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Pierre-Alexis Mouthuy,1,2 Maja Somogyi Škoc,3 Ana Čipak Gašparović,1 Lidija Milković,1 Andrew J Carr,2 Neven Žarković1 1Laboratory for Oxidative Stress, Rudjer Boskovic Institute, Zagreb, Croatia; 2Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Medical Science Division, University of Oxford, Oxford, UK; 3Department of Materials, Fibres and Textile Testing, University of Zagreb, Zagreb, Croatia Abstract: Electrospun filaments represent a new generation of medical textiles with promising applications in soft tissue repair. A potential strategy to improve their design is to combine them with bioactive molecules. Curcumin, a natural compound found in turmeric, is particularly attractive for its antioxidant, anti-inflammatory, and antimicrobial properties. However, investigating the range of relevant doses of curcumin in materials designed for tissue regeneration has remained limited. In this paper, a wide range of curcumin concentrations was explored and the potential of the resulting materials for soft tissue repair applications was assessed. Polydioxanone (PDO) filaments were prepared with various amounts of curcumin: 0%, 0.001%, 0.01%, 0.1%, 1%, and 10% (weight to weight ratio). The results from the present study showed that, at low doses (≤0.1%), the addition of curcumin has no influence on the spinning process or on the physicochemical properties of the filaments, whereas higher doses lead to smaller fiber diameters and improved mechanical properties. Moreover, filaments with 0.001% and 0.01% curcumin stimulate the metabolic activity and proliferation of normal human dermal fibroblasts (NHDFs) compared with the no-filament control. However, this stimulation is not significant when compared to the control filaments (0%). Highly dosed filaments induce either the inhibition of proliferation (with 1%) or cell apoptosis (with 10%) as a result of the concentrations of curcumin found in the medium (9 and 32 µM, respectively), which are near or above the known toxicity threshold of curcumin (~10 µM). Moreover, filaments with 10% curcumin increase the catalase activity and glutathione content in NHDFs, indicating an increased production of reactive oxygen species resulting from the large concentration of curcumin. Overall, this study suggested that PDO electrospun filaments loaded with low amounts of curcumin are more promising compared with higher concentrations for stimulating tissue repair. This study also highlighted the need to explore lower concentrations when using polymers as PDO, such as those with polycaprolactone and other degradable polyesters. Keywords: electrospinning, electrospun filaments, polydioxanone, PDO, curcumin, human fibroblasts

Bav Shergill,1 Simon Zokaie,2 Alison J Carr3 1Department of Dermatology, Brighton and Sussex University Hospitals, Elm Grove, Brighton, UK; 2Leo Pharma, Princes Risborough, 3Hamell, London, UK Background: There is limited information on the patterns of use, adherence rates, and factors that impact adherence with topical treatments for actinic keratosis (AK). Objectives: To establish patterns of use and adherence with topical treatments for AK and to identify treatment-related factors that impact on adherence. Methods: A community-based, cross-sectional study was performed using a standardized questionnaire completed online or via telephone interview. Patients were stratified according to the presence of AK lesions on the scalp and/or other extremities; and presence of scarring resulting from treatment. Results: This study included 305 patients with AK who were currently using a patient-applied topical therapy for AK or had used one within the previous 12 months. In total, 88% (n = 268/305) of patients were either non-adherent, non-persistent or both non-adherent and non-persistent to topical therapy. Duration of treatment was associated with increasing rates of non-adherence (adjusted odds ratio [OR]; for treatment durations greater than 4 weeks, 2.2, P < 0.01): 52% of patients were non-adherent with 3–4 week treatment duration; 69% of patients with 4–8 week treatment duration; and 71% of patients with 6–12 week treatment duration. There were similar increases in non-persistence with increasing treatment duration (adjusted OR; for treatment durations greater than 4 weeks, 2.1, P < 0.05). Conclusion: This study found high rates of non-adherence and non-persistence in patients with AK. Duration of treatment was a significant factor contributing to non-adherence and non-persistence to topical treatments. Patient-applied topical therapies that require less frequent application and have shorter treatment duration may be associated with improved adherence rates. Keywords: patient compliance, chronic skin disease, treatment duration, patient behavior

OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease. [ABSTRACT FROM AUTHOR]

Alkaptonuria is a rare single-gene disorder characterized by black pigmentation of cartilage and other connective tissues. Premature degenerative arthritis affects the large joints in many of these of patients. Medical treatment is limited to a protein-restricted diet (phenylalanine and tyrosine) with surgery reserved for end-stage joint disease. As in other metabolic bone diseases, there are concerns about the quality and strength of affected bones and therefore the suitability and longevity of replacement arthroplasty. The histopathology and outcome of joint replacement for alkaptonuric arthritis is unknown and limited to sporadic case reports. We describe 11 joint replacements in 3 patients with alkaptonuric polyarthropathy, including shoulder and elbow replacements not previously reported. No prosthetic failures occurred in up to 12 years of follow-up. Total joint replacement is an acceptable treatment for degenerative joint disease in aikaptonuric patients, with implant survival comparable to that found in patients with osteoarthritis. [ABSTRACT FROM AUTHOR]

Previous research has demonstrated that complex carbohydrates (maltodextrins) can be perceived in the oral cavity. However, little research has been conducted to thoroughly investigate complex carbohydrate taste perception and contributing factors. This study explored the effects of the degree of polymerization and the concentration of complex carbohydrates on taste perception. Additionally, the impact of lactisole and acarbose on carbohydrate taste perception was investigated. Using a blinded, Latin Square design, participants ( n = 40) received samples (control) or samples with acarbose (5 mM) or lactisole (1.4 mM). Per visit, participants received solutions: (1) short chain maltodextrin (average DP 6) (SCM), (2) long chain maltodextrin (average DP 24) (LCM), (3) maltose, and (4) glucose. Samples were evaluated in duplicate, both at low concentration and high concentration. Participants tasted the samples and rated sweetness, starchiness, and viscosity (mouthfeel) perceived on a 10 cm continuous line scale and perceived intensity on a Labelled Magnitude Scale. There was a significant effect of degree of polymerisation on sweetness ( p = 0.001) and intensity ( p = 0.001). For low concentration samples, no significant differences were found between LCM and acarbose LCM or SCM and acarbose SCM for sweetness, starchiness, or mouthfeel (all p > 0.05). Significant differences were observed between LCM and lactisole LCM for sweetness (1.1 ± 0.1 vs. 2.5 ± 0.3, p = 0.001), starchiness (1.4 ± 0.2 vs. 2.3 ± 0.3, p = 0.005), and mouthfeel (1.4 ± 0.2 vs. 2.3 ± 0.3, p = 0.013). In conclusion, the taste perception of maltodextrins is influenced by the degree of polymerisation. Furthermore, for this study, the sweet taste receptor was not involved in maltodextrin taste perception. While salivary α-amylase did not appear to influence taste perception with low concentration maltodextrins, further investigation is necessary.

Graphene oxide (GO) is a promising material for separations. Nanoscale GO thin films at the air/water interface are excellent experimental models to understand molecular-scale interactions of ions and water with GO. However, the characteristics of GO, such as functional groups and flake size, also affect the thin film properties making it difficult to make systematic studies with GO thin films. This paper reports a simple, reliable, and quick method of preparing ultra-thin GO films, irrespective of their origin, and demonstrates the new opportunities possible with the utilization of this method. The total amount of GO used to form the thin film is significantly less compared to previous examples in the literature, minimizing the dissolved GO in the subphase. X-ray reflectivity (XR) studies show that the majority of the GO film has 1.5 nm thickness over a macroscopic area (∼100 cm 2 ) with very small roughness. Sum frequency generation (SFG) spectroscopy measurements show that H 2 O and D 2 O interact differently with GO films, a property that was not observed before. SFG data show that functional groups vary significantly between different commercially available GO samples. The differences are also characterized with XR at high resolution. X-ray fluorescence near total reflection (XFNTR) measurements show that these differences strongly affect ion adsorption and interfacial water behavior near GO, which are vital properties in separation applications. The results pave the way for future studies to elucidate the complex separation mechanisms with GO., Competing Interests: The authors declare no competing interest., (This journal is © The Royal Society of Chemistry.)

Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTK low CD48 + macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases., (© 2024. The Author(s).)

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2 P522R , is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2 M28L , that confers an increased AD risk. PLCG2 P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2 M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2 M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores., Methods: Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected., Results: The proportion of immune cells in OA synovium varied between patients (8-38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45-PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer., Conclusions: There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: To investigate the effect of age-related rotator cuff tears on shoulder strength in a general population cohort., Design: Cross sectional observational study., Setting: This study was set in an outpatient clinic setting in Chingford, North East London, and was a component of the 20 year visit of the Chingford 1000 women cohort., Participants: Individuals were part of the Chingford 1000 women cohort, a 20-year-old longitudinal population study. This cohort has been extensively characterised as representative of the population of the UK. At the 20 year visit, 446 attended for shoulder assessment and were aged between 64 and 87., Primary and Secondary Outcome Measures: Isometric shoulder abduction strength measured using a Nottingham Mecmesin Myometer and the presence of rotator cuff pathology, determined via ultrasound examination (GE voluson i portable ultrasound machine with a 10-16MHz linear probe). Shoulders were classified into normal, abnormal tendon/partial tear, full-thickness tears (>0 and ≤2.5 cm) and full-thickness tears (>2.5 cm). Symptoms were defined using the Oxford Shoulder Score, where an abnormal score was defined as symptomatic., Results: 446 women (891 shoulders) aged 71 (range 65-84) were included in the study. Age, the presence of pain and the non-dominant arm were demonstrated to reduce strength. Rotator cuff tears and pathology had no isolated effect on shoulder strength in those aged under 70. However, in the over 70s full-thickness tears>0 and ≤2.5 cm, and >2.5 cm had mean reductions of 6.3 and 12.7 N, respectively (p<0.001)., Conclusion: Rotator cuff tears of all sizes in those aged under 70 were not associated with a loss of shoulder strength. In those aged over 70, strength was reduced by 30% with small and 40% with large full thickness tears. Loss in strength was associated a loss of ability to perform activities of daily living but only for large tears., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To define the population prevalence of rotator cuff tears and test their association with pain and function loss; determine if severity symptom correlates with tear stage severity, and quantify the impact of symptomatic rotator cuff tears on primary healthcare services in a general population cohort of women., Design: Cross-sectional observational study., Participants: Individuals were part of the Chingford 1000 Women cohort, a 20-year-old longitudinal population study comprising 1003 women aged between 64 and 87, and representative of the population of the UK., Main Outcome Measures: Rotator cuff pathology prevalence on ultrasound, shoulder symptoms using the Oxford Shoulder Score and resultant number of general practitioner (GP) consultations., Results: The population prevalence of full-thickness tears was 22.2%, which increased with age (p=0.004) and whether it was the dominant arm (Relative Risk 1.64, OR 1.58, 95% CI 1.07 to 2.33, p=0.021).Although 48.4% of full-thickness tears were asymptomatic, there was an association between rotator cuff tears and patient-reported symptoms. Individuals with at least one full-thickness tear were 1.97 times more likely than those with bilateral normal tendons (OR 3.53, 95% CI 2.00 to 5.61, p<0.001) to have symptoms. Severity of symptoms was not related to the severity of the pathology until tears are >2.5 cm (p=0.009).In the cohort, 8.9% had seen their GP with shoulder pain and a full-thickness rotator cuff tear, 18.8% with shoulder pain and an abnormality and 29.3% with shoulder pain., Conclusion: Rotator cuff tears are common, and primary care services are heavily impacted. As 50% of tears remain asymptomatic, future research may investigate the cause of pain and whether different treatment modalities, aside from addressing the pathology, need further investigation., 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.)

Introduction: The Tokyo 2021 Olympic Games was anticipated to expose athletes to the most challenging climatic conditions experienced in the history of the modern Olympic Games. This study documents strategies executed by Australian endurance athletes during the team holding camp and Olympic Games experiences, including (1) baseline physiological data, training data, and heat acclimation/acclimatization practices; (2) pre- and in-race cooling and nutritional strategies, and (3) Olympic Games race performance data., Methods: Six athletes (three males, three females; age 24 ± 4 years; VO 2max 63.2 ± 8.7 mL⋅kg -1 ⋅min -1 ; sum of 7 skinfolds 53.1 ± 23.4 mm) were observed prior to and during the team holding camp held in Cairns, QLD, Australia. Athletes completed 6-7 weeks of intermittent heat acclimation training, utilizing a combination of 2-4 passive and active acclimation sessions per week. Active acclimation was systematically increased via exposure time, exercise intensity, temperature, and humidity. In the team holding camp, athletes undertook a further 23 heat acclimatization training sessions over 18 days in a continuous fashion. Hyperhydration (using sodium and glycerol osmolytes), and internal and external pre-and in-race cooling methods were also utilized. A low energy availability intervention was implemented with two athletes, as a strategy to periodize ideal race body composition. Race performance data and environmental conditions from the 2021 Olympic Games were also documented., Results: The highest values for aerobic capacity were 63.6 mL⋅kg -1 ⋅min -1 for female race walkers and 73.7 mL⋅kg -1 ⋅min -1 for males. Training volume for the six athletes was the highest in the second week of the team holding camp, and training intensity was lowest in the first week of the team holding camp. Performance outcomes included 6th place in the women's 20 km event (1:30:39), which was within 2% of her 20 km personal best time, and 8th place in the men's 50 km event (3:52:01), which was a personal best performance time., Conclusion: Periodized training, heat acclimation/acclimatization, cooling and nutritional strategies study may have contributed to the race outcomes in Olympic Games held hot, humid conditions, for the race walkers within this observational study., 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., (Copyright © 2022 Carr, Vallance, Rothwell, Rea, Burke and Guy.)

Biomaterial augmentation of surgically repaired rotator cuff tendon tears aims to improve the high failure rates (∼40%) of traditional repairs. Biomaterials that can alter cellular phenotypes through the provision of microscale topographical cues are now under development. We aimed to systematically evaluate the effect of topographic architecture on the cellular phenotype of fibroblasts from healthy and diseased tendons. Electrospun polydioxanone scaffolds with fiber diameters ranging from 300 to 4000 nm, in either a highly aligned or random configuration, were produced. Healthy tendon fibroblasts cultured for 7 days on scaffolds with highly aligned fibers demonstrated a distinctive elongated morphology, whilst those cultured on randomly configured fibers demonstrated a flattened and spread morphology. The effect of scaffold micro-architecture on the transcriptome of both healthy and diseased tendon fibroblasts was assessed with bulk RNA-seq. Both healthy ( n = 3) and diseased tendon cells ( n = 3) demonstrated a similar transcriptional response to architectural variants. Gene set enrichment analysis revealed that large diameter (≥2000 nm) aligned scaffolds induced an upregulation of genes involved in cellular replication and a downregulation of genes defining inflammatory responses and cell adhesion. Similarly, PDPN and CD248 , markers of inflammatory or "activated" fibroblasts, were downregulated during culture of both healthy and diseased fibroblasts on aligned scaffolds with large (≥2000 nm) fiber diameters. In conclusion scaffold architectures resembling that of disordered type III collagen, typically present during the earlier phases of wound healing, resulted in tendon fibroblast activation. Conversely, scaffolds mimicking aligned diameter collagen I fibrils, present during tissue remodelling, did not activate tendon derived fibroblasts. This has implications for the design of scaffolds used during rotator cuff repair augmentation., 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., (Copyright © 2022 Baldwin, Mimpen, Cribbs, Stace, Philpott, Dakin, Carr and Snelling.)

Background: This study assessed relationships and sex differences between psychological state (recovery, stress, anxiety, and self-confidence) and gastrointestinal symptoms (GIS) prior to and during a 56 km ultramarathon running race and identified predictive factors of race GIS. Forty-four (26 males, 18 females) ultramarathon competitors completed anxiety, recovery, stress and GIS questionnaires for three days prior to the race and immediately pre-race. Race GIS were assessed immediately post-race. Spearman's rank order, Mann-Whitney U tests and regression analyses were used to determine correlations and identify sex differences between psychological state and GIS and determine predictors of race GIS., Results: Race GIS were significantly correlated with recovery (r s  =  - 0.381, p = 0.011), stress (r s  = 0.500, p = 0.001) and anxiety (r s  = 0.408, p = 0.006), calculated as the mean of the three days preceding the race and on race morning. The correlation between anxiety and GIS was strongest in the 24 h immediately prior to the race (all r s  > 0.400, and all p < 0.05), but unclear patterns were identified for stress and recovery. Regression analyses showed 36% and 40% of variation in the severity and number of race GIS was accounted for by body mass and measures of stress, anxiety, and GIS over the three days preceding the race and on race morning (both p < 0.001). There were no sex differences in the number and severity of GIS leading up to or during the race (all p > 0.05), however, females reported greater state anxiety (p = 0.018) and lower self-confidence than males (p = 0.006) over the three days preceding the race and on race morning., Conclusion: Endurance athletes that experience GIS during competition should investigate elevated stress and/or anxiety as a potential contributor and identify if management strategies can reduce the occurrence and severity of GIS., (© 2021. The Author(s).)

Objective: Base of thumb OA (BTOA) is a common age-related disease that has a significant negative impact on quality of life, while little is known about the structure and pathways of interface services. Our aim was to assess disease burden, referral pathways, service structure and management pathways in UK interface services., Methods: A structured questionnaire was carried out with a participating clinician at each centre to detail the local guidelines and management of BTOA. Five patients referred with BTOA were prospectively identified in each of 32 UK interface centres., Results: Most centres (72%) had a local guideline and a standardized treatment regime consisting of education (100%), joint protection (100%), range of motion exercises (84%), strengthening exercises (88%), splintage (100%) and use of assistive devices (78%). No centre routinely offered a steroid injection at the first appointment and no centre had a specific threshold for offering an injection. Injection delivery was variable. Most patients had not been referred previously (82%). Most patients used analgesia (72%), but a minority of patients had been treated with a splint (46%), therapy (43%) and steroid injection (27%) prior to their latest attendance., Conclusion: Most BTOA patients newly referred to interface services have been treated with analgesics and have not received comprehensive multimodal intervention. The management of BTOA at interface services is standardized in terms of education, splintage and therapy. However, there is a lack of standardization in terms of both the threshold for, timing of and mode of delivery of injection therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges., Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials., Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout., Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines., Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect., Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial., Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS., Future Work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space., Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme.

Background: A rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The patch augmented rotator cuff surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible., Methods: A mixed methods feasibility study of conducing a subsequent RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder Society's (BESS) surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting., Results: The BESS surgeons' survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting., Conclusions: Randomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders., (© 2021. The Author(s).)

Objectives: To compare blood alkalosis, gastrointestinal symptoms and indicators of strong ion difference after ingestion of 500 mg.kg-1 BM sodium citrate over four different periods., Methods: Sixteen healthy and active participants ingested 500 mg.kg-1 BM sodium citrate in gelatine capsules over a 15, 30, 45 or 60 min period using a randomized cross-over experimental design. Gastrointestinal symptoms questionnaires and venous blood samples were collected before ingestion, immediately post-ingestion, and every 30 min for 480 min post-ingestion. Blood samples were analysed for blood pH, [HCO3-], [Na+], [Cl-] and plasma [citrate]. Linear mixed models were used to estimate the effect of the ingestion protocols., Results: For all treatments, blood [HCO3-] was significantly elevated above baseline for the entire 480 min post-ingestion period, and peak occurred 180 min post-ingestion. Blood [HCO3-] and pH were significantly elevated above baseline and not significantly below the peak between 150-270 min post-ingestion. Furthermore, blood pH and [HCO3-] were significantly lower for the 60 min ingestion period when compared to the other treatments. Gastrointestinal symptoms were minor for all treatments; the mean total session symptoms ratings (all times summed together) were between 9.8 and 11.6 from a maximum possible rating of 720., Conclusion: Based on the findings of this investigation, sodium citrate should be ingested over a period of less than 60 min (15, 30 or 45 min), and completed 150-270 min before exercise., Competing Interests: The authors have declared that no competing interests exist.

Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype., 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., (Copyright © 2021 Mimpen, Baldwin, Cribbs, Philpott, Carr, Dakin and Snelling.)

Medical devices are a very important but largely under-recognized and fragmented component of healthcare.The limited regulation of the past and the lack of systematic rigorous evaluation of devices leading to numerous high-profile failures will now be replaced by stricter legal requirements and more transparent evaluation processes.This constitutes an unprecedented opportunity, but it also uncovers urgent needs in landscaping, methodology development, and independent comprehensive assessment of device risks and benefits for individual patients and society, especially in the context of increasingly complex devices.We argue that an academic discipline of 'medical device science' is well placed to lead and coordinate the efforts necessary to achieve much needed improvement in the medical device sector.Orthopaedics and traumatology could contribute and benefit considerably as one of the medical specialties with the highest use of medical devices. Cite this article: EFORT Open Rev 2021;6:160-163. DOI: 10.1302/2058-5241.6.200094., Competing Interests: ICMJE Conflict of interest statement: AL declares no conflict of interest relevant to this work. JAS reports consultancy for Biolacuna Ltd, outside the submitted work. DPA reports fees for speaker services and advisory board membership. AMGEN, fees for consultancy services from UCB Biopharma, grants from Les Laboratoires Servier, all outside the submitted work; and Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA's department and open for external participants. AJC reports consultancy for the Novartis musculoskeletal advisory board and patents with BioPatch, outside the submitted work., (© 2021 The author(s).)

Background: A rotator cuff tear is a common, disabling shoulder problem. Symptoms may include pain, weakness, lack of shoulder mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a need to improve the outcome of rotator cuff surgery, and the use of patch augmentation (on-lay or bridging) to provide support to the healing process and improve patient outcomes holds promise. Patches have been made using different materials (e.g. human/animal skin or tissue and synthetic materials) and processes (e.g. woven or mesh)., Objectives: The aim of the Patch Augmented Rotator Cuff Surgery (PARCS) feasibility study was to determine the design of a definitive randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible., Design: A mixed-methods feasibility study of a randomised controlled trial., Data Sources: MEDLINE, EMBASE and the Cochrane Library databases were searched between April 2006 and August 2018., Methods: The project involved six stages: a systematic review of clinical evidence, a survey of the British Elbow and Shoulder Society's surgical membership, a survey of surgeon triallists, focus groups and interviews with stakeholders, a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. The various stakeholders (including patients, surgeons and industry representatives) were involved in stages 2-6., Results: The systematic review comprised 52 studies; only 15 were comparative and, of these, 11 were observational (search conducted in August 2018). These studies were typically small (median number of participants 26, range 5-152 participants). There was some evidence to support the use of patches, although most comparative studies were at a serious risk of bias. Little to no published clinical evidence was available for a number of patches in clinical use. The membership survey of British Elbow and Shoulder surgeons [105 (21%) responses received] identified a variety of patches in use. Twenty-four surgeons (77%) completed the triallist survey relating to trial design. Four focus groups were conducted, involving 24 stakeholders. Differing views were held on a number of aspects of trial design, including the appropriate patient population (e.g. patient age) to participate. Agreement on the key research questions and the outline of two potential randomised controlled trials were achieved through the Delphi study [29 (67%)] and the consensus meeting that 22 participants attended., Limitations: The main limitation was that the findings were influenced by the participants, who are not necessarily representative of the views of the relevant stakeholder groups., Conclusion: The need for further clinical studies was clear, particularly given the range and number of different patches available., Future Work: Randomised comparisons of on-lay patch use for completed rotator cuff repairs and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. These elements are included in the trial designs proposed in this study., Study Registration: The systematic review is registered as PROSPERO CRD42017057908., 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. 25, No. 13. See the NIHR Journals Library website for further project information.

Objective: To appraise studies reporting on clinical effectiveness and safety of surgical meshes used to augment rotator cuff repairs (RCRs)., Design: Systematic review and meta-analysis., Data Sources: MEDLINE, Embase and Cochrane databases were searched between April 2006 and April 2020., Eligibility Criteria: All studies evaluating adults (≥18 years) undergoing RCR were considered. There were no language restrictions., Data Extraction and Synthesis: Screening, data extraction and quality appraisal were conducted by two independent reviewers. Meta-analysis was conducted using a random-effects models if ≥2 comparative studies reported the same outcome measure. Risk of bias assessment was undertaken for randomised (RoB2, Cochrane) and comparative studies (ROBINS-I, Cochrane)., Results: We included 60 studies, consisting of 7 randomised controlled trials, 13 observational comparative studies and 40 observational case series. All comparative studies reported on shoulder-specific functional outcome scores, 18 on the radiographic occurrence of re-tear and 14 on pain score metrics. All studies contained some risk of bias.Compared with non-augmented repair, a small improvement in shoulder-specific function or pain scores was observed for synthetic patches with a mean improvement of 6.7 points on the University of California Los Angles (UCLA) shoulder score (95% CI 0.1 to 13.4) and 0.46 point reduction on the Visual Analogue Scale (95% CI -0.74 to -0.17), respectively. A reduced likelihood of radiologically observed re-tear was observed for synthetic (risk ratio (RR) 0.41, 95% CI 0.27 to 0.61) and allograft (RR 0.34, 95% CI 0.18 to 0.65) patches. A total of 49 studies reported on the occurrence of complications. Slightly higher crude complication rates were observed following patch-augmented repair (2.1%) than standard repair (1.6%)., Conclusions: While several studies suggest a decreased failure rate and small improvements in shoulder function and pain following augmented RCR, a paucity of rigorous clinical evaluation, for both effectiveness and safety, prevents firm recommendations., Prospero Registration Number: CRD42017057908., Competing Interests: Competing interests: AC has applied for a patent for a device which would be eligible for this type of review if it is approved for clinical use, AR has received educational and research grants from DePuy Ltd., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)