

Advances in musculoskeletal (MSK) research have been successfully curated into widely endorsed evidence-based recommendations and guidelines. However, there continues to exist significant variations in care and quality of care, and the global health and socio-economic burdens associated with MSK conditions continues to increase. Limited accessibility, and applicability of guideline recommendations have been suggested as contributory factors to less than adequate guideline implementation. Since patient and public involvement (PPI) is being credited with increasing relevance, dissemination and uptake of MSK research, the success of guidelines implementation strategies may also be maximised through increasing opportunities for PPI input. We therefore conducted a scoping review of literature to explore PPI in implementation of evidence-based guidance for MSK conditions. A comprehensive search was used to identify relevant literature in three databases (Medline, Embase, Cinahl) and two large repositories (WHO, G-IN), supplemented by grey literature search. Eligibility was determined with criteria established a priori and narrative synthesis was used to summarise PPI activities, contexts, and impact on implementation of MSK related evidence-based guidance across ten eligible studies (one from a low-and middle-income country LMIC). A prevalence of low-level PPI (mainly consultative activities) was found in the current literature and may partly account for current experiences of significant variations and quality of care for MSK patients. The success of PPI in MSK research may be lessened by the oversight of PPI in implementation. This has implications for both high- and low-resource healthcare systems, especially in LMICs where evidence is limited. Patient and public partnership for mobilising knowledge, maximising guideline uptake, and bridging the research-practice gap particularly in low resource settings remain important and should extend beyond PPI in research and guideline dissemination activities only. This review is a clarion call to stakeholders, and all involved, to transform PPI in MSK research into real world benefits through implementation approaches underpinned by patient and public partnerships. We anticipate that this will enhance and drive quality improvements in MSK care with patients and for patients across health and care settings., (© 2022. The Author(s).)

A clinical guideline is a document with the aim of guiding decisions based on evidence regarding diagnosis, management and treatment in specific areas of healthcare. Specific to rheumatic and musculoskeletal diseases (RMDs), adherence to clinical guidelines recommendations impacts the outcomes of people with these diseases. However, currently, the implementation of recommendations is less than optimal in rheumatology.The WHO has described the implementation of evidence-based recommendations as one of the greatest challenges facing the global health community and has identified the importance of scaling up these recommendations. But closing the evidence-to-practice gap is often complex, time-consuming and difficult. In this context, the implementation science offers a framework to overcome this scenario.This article describes the principles of implementation science to facilitate and optimise the implementation of clinical recommendations in RMDs. Embedding implementation science methods and techniques into recommendation development and daily practice can help maximise the likelihood that implementation is successful in improving the quality of healthcare and healthcare services., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Total phenolic content (TPC) in extracts of basil depended on the cultivar and type of fertilization used in cultivation. TPC was determined spectrophotometrically with the Folin−Ciocalteu reagent. The antioxidant activity of extracts was analyzed by scavenging of DPPH and ABTS radicals, on the basis of metal chelating ability (MetChel) and ferric reducing antioxidant power (FRAP). The greatest TPC was determined in the purple cultivars—141.35 and 165.44 mg gallic acid/g d.m. for fertilized with ammonium nitrate (NH4NO3) and ammonium sulfate ((NH4)2SO4), respectively. Their extracts had the greatest antioxidant capacity in the majority of the methods used. The results varied depending on the modelling system used. The amount of polyphenols in individual basil cultivars differed significantly (p < 0.05) depending on the fertilization used in the culture. Regarding TPC, DPPH, ABTS, FRAP, and MetChel variables, we observed a significant effect for the applied cultivation. In the case of MetChel factor, lower results of all investigated basil species were observed for cultivation with ammonium sulfate. PCA demonstrated in the present study shows that Sweet and Cinnamon Basil samples cultivated with ammonium nitrate create a separated group. We recommend cultivation with ammonium sulfate fertilizers for these varieties of basil. The high content of phenolic compounds demonstrated in Sweet and Cinnamon Basil cultivated with ammonium sulfate, and thus associated antioxidant activity, indicates that it can constitute a valuable source for bioactive compounds in a balanced diet.

Tartary buckwheat sprouts have a high nutritional value and are gluten-free, and polyphenols are their main active constituents. However, information regarding the active constituents' difference of Tartary buckwheat sprouts grown from seeds with different morphology, at different developmental stages and environments is limited. Here, we developed a LC-MS-based targeted metabolomics approach to analyze polyphenols (46 flavonoids and 6 anthraquinones) in 40 Tartary buckwheat sprouts varieties. Both flavonoids and anthraquinones contributed to significant differences in sprouts grown from seed with different color or shape. Twenty-seven differential compounds were all at a higher level in 3-day-old sprouts, and the fold change from 3-day-old to 8-day-old sprouts was 1.42-6.64. A total of 25 differential compounds were all significantly upregulated upon UV-B radiation, especially for epicatechin. This study is valuable not only for better breeding cultivars of Tartary buckwheat sprouts, but also assessing their metabolic quality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Ltd.)

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).)

Introduction: Hand osteoarthritis (OA) is a common joint disorder in the adult population. No cure for hand OA is known yet, but treatment aims to reduce symptoms. Non-surgical and non-pharmacological therapy interventions can include splinting, patient education, and strengthening and range of movement exercises. However, it is still unclear which treatment is most beneficial for which patient. This study aims to identify subgroups of patients with hand OA that benefit most from the different non-surgical and non-pharmacological treatments., Methods and Analysis: We will conduct an individual patient data (IPD) meta-analysis by extracting IPD of eligible published randomised controlled trials (RCTs). A systematic literature search through Embase, Medline and Cochrane was performed on 8 February 2021. The primary outcome will be hand pain, and our secondary outcomes are objective and subjective hand physical functions. Subgroups include age, sex, body mass index, hypermobility and other comorbidities, pain medication, occupation, baseline pain, erosive OA, type and the number of hand joints involved, radiological severity of OA, and duration of symptoms. IPD of RCTs with homogeneous treatment interventions will be pooled and analysed using a two-stage approach to evaluate treatment effect on different subgroups., Ethics and Dissemination: No new data will be collected, so research ethical or governance approval is exempt. Findings will be disseminated via national and international conferences, publications in peer-reviewed journals, and summaries posted on websites accessed by the public and clinicians., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Difficult-to-treat populations with chronic hepatitis C (CHC), in the era of interferon treatment, included patients with liver cirrhosis, kidney impairment, treatment-experienced individuals, and those coinfected with the human immunodeficiency virus. The current study aimed to determine whether, in the era of direct-acting antivirals (DAA), there are still patients that are difficult-to-treat. The study included all consecutive patients chronically infected with hepatitis C virus (HCV) who started interferon-free therapy between July 2015 and December 2020 in the Department of Infectious Diseases in Kielce. The analyzed real-world population consisted of 963 patients, and most of them were infected with genotype 1 (87.6%) with the predominance of subtype 1b and were treatment-naïve (78.8%). Liver cirrhosis was determined in 207 individuals (21.5%), of whom 82.6% were compensated. The overall sustained virologic response, after exclusion of non-virologic failures, was achieved in 98.4%. The univariable analysis demonstrated the significantly lower response rates in males, patients with liver cirrhosis, decompensation of hepatic function at baseline, documented esophageal varices, concomitant diabetes, body mass index ≥25, and previous ineffective antiviral treatment. Despite an overall very high effectiveness, some unfavorable factors, including male gender, genotype 3 infection, liver cirrhosis, and treatment experience, significantly reduce the chances for a virologic response were identified.

Background: Cystic fibrosis (CF) and CF-related liver disease can lead to disturbances in bile acid metabolism., Aim: This study determined serum bile acid concentrations in CF to define their usefulness in liver disease assessment., Methods: Primary, secondary and conjugated bile acid levels were measured in three CF groups (25 patients each) exhibiting: liver cirrhosis, other liver disease, no liver disease, and in 25 healthy subjects (HS)., Results: Bile acid levels were higher in CF patients than in HS, except for glycodeoxycholic acid (GDCA). However, bile acid concentrations did not differ between patients with cirrhosis and other liver involvement. GDCA and deoxycholic acid (DCA) differentiated CF patients with non-cirrhotic liver disease from those without liver disease (GDCA-AUC: 0.924, 95%CI 0.822-1.000, p<0.001; DCA-AUC: 0.867, 95%CI: 0.731-1.000, p<0.001). Principal component analysis revealed that in CF liver disease was related to GDCA, GGTP activity, severe genotype and pancreatic insufficiency., Conclusions: A CF-specific bile acid profile was defined and shown to relate to liver disease. GDCA differentiates patients with non-cirrhotic liver involvement from those with no detectable liver disease. Hence, GDCA is a candidate for validation as a biomarker of non-cirrhotic progression of liver disease in CF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Aim of this study was to evaluate the rate of incidental detection of second primary cancer (SPC) at 18F-fluorocholine ([18F]FCH) positron emission tomography/computed tomography (PET/CT) performed in prostate cancer patients., Material and Methods: A retrospective analysis was performed on a group of 1345 prostate cancer patients, who underwent [18F]FCH PET/CT study because of suspicion of recurrence (n = 937) or for initial staging (n = 408). Images were acquired after intravenous injection [18F]FCH with a mean activity of 200 ± 75 MBq (5.4 ± 2 mCi), from the top of the head to the half of the thigh. The confirmation of second primary cancer was obtained from the cancer registry., Results: Based on the [18F]FCH PET/CT scans, a second primary cancer was suspected in 89 patients (6.6%). Of these, a malignancy was histologically confirmed in 26 patients (29% of all suspected findings and 1.9% of the complete cohort). Lung cancer (including adenocarcinoma, neuroendocrine cancer) was diagnosed in 13 patients (50%) and hematologic neoplasm (including chronic lymphocytic leukemia, Hodgkin lymphoma, follicular lymphoma, and multiple myeloma) in 5 patients (19%). 18F-fluorocholine PET/CT also revealed esophageal cancer, mesothelioma, testicular, renal, bladder, and colorectal cancer inindividual patients, non-keratinizing squamous cell carcinoma (SCC) of the skin as well as head and neck SCC with unknown primary., Conclusion: We conclude that incidental detection of a second primary cancer in prostate cancer patients using [18F]FCH PET/CT is not very common and that lung cancer and hematologic malignancies are most frequently detected.

Background: Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC., Methods: We analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis., Results: Skin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1 eKO ). Papillomas that developed in Mcpip1 eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-β). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9., Conclusions: Overall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma., (© 2021. The Author(s).)

Objective: Physical function is one of the Outcome Measures in Rheumatology (OMERACT) core outcome domains for hand osteoarthritis studies. Our aim was to select appropriate instrument(s) to measure this domain, as part of the development of a core outcome measurement set., Methods: Following the OMERACT Filter 2.1 instrument selection process, the (function subscale of) the Australian/Canadian Hand Osteoarthritis Index (AUSCAN), Functional Index for Hand Osteoarthritis (FIHOA) and Michigan Hand Outcomes Questionnaire (MHQ) were assessed for domain match, feasibility, truth and discrimination. Data gathered from available literature, working group and patient surveys, and additional analyses in two hand osteoarthritis cohorts were used to inform a consensus process. Results were summarized in Summary of Measurements Properties tables and reviewed by the OMERACT technical advisory group., Results: MHQ passed the assessment of domain match and feasibility by the working group and patient research partners. For AUSCAN important limitations in feasibility were noted, but domain match was good. FIHOA did not pass the assessment and was not taken through the follow-up assessment. Based on published literature, reliability and construct/longitudinal validity of both MHQ and AUSCAN fulfilled OMERACT standards. While clinical trial discrimination and thresholds of meaning were good for AUSCAN, results for MHQ were ambiguous., Conclusion: MHQ was provisionally endorsed as OMERACT core outcome measure for the core domain physical function. While AUSCAN may have better metric properties than MHQ, it received provisional endorsement as a second measure of function due to important feasibility issues. A research agenda to merit full endorsement was set., Competing Interests: Declaration of Competing Interest AA reports grants from AstraZeneca, Oxford Immunotech; royalties from Uptodate; consulting fees from inflazome, NGM Biopharmaceuticals; honoraria from Menarini; and support from Pfizer; all outside the submitted work. FBe reports personal fees from Boehringer, Bone Therapeutics, CellProthera, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4P Pharma, 4Moving Biotech, and grants from TRB Chemedica; all outside the submitted work. FBl reports grants from Abbvie, grants and personal fees from Pfizer, grants from UCB, grants from Bristol-Mayers Squibb, grants from Roche, grants from Servier, grants from Bioiberica, grants from Sanofie, grants from Grunenthal, grants from GlaxoSmithKline, grants from Lilly, grants from Janssen, grants from Regeneron, grants from Amgen, and grants from TRB Chemedica; all outside the submitted work. DB reports to be on the executive of OMERACT and Technical Advisory Group, and is involved in supporting upper limb outcome measures (none that were considered here). PC reports personal fees from Eli Lilly, personal fees from EMD Serono, personal fees from Flexion Therapeutics, personal fees from Galapagos, personal fees from Novartis, personal fees from Pfizer; all outside the submitted work. KD reports grants from the National Institute for Health Research (NIHR). TS reports personal fees from AbbVie, Sanofi Genzyme, Roche, and Takeda; all outside the submitted work. IKH reports personal fees from AbbVie, grants from Pfizer, and personal fees from Novartis; all outside the submitted work. DvdH reports personal fees from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma; all outside the submitted work; and is Director of Imaging Rheumatology BV. MK reports grants from Dutch Arthritis Association, during the conduct of the study, fee for consultancy (Abbvie, Pfizer, Levicept, GlaxoSmithKline, Merck-Serono, Kiniksa, Flexion, Galapagos, CHDR) and local investigator of industry-driven trial (Abbvie), from Wolters Kluwer (UptoDate), Springer Verlag (Reumatologie en klinische immunologie), grants from Pfizer, grants from IMI-APPROACH; all outside the submitted work. LM reports to be a paid staff member of OMERACT and helped develop the methodology applied within this manuscript. FK, CH, MI, VR, and RW have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study assessed the measurement properties of two commonly used self-report physical activity (PA) measures: the International Physical Activity Questionnaire-Short Form (IPAQ-SF) and the Physical Activity Scale for the elderly (PASE) in adults with osteoarthritis., Methods: Secondary analysis of the MOSAICS cluster randomised controlled trial baseline and 3-month follow-up questionnaires, total scores and subdomains of the IPAQ-SF and PASE were compared. Intra-class correlations (ICC) were used to assess test-retest reliability, measurement error was assessed using standard error of measurement (SEM), smallest detectable change (SDC) and 95% limits of agreement (LoA). Responsiveness was assessed using effect size (ES), standard responsive measurement (SRM) and response ratio (RR)., Results: There was moderate correlation (r = 0.56) between the total IPAQ-SF scores (score ranges 0-16,398) and the total PASE scores (score ranges 0-400). Subdomain correlations were also moderate (ranges 0.39-0.57). The PASE showed greater reliability compared to the IPAQ-SF (ICC = 0.68; 0.61-0.74 95% CI and ICC = 0.64; 0.55-0.72, respectively). Measurement errors in both measures were large: PASE SEM = 46.7, SDC = 129.6 and 95% LoA ranges = -117 to 136, the IPAQ-SF SEM = 3532.2 METS -1 min-1 week , SDC = 9790.8 and 95% LoA ranges = -5222 to 5597. Responsiveness was poor: ES -0.14 and -0.16, SRM -0.21 and -0.21, and RR 0.12 and 0.09 for the IPAQ-SF and PASE, respectively., Discussion: The IPAQ-SF and PASE appear limited in reliability, measurement error and responsiveness. Researchers and clinicians should be aware of these limitations, particularly when comparing different levels of PA and monitoring PA levels changes over time in those with osteoarthritis., (© 2021 John Wiley & Sons Ltd.)

Introduction: The introduction of direct-acting antivirals (DAAs) has provided us with hope to eliminate hepatitis C virus (HCV) infection as a significant public health problem in the coming years. Objective: Our study aimed to compare the effectiveness and safety of genotype-specific and pangenotypic regimens in genotype 1b–infected patients treated in real-world settings. Patients and methods: Patients were selected from 990 HCV-infected individuals treated with DAAs in the Department of Infectious Diseases in Kielce, Poland, who had the therapy initiated between July 1, 2015 and December 31, 2020. Results: A total of 795 genotype 1b–infected patients with a median age of 51 years, female predominance (55%), and a 21.1% rate of cirrhosis were included in the analysis. A total of 69.9% of patients were treated with genotype-specific regimens. Those patients were significantly older, more often were treatment experienced, and had advanced liver fibrosis and cirrhosis compared with patients assigned to pangenotypic regimens. An overall sustained virologic response rate of 97.9% in the intention-to-treat (ITT) analysis and 99% after excluding nonvirologic nonresponders was achieved, with no significant difference between patients in the 2 treatment arms. Significantly higher proportions of men (P = 0.001) and DAA-experienced patients (P = 0.049) were documented among virologic nonresponders. Conclusions: We confirmed very high effectiveness and a good safety profile of both genotype-specific and pangenotypic regimens used in patients with genotype 1b HCV infection, and we found no differences between these 2 generations of medications. Male sex and previous treatment with DAAs were identified as negative predictors for therapy effectiveness.

Despite consistent international guidelines for osteoarthritis (OA) management, evidence-based treatments are underutilised. OA management programmes (OAMPs) are being implemented internationally to address this evidence-practice gap. An OAMP is defined as a 'model of evidence-based, non-surgical OA care that has been implemented in a real-world setting'. Our objective is to identify, synthesise and appraise qualitative research identifying anticipated or experienced micro (individual/behavioural), meso (organisational) or macro (context/system) level barriers or facilitators to the implementation of primary or community care-based OAMPs. Five electronic databases will be searched for papers published between 2010 and 2021. Qualitative or mixed-methods studies that include qualitative data on the anticipated or experienced barriers or facilitators to the implementation of primary or community care-based OAMPs, from the perspective of service users or service providers, will be included. The review will be reported using the PRISMA and ENTREQ guidelines. A data extraction form will be used to provide details of the included studies. Data will be analysed and identified barriers and facilitators will be mapped onto an appropriate implementation framework, such as the Theoretical Domains Framework. The appropriate JBI critical appraisal tools will be used to assess methodological quality, while the GRADE-CERQual approach will be used to assess confidence in the findings. Translation of evidence-based guidelines into practice is challenging and reliant on the quality of implementation. By comparing and contrasting anticipated and experienced barriers, this review will determine the extent of congruence between the two, and provide valuable insights into the views and experiences of key stakeholders involved in the implementation of OAMPs. The mapping of identified barriers and facilitators to behaviour change theory will enhance the applicability and construct validity of our findings and will offer significant utility for future development and implementation of OAMPs. Registration: This protocol was registered with PROSPERO (CRD42021255698) on 15/07/21., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Cunningham J et al.)

The design of concrete for radiation shielding structures is principally based on the selection of materials of adequate elemental composition and mix proportioning to achieve the long-term durability in nuclear environment. Concrete elements may become radioactive through exposure to neutron radiation from the nuclear reactor. A selection of constituent materials of greatly reduced content of long-lived residual radioisotopes would reduce the volume of low-level waste during plant decommissioning. The objective of this investigation is an assessment of trace elements with a large activation cross section in concrete constituents and simultaneous evaluation of susceptibility of concrete to detrimental alkali-silica reaction. Two isotopes 60 Co and 152 Eu were chosen as the dominant long-lived residual radioisotopes and evaluated using neutron activation analysis. The influence of selected mineral aggregates on the expansion due to alkali-silica reaction was tested. The content of 60 Co and 152 Eu activated by neutron radiation in fine and coarse aggregates, as well as in four types of Portland cement, is presented and discussed in respect to the chemical composition and rock origin. Conflicting results were obtained for quartzite coarse aggregate and siliceous river sand that, despite a low content, 60 Co and 152 Eu exhibited a high susceptibility to alkali-silica reaction in Portland cement concrete. The obtained results facilitate a multicriteria selection of constituents for radiation-shielding concrete.

Immunosuppression is one of the main mechanisms facilitating tumor expansion. It may be driven by immune checkpoint protein expression, anti-inflammatory cytokine secretion or enhanced metabolic enzyme production, leading to the subsequent build-up of metabolites such as adenosine. Under physiological conditions, adenosine prevents the development of tissue damage resulting from a prolonged immune response; the same mechanism might be employed by tumor tissue to promote immunosuppression. Immune cells expressing A 2A and A 2B adenosine receptors present in an adenosine-rich environment have suppressed effector functions, such as cytotoxicity, proinflammatory cytokine release, antigen presentation and others, making them inert to cancer cells. This study was designed to investigate the dual antagonist potential of SEL330-639 to abolish adenosine-driven immunosuppression. SEL330-639 has slow dissociation kinetics. It inhibits cAMP production in human CD4 + cells, CD8 + cells and moDCs, which leads to diminished CREB phosphorylation and restoration of antitumor cytokine production (IL-2, TNFα, IL-12) in multiple primary human immune cells. The aforementioned results were additionally validated by gene expression analysis and functional assays in which NK cell line cytotoxicity was recovered by SEL330-639. Adenosine-driven immunosuppression is believed to preclude the effectiveness of immune checkpoint inhibitor therapies. Hence, there is an urgent need to develop new immuno-oncological strategies. Here, we comprehensively characterize SEL330-639, a novel dual A 2A /A 2B receptor antagonist effective in both lymphoid and myeloid cell populations with nanomolar potency. Due to its tight binding to the A 2A and A 2B receptors, this binding is sustained even at high adenosine concentrations mimicking the upper limit of the range of adenosine levels observed in the tumor microenvironment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To investigate the clinical effectiveness, efficacy and cost effectiveness of splints (orthoses) in people with symptomatic basal thumb joint OA (BTOA)., Methods: A pragmatic, multicentre parallel group randomized controlled trial at 17 National Health Service (NHS) hospital departments recruited adults with symptomatic BTOA and at least moderate hand pain and dysfunction. We randomized participants (1:1:1) using a computer-based minimization system to one of three treatment groups: a therapist supported self-management programme (SSM), a therapist supported self-management programme plus a verum thumb splint (SSM+S), or a therapist supported self-management programme plus a placebo thumb splint (SSM+PS). Participants were blinded to group allocation, received 90 min therapy over 8 weeks and were followed up for 12 weeks from baseline. Australian/Canadian (AUSCAN) hand pain at 8 weeks was the primary outcome, using intention to treat analysis. We calculated costs of treatment., Results: We randomized 349 participants to SSM (n = 116), SSM+S (n = 116) or SSM+PS (n = 117) and 292 (84%) provided AUSCAN Osteoarthritis Hand Index hand pain scores at the primary end point (8 weeks). All groups improved, with no mean treatment difference between groups: SSM+S vs SSM -0.5 (95% CI: -1.4, 0.4), P = 0.255; SSM+PS vs SSM -0.1 (95% CI: -1.0, 0.8), P = 0.829; and SSM+S vs SSM+PS -0.4 (95% CI: -1.4, 0.5), P = 0.378. The average 12-week costs were: SSM £586; SSM+S £738; and SSM+PS £685., Conclusion: There was no additional benefit of adding a thumb splint to a high-quality evidence-based, supported self-management programme for thumb OA delivered by therapists., Trial Registration: ISRCTN 54744256 (http://www.isrctn.com/ISRCTN54744256)., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Group consultations are a relatively new concept in UK primary care and are a suggested solution to current workload pressures in general practice. Little is known about the experience of implementing and delivering this approach from staff and organisational perspectives., Aim: To explore the experience of implementing and delivering group consultations in general practice., Design and Setting: Qualitative telephone interview study., Method: Topic guides explored the perspectives and experiences of general practice staff on the implementation and delivery of group consultations. Data analysis adopted principles of the Framework Method underpinned by Normalisation Process Theory., Results: Interviews were conducted with 8 GPs, 8 practice nurses, 1 nurse associate, 1 practice pharmacist, 1 deputy practice manager, and 1 healthcare assistant. Four themes were identified: sense making of group consultations; the work associated with initiating group consultations; the experiences of operationalising group consultations; and sustaining change. Group consultations made sense to participants as a mechanism to reduce burden on primary care, enhance multidisciplinary working, and provide patient-centred care. Implementation required strong leadership from a 'champion', and a facilitator had a pivotal role in operationalising the approach. The associated workload was often underestimated. Barriers to embedding change included achieving whole practice buy-in, competing practice priorities, and system-level flexibility., Conclusion: General practice clinicians enjoyed group consultations, yet significant work is required to initiate and sustain the approach. An implementation plan considering leadership, roles and responsibilities, and wider organisational support is required at the outset. Further research or evaluation is needed to measure process outcomes., (© The Authors.)

Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded., Methods: In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes., Results: In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction., Conclusions: These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α over-activation., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Magnesium ions (Mg 2+ ) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg 2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination., Methods: Tramadol was administered to healthy Caucasian subjects with and without Mg 2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg 2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured., Results: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for C max and AUC 0-t geometric mean ratios for tramadol were 91.95-102.40% and 93.22-102.76%. The 90% confidence intervals for C max,ss and AUC 0-τ geometric mean ratios for tramadol were 93.85-103.31% and 99.04-105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg 2+ ., Conclusions: The absence of Mg 2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.