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The Brief Illness Perception Questionnaire (B-IPQ) is a frequently used measure of illness perception (IP). The aim of this study was to explore the psychometric properties of the questionnaire when used in elderly people with knee pain. Based on data from the Frederiksberg Cohort on elderly people reporting knee pain (N = 836), the psychometric properties of the eight B-IPQ items (1 'Consequences', 2 'Timeline', 3 'Personal control', 4 'Treatment control', 5 'Identity', 6 'Concern', 7 'Coherence', and 8 'Emotions') were analysed using Rasch analysis to establish whether the questionnaire provides reliable and valid measures of IP. Threshold disordering was found on the 1–10 rating scale in all items. When rescaling to a 0–2 rating scale, disordering was resolved in six items. Item goodness-of-fit analyses revealed that two items displayed underfit misfit and four items overfit misfit; hence, the B-IPQ does not present unidimensionality. The person separation index indicated that items separate respondents into only two IP levels. Finally, floor and ceiling effects were found, indicating that the B-IPQ may not fully describe the extent of IP in this population. The 1–10 rating scale used in the Danish B-IPQ targeting knee pain is suboptimal, while a 0–2 scale improves the psychometric properties of the scale. The B-IPQ does not present unidimensionality and the use of a sum score is therefore not recommended when assessing IP. The B-IPQ may not cover the extent of IP in elderly people with knee pain. [ABSTRACT FROM AUTHOR]

Introduction: B‐domain modification can improve production of recombinant factor VIII (rFVIII) proteins. However, the engineered junction results in non‐native peptide sequences with the potential to elicit immune responses via major histocompatibility complex class‐II (MHC‐II)‐binding and CD4+ T cell activation. Aim: Assess the immunogenic potential of B‐domain junction peptides of turoctocog alfa and other B‐domain‐modified rFVIII proteins using in silico and in vitro immunogenicity assessment techniques. Methods: Peptides with amino acid sequences identical to the B‐domain junction of turoctocog alfa, simoctocog alfa and moroctocog alfa were evaluated by in silico peptide‐MHC‐II binding prediction, in vitro peptide‐MHC‐II‐binding measurement and in vitro T cell‐activation assays. Moreover, turoctocog alfa was assessed for peptide presentation on dendritic cells (DCs) using MHC‐associated peptide proteomics. Results: In silico analysis predicted virtually no neo‐epitopes in the B‐domain junction for turoctocog alfa, whereas some were predicted for simoctocog alfa and moroctocog alfa. Turoctocog alfa and moroctocog alfa peptides showed minimal capacity to bind high‐frequency MHC‐II molecules in vitro, whereas simoctocog alfa peptide demonstrated some degree of binding to approximately half of the MHC‐II molecules tested. In line with this, no B‐domain peptides from turoctocog alfa were found to be presented on MHC‐II complexes on DCs. B‐domain junction peptides from all 3 compounds induced T cell responses in only a few percentages of donors. Conclusion: All 3 junction peptides were found to have a low immunogenicity potential, suggesting that modification of the B‐domain does not constitute an increased immunogenicity risk for any of the products examined. [ABSTRACT FROM AUTHOR]

Infection with murine gammaherpesvirus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpesvirus infections. Previous studies using gene-deficient mice have revealed that neither IFN γ nor perforin is essential in controlling the outcome of infection or the virus load during chronic infection in C57BL/6 mice. However, pronounced multiorgan fibrosis and splenic atrophy are observed in mice lacking IFN γ or the IFN γ receptor. To study the interplay between perforin and IFN γ in controlling the virus-induced pathology and the viral load during chronic gammaherpesvirus infection, we infected IFN γ/perforin double-deficient C57BL/6 mice and followed the course of infection. While absence of perforin prevented the splenic atrophy in IFN γ-deficient mice, fibrosis did not disappear. Moreover, double-deficient mice developed extreme splenomegaly, were unable to control the viral load and displayed chronic immune activation. Thus, IFN γ and perforin act in concert to minimize pathology and control the viral load in mice chronically infected with MHV68. Furthermore, while certain aspect of the virus-induced pathology in IFN γ-deficient mice may be alleviated in double-deficient mice, other aspects are exaggerated, and the normal architecture of the spleen is completely destroyed. We believe that these findings add to the understanding of the virus/host interaction during chronic gammaherpes virus infection. [ABSTRACT FROM AUTHOR]

Stability of anti-drug antibodies (ADAs) is important as ADA-analysis should be reliable over time at different storage conditions. Stability of anti-insulin antibodies in serum samples was assessed after short-term storage at different temperatures and after long-term storage at -20 °C. Correlation between measurements was tested and acceptance criteria for incurred sample reanalysis were applied. ADAs were stable after 72 h at 22 °C, after 2 weeks at 4 °C, and after 6.3 years at -20 °C. The study confirms that ADAs in serum are stable for several years at -20 °C and suggests that investigation of short- and long-term stability of ADAs is not needed if samples are handled at standard laboratory-conditions., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Laboratory mice live in specific pathogen-free (SPF) conditions, resulting in an immature immune system comparable to that of newborns rather than adult humans or mice from pet shops. This condition may compromise their translational value. Reintroducing pathogens would lead to the uncontrolled spread of infections and associated diseases, so research facilities should seek safer alternatives. We immunized laboratory mice with a cocktail of pathogens, which were inactivated by ultraviolet irradiation and mixed with the adjuvant AddaVax. This immunization resulted in a higher percentage of CD8+ effector memory T cells compared to untreated mice, although the response was not as robust as in pet shop mice. In a model of skin inflammation, pre-immunization led to an increased skin inflammatory response compared to non-immunized mice. All immunized mice seroconverted to the pathogens in the mixture, while none of the non-immunized mice housed together seroconverted to the pathogens applied to the pre-immunized mice. In conclusion, pre-immunization of mice impacts the immune system, which includes increasing the levels of CD8+ effector memory T cells., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8 + T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases., (© 2023. The Author(s).)

Purpose: This study assessed the effects of 12-week supervised resistance training combined with home-based physical activity on physical fitness, cancer-related fatigue, depressive symptoms, health-related quality of life (HRQoL), and life satisfaction in female breast cancer survivors., Methods: A parallel-group, outcome assessor-blinded, randomized controlled trial included 60 female breast cancer survivors who had completed their core treatments within the previous 10 years. Through computer-generated simple randomization, participants were assigned to resistance training (RTG; two sessions/week for 12 weeks plus instructions to undertake ≥ 10,000 steps/d) or control (CG; ≥ 10,000 steps/d only). Outcomes were evaluated at baseline and week 12. Muscular strength was assessed with electromechanical dynamometry. A standardized full-body muscular strength score was the primary outcome. Secondary outcomes included cardiorespiratory fitness, shoulder mobility, cancer-related fatigue, depressive symptoms, HRQoL, and life satisfaction., Results: Thirty-two participants were assigned to RTG (29 achieved ≥ 75% attendance) and 28 to CG (all completed the trial). Intention-to-treat analyses revealed that the standardized full-body muscular strength score increased significantly in the RTG compared to the CG (0.718; 95% CI 0.361-1.074, P < 0.001, Cohen's d = 1.04). This increase was consistent for the standardized scores of upper-body (0.727; 95% CI 0.294-1.160, P = 0.001, d = 0.87) and lower-body (0.709; 95% CI 0.324-1.094, P = 0.001, d = 0.96) strength. There was no effect on cardiorespiratory fitness, shoulder flexion, cancer-related fatigue, depressive symptoms, HRQoL, or life satisfaction. The sensitivity analyses confirmed these results., Conclusion: and implication for cancer survivors. In female breast cancer survivors who had completed their core treatments within the past 10 years, adding two weekly sessions of supervised resistance training to a prescription of home-based physical activity for 12 weeks produced a large increase in upper-, lower-, and full-body muscular strength, while other fitness components and patient-reported outcomes did not improve., Trial Registration Number: ISRCTN14601208., (© 2022. The Author(s).)

Background: We aimed to identify important components of, and practical resources relevant for inclusion in, a toolkit to aid exercise delivery for people with hip/knee osteoarthritis., Method: An online international multi-disciplinary survey was conducted across 43 countries (139 clinicians, 44 people with hip/knee osteoarthritis and 135 osteoarthritis researchers). Participants were presented with the seeding statement 'Practical resources to aid the implementation of exercise for people with hip/knee osteoarthritis should…' and asked to provide up to 10 open text responses. Responses underwent refinement and qualitative content analysis to create domains and categories., Results: Refinement of 551 open text responses yielded 72 unique statements relevant for analysis. Statements were organised into nine broad domains, suggesting that resources to aid exercise delivery should: (1) be easily accessible; (2) be of high quality; (3) be developed by, and for, stakeholders; (4) include different ways of delivering information; (5) include different types of resources to support exercise and non-exercise components of self-management; (6) include resources on recommended exercises and how to perform/progress them; (7) include tools to support motivation and track progress; (8) include resources to enable tailoring of the programme to the individual and; (9) facilitate access to professional and peer support., Conclusion: Our findings identified important components of, and practical resources to include within, a toolkit to aid delivery of exercise for people with hip/knee osteoarthritis. These findings have implications for exercise providers and lay the foundation for the development of a toolkit to help ensure exercise provision aligns with current international recommendations., (© 2023 John Wiley & Sons Ltd.)

The immunogenicity risk of therapeutic protein aggregates has been extensively investigated over the past decades. While it is established that not all aggregates are equally immunogenic, the specific aggregate characteristics, which are most likely to induce an immune response, remain ambiguous. The aim of this study was to perform comprehensive in vitro and in vivo immunogenicity assessment of human insulin aggregates varying in size, structure and chemical modifications, while keeping other morphological characteristics constant. We found that flexible aggregates with highly altered secondary structure were most immunogenic in all setups, while compact aggregates with native-like structure were found to be immunogenic primarily in vivo. Moreover, sub-visible (1-100 µm) aggregates were found to be more immunogenic than sub-micron (0.1-1 µm) aggregates, while chemical modifications (deamidation, ethylation and covalent dimers) were not found to have any measurable impact on immunogenicity. The findings highlight the importance of utilizing aggregates varying in few characteristics for assessment of immunogenicity risk of specific morphological features and may provide a workflow for reliable particle analysis in biotherapeutics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vito Foderà reports financial support was provided by Novo Nordisk A/S., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Knee joint functional deficits are common after anterior cruciate ligament (ACL) injury, but different assessment methods of joint function seem to provide contradicting information complicating recovery monitoring. We previously reported improved perceived knee function and functional performance (forward lunge ground contact time) in patients with an ACL injury from pre to 10 months post ACL reconstruction without improvement in knee-specific biomechanics. To further investigate this discrepancy, we additionally analyzed knee extensor and flexor muscle strength, and movement quality in the forward lunge (subjective and objective evaluations) and performed a full lower limb biomechanical analysis of the forward lunge movement. We included 12 patients with an ACL injury (tested before and after ACL reconstructive surgery) and 15 healthy controls from the previous study to the current investigation. Outcome measures were obtained pre and ~11 months post ACL reconstruction for the patients and at a single time point for the controls. Objective movement quality in the patients with an ACL injury showed an improvement from their pre reconstruction surgery visit to the post reconstruction visit but this was not observable in the subjective evaluation. Knee extensor muscle strength declined after the ACL reconstruction by 29% ( p = 0.002) and both knee extensors ( p < 0.001) and flexors ( p = 0.027) were weaker in the patients post ACL reconstruction compared to healthy controls. ACL injured patients had an altered movement strategy in the forward lunge with reduced knee extensors contribution and increased hip extensor contribution compared to the controls both before and after the reconstruction. The altered movement strategy was associated with knee extensor muscle strength. This explorative study with a limited sample size found that clinicians should be aware that significant functional deficits in the knee extensor muscles, both in isolated muscle strength testing and during a functional movement, may be present although patients perceive an improvement in their knee function and present good functional performance without obvious movement quality issues., 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 Stenroth, Bartholdy, Schwarz Larsen, Sørensen, Smale, Flaxman, Benoit, Krogsgaard and Alkjær.)

Objective: To compare the efficacy of an exercise and education programme with open-label placebo given as intra-articular injections of inert saline on pain and function in individuals with knee osteoarthritis (OA)., Methods: In this open-label, randomised controlled trial, we recruited adults aged ≥50 years with symptomatic and radiographically confirmed knee OA in Denmark. Participants were randomised 1:1 to undergo an 8-week exercise and education programme or four intra-articular saline injections over 8 weeks. Primary outcome was change from baseline to week 9 in the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire pain subscale (range 0 (worst)-100 (best)). Prespecified equivalence margins of ±8 KOOS pain points were chosen for the demonstration of comparable efficacy. Key secondary outcomes were the KOOS function and quality of life subscales, and patients' global assessment of disease impact., Results: 206 adults were randomly assigned: 102 to exercise and education and 104 to intra-articular saline injections. For the primary outcome, the least squares mean changes in KOOS pain were 10.0 for exercise and education and 7.3 for saline injections (difference 2.7 points, 95% CI -0.6 to 6.0; test for equivalence p=0.0008). All group differences in the key secondary outcomes respected the predefined equivalence margins. Adverse events and serious adverse events were similar in the two groups., Conclusion: In individuals with knee OA, an 8-week exercise and education programme provided efficacy for symptomatic and functional improvements equivalent to that of four open-label intra-articular saline injections over 8 weeks., Trial Registration Number: NCT03843931., Competing Interests: Competing interests: EAB reports grants from The Lundbeck Foundation, The Danish Physiotherapists Association and The Oak Foundation during the conduct of the study; and membership in the Danish Physiotherapist Association. LEK reports receiving fees for speaking and consultancy from Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly and Janssen pharmaceuticals. JG-M reports personal fees from AbbVie, Eli-Lilly and BK Ultrasound; and grants and personal fees from Novartis outside the submitted work. DJH reports personal fees from Pfizer, Lilly, TLCBio, Novartis, Tissuegene and Biobone outside the submitted work. RA reports personal fees from Novartis, Pfizer and Sorrento; others from Olatec, GSK, Noven, Sanofi and Teva outside the submitted work; and consultancy for GSK, Noven, Novartis, Olatec, Pfizer, Sanofi, Sorrento and Teva. MH reports grants from The Oak Foundation and Aase & Ejnar Danielsens Foundation during the conduct of the study; personal fees from Thuasne Group, outside the submitted work; and membership of Danish Physiotherapist Association., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess if a change in physical activity occurred after a one-year weight loss period on either liraglutide or placebo in patients with knee osteoarthritis (OA) and overweight., Method: This is secondary analysis of a one-year weight loss trial, with participants randomised (1:1) to either liraglutide 3 ​mg/day or placebo. The main outcome was change in physical activity (min/day) after one year assessed by accelerometer. Physical function was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS), function subscale with 100 indicating no disability and 0 indicating extreme disability. Analyses were done on the modified intention to treat population defined as complete baseline accelerometer data., Results: A total of 135 participants were analysed (66 liraglutide; 69 placebo). Daily physical activity time did not change in either group (liraglutide: 15.8 ​min/day; placebo: 14.2 ​min/day; mean difference 1.6 ​min/day (95%CI -16 to 19; P ​= ​0.90)). The liraglutide group lost -4.1 ​kg more than placebo (95% CI -6.0 to -2.1; P ​< ​0.0001) and improved in KOOS function 3.8 points more than placebo (95% CI 0.9 to 6.7; P ​= ​0.01)., Conclusion: Despite better outcomes on body weight and self-reported physical functioning liraglutide did not induce changes in physical activity over one year in individuals with knee OA., Competing Interests: None., (© 2022 The Authors.)

Background: Weight loss is critical for preventing and managing obesity-related diseases. There is a notable lack of valid and reliable means to manage patients with overweight/obesity and knee osteoarthritis (KOA)., Objective: To determine the efficacy and safety of liraglutide in a 30 mg/d dosing in patients with overweight/obesity and KOA., Methods: The trial was designed as a randomized controlled trial including patients between the age of 18 and 74 y with KOA and a BMI ≥27 (measured in kg/m2).Patients underwent a pre-random assignment diet intervention (week -8 to 0). At week 0, patients having lost >5% of their body weight were randomly assigned to liraglutide 3 mg/d or placebo for 52 wk. The coprimary outcomes were changes in body weight and the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale from week 0 to 52., Results: In total, 168 patients enrolled and 156 were randomly assigned to receive liraglutide or placebo. Patients experienced a significant reduction in body weight and KOOS pain during the pre-random assignment dietary intervention period (week -8 to 0). From week 0 to 52 there was a significant difference in body weight between the liraglutide and placebo group (mean changes: -2.8 and +1.2 kg, respectively; group difference, 3.9 kg; 95% CI: -6.9, -1.0; P = 0.008). There was, however, no group difference in KOOS pain (mean changes: 0.4 and -0.6 points, respectively; group difference, 0.9 points; 95% CI: -3.9, 5.7; P = 0.71). Treatment-emergent adverse events related to the gastrointestinal system were experienced by 50.2% and 39.2% of patients in the liraglutide and placebo groups, respectively., Conclusions: In patients with KOA and overweight/obesity liraglutide added after an 8-wk pre-random assignment diet induced a significant weight loss at >52 wk but did not reduce knee pain compared to placebo. This trial was registered at clinicaltrials.gov as NCT02905864., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended as first-line treatments based on extensive research evidence. However, none of the numerous randomised controlled trials of exercise and education for knee OA has used adequate sham/placebo comparison groups because the 'active' ingredients are unknown. Designing and executing an adequate and 'blindable placebo' version of an exercise and education intervention is impossible. Therefore, using an open-label study design, this trial compares the efficacy of a widely used 'state-of-art' exercise and education intervention (Good Life with osteoarthritis in Denmark; GLAD) with presumably inert intra-articular saline injections on improvement in knee pain in patients with knee OA., Methods: In this open-label randomised trial, we will include 200 patients with radiographically verified OA of the knee and randomly allocate them to one of two interventions: (i) 8 weeks of exercise and education (GLAD) or (ii) Intra-articular injections of 5 ml isotonic saline every second week for a total of 4 injections. Outcomes are taken at baseline, after 8 weeks of treatment (week 9; primary endpoint) and after an additional 4 weeks of follow-up (week 12). The primary outcome is change from baseline in the Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale score. Secondary outcomes include the Physical function in Activities of Daily Living, Symptoms, and Knee-related Quality of Life subscales of the KOOS, the patients' global assessment of disease impact, physical performance tests, and presence of knee joint swelling., Discussion: This current trial compares a presumably active treatment (GLAD) with a presumably inert treatment (IA saline injections). Both study interventions have well-established and anticipated similar effects on knee OA symptoms, but the underlying mechanisms are unknown. The interpretation of the results of this trial will likely be difficult and controversial but will contribute to a better understanding of the bias introduced in the effect estimation of classically unblindable exercise and education interventions for knee OA., Trial Registration: www.ClinicalTrials.gov NCT03843931 . Prospectively registered on 18 February 2019.

Objective: This study investigated the effect of exercise therapy on inflammatory activity in synovitis and bone marrow lesions (BMLs) assessed by magnetic resonance imaging (MRI) in patients with knee OA., Methods: 60 patients with knee OA were randomized 1:1 to 12 weeks of supervised exercise therapy 3 times/week (ET) or a no-attention control group (CG). Synovitis and BMLs were assessed with static MRI with and without contrast and with dynamic contrast enhanced MRI (DCE-MRI). DCE-MRI data was quantified using pixel-by-pixel methodology based on analysis of signal intensity curves. Pain was assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS). Analyses of covariance were used assessing group differences in changes from baseline to week 12., Results: 33 patients adhered to the protocol and had valid MRI and KOOS data (ET, n = 16, CG, n = 17). Statistically significant and clinically relevant group difference in favour of ET was seen in KOOS pain change (-11.7 points, 95%CI: -20.1 to -3.4). There were statistically significant group differences in DCE-MRI assessed synovitis in the anterior synovium with unchanged inflammatory activity in the ET group compared to the CG. There were no group differences in BMLs and static MRI., Conclusion: Inflammatory activity was unchanged, and pain was reduced in patients with knee OA adhering to 12 weeks of exercise therapy compared to a no-attention control group. The reduction in pain was not explained by changes in inflammatory activity. Overall, the results suggest that exercise is not harmful in knee OA. ClinicalTrials.gov number: NCT01545258., Competing Interests: Declaration of Competing Interest MB is shareholder and chairman of the medical and scientific board, Image Analysis Ltd., London, UK, from which he has received fees/honoraria (<$10,000) covering travel/accommodation costs as well as a small yearly honorarium. OK is the founder and CEO of Image Analysis Ltd., London, UK. MH is a member of Thuasne Group European Advisory Board from which he has received fees/honoraria covering travel/accommodation costs as well as a small yearly honorarium. All other authors have nothing to declare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Physical inactivity is a global problem and patients with knee osteoarthritis (OA) are predisposed to inactivity and its health-related consequences. Current guidelines recommend exercise as primary treatment but whether this affects time spent physically inactive is unknown. The objective was to investigate changes in physical inactivity among individuals with knee OA following an educational and exercise program., Methods: Pragmatic prospective cohort study performed in six physical therapy clinics in Denmark offering a nationwide education and exercise program for knee OA. The program consists of physiotherapy guided education and group-based or home exercise sessions, performed biweekly for approximately eight weeks. The exercises target knee and hip joint stability as well as focus on increasing muscle strength. Primary outcome was time spent physically inactive (min/day), measured with a tri-axial accelerometer mounted on the lateral side of the thigh during the entire exercise program duration. OA symptoms were assessed using the Knee injury and Osteoarthritis Outcome Score (KOOS)., Results: Thirty-two individuals with knee OA were analyzed. From baseline to post-intervention, no changes occurred in average time spent physically inactive (mean change: +16.2 min [95% CI -15.7 to 48.1]; P = 0.31), but statistically significant improvements in KOOS pain (+6.7 points [95% CI 2.3 to 11.0]; P = 0.0032) and KOOS function (+5.8 points [95% CI 1.9 to 9.7]; P = 0.0046) were found., Conclusions: Participating and completing a widely adopted education and exercise program are not associated with spontaneous improvements in physical inactivity despite changes in self-reported pain and function. Interventions specifically targeting physical inactivity are needed. Registration number: www.clinicaltrials.gov: NCT03125954., Competing Interests: Declaration of competing interest CB has no competing interest related to this study. STS is associate editor of the Journal of Orthopaedic & Sports Physical Therapy and has received grants from The Lundbeck Foundation and personal fees from Munksgaard, all of which are outside the submitted work. He is co-founder of GLA:D ®. GLA:D® is a non-profit initiative hosted at University of Southern Denmark. HB has no competing interest related to this study. MH has no competing interest related to this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Manufacturing processes for polypeptide/protein drugs are designed to ensure robust quality, efficacy and safety. Process differences introduced by follow-on manufacturers may result in changes in quality and clinical outcomes. This study investigated the impact of production methods on the stability and impurities of liraglutide and semaglutide drug substances/products, and the potential impact on drug quality, efficacy and safety., Methods: State-of-the-art analytical methods were used to compare physical and chemical stability, and impurity profiles of drug substances/products from different suppliers. Identified polypeptide-related impurities were evaluated for immunogenicity potential by in silico T cell epitope prediction. Semaglutide immunogenicity in clinical trials (SUSTAIN) was evaluated using a tiered antibody analysis., Results: Manufacturing scale and process strongly impacted the physical stability of the products. Trace metals increased high-molecular-weight protein formation for liraglutide and semaglutide. Synthetic and recombinant liraglutide produced by five suppliers had distinct impurity profiles compared with the originator. In silico evaluation suggested that new impurities could be immunogenic. Immunogenicity of semaglutide in clinical trials was lower than for liraglutide., Conclusions: Differences in manufacturing processes affect chemical/physical stability and impurity profile, and may impact immunogenicity. Follow-on versions of liraglutide and semaglutide, and possibly other polypeptides, should be clinically evaluated for efficacy and safety.

Objective: To describe spontaneous changes in time spent being physically inactive that is measured continuously by accelerometry during an 8-week weight-loss intervention in overweight/obese individuals with knee osteoarthritis (OA)., Methods: This study was designed as an observational cohort study including individuals from an OA outpatient clinic who were concomitantly overweight/obese and had symptomatic knee OA. Participants completed an 8-week dietary intervention that had been previously shown to induce substantial weight loss. The main outcome was accelerometer-based measurement of daily physical inactivity for 24 hours during the 8-week intervention period that was presented as change in the average daily time spent inactive (sitting, reclined, or sleeping) from 1 week prior to intervention to the last week of the intervention., Results: A total of 124 participants completed the dietary intervention and had valid accelerometer recordings. The mean weight loss was 12.7 kg (95% confidence interval [95% CI] -13.2, -12.1; P < 0.0001) after 8 weeks, which corresponded to a decrease in body mass index of 4.3 kg/m 2 (95% CI -4.5, -4.2; P < 0.0001). Significant improvements in OA symptoms (assessed by the Knee Injury and Osteoarthritis Outcome Score [KOOS]) was found across all subscales; an improvement of 12.8 points (95% CI 10.6, 15.0; P < 0.0001) was observed for pain using the KOOS. No statistically significant change occurred in the average daily time spent inactive from baseline to follow-up (mean change 8.8 minutes/day [95% CI -12.1, 29.7]; P = 0.41)., Conclusion: Physical inactivity remains stable despite a clinically significant weight loss and improvements in knee OA symptoms. Change in inactivity does not seem to occur spontaneously, suggesting that focused efforts to reduce inactive behaviors are needed., (© 2019, American College of Rheumatology.)

Objective: To investigate differences in gait variability induced by two different single-dose opioid formulations and an inert placebo in healthy volunteers and knee osteoarthritis patients., Design: Experimental, randomized, double-blinded, crossover study of inert placebo (calcium tablets), 50 mg of tapentadol, and 100 mg of tramadol., Setting: Laboratory setting., Subjects: Healthy volunteers and knee osteoarthritis patients., Methods: At three visits, separated by seven days, one tablet was administered per visit according to the randomization code. At each visit, a baseline measurement was done before tablet administration, after which hourly measurements were performed for six hours, yielding a total of seven measurements per visit. Gait variability was measured by three-dimensional gait analysis, recorded during six minutes of continuous treadmill walking at self-selected speed. One hundred seventy gait cycles were identified from detection of clear events of the knee joint angle trajectories. Gait variability was assessed as average standard deviations over a gait cycle of the sacrum displacements and accelerations; sagittal plane ankle, knee, and hip joint angles; step widths; and stride times., Results: Twenty-four opioid-naïve and neurologically intact participants (12 healthy volunteers and 12 knee osteoarthritis patients) were included and completed the experiment. Tapentadol reduced the variability of sacrum displacements and accelerations compared with placebo and tramadol. There were no differences between experimental conditions regarding the variability in lower-extremity joint angle variability, step widths, or stride times., Conclusions: In opioid-naïve and neurologically intact individuals, tapentadol seems to reduce movement variability during treadmill walking, compared with placebo and tramadol. This can be interpreted as a loss of adaptability that might increase the risk of falling if the system is perturbed., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Exercise therapy is recommended for knee osteoarthritis (OA), but the underlying mechanisms of pain relief are not fully understood. The purpose of this study was to explore the effects of exercise on muscle perfusion assessed by dynamic contrast enhanced MRI (DCE-MRI) and its association with changes in pain in patients with knee OA., Methods: Exploratory outcome analyses of a randomised controlled study with per-protocol analyses ( ClinicalTrials.gov : NCT01545258) performed at an outpatient clinic at a public hospital in Denmark. We compared 12 weeks of supervised exercise therapy 3 times per week (ET) with a no attention control group (CG). Analyses of covariance (ANCOVA) were used to assess group mean differences in changes from baseline to week 12 in knee muscle perfusion quantified by DCE-MRI, patient-reported pain and function using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, knee extensor and flexor muscle strength tests, and the six-minute walking test (6MWT). Spearman's correlation coefficients were used to determine the correlation between changes in DCE-MRI variables, KOOS, muscle strength, and 6MWT. The potential effect mediation of the DCE-MRI perfusion variables was investigated in a post-hoc mediation analysis., Results: Of 60 participants randomised with knee osteoarthritis, 33 (ET, n = 16, CG, n = 17) adhered to the protocol and had complete DCE-MRI data. At follow-up, there were significant group differences in muscle perfusion changes and clinically relevant group differences in KOOS pain changes (10.7, 95% CI 3.3 to 18.1, P = 0.006) in favor of ET. There were no significant between-group differences on muscle strength and function. The changes in pain and muscle perfusion were significantly correlated (highest Spearman's rho = 0.42, P = 0.014). The mediation analyses were generally not statistically significant., Conclusion: The pain-reducing effects of a 12-week exercise program are associated with changes in knee muscle perfusion quantified by DCE-MRI in individuals with knee OA, but whether the effects are mediated by muscle perfusion changes remains unclear., Trial Registration: ClinicalTrials.gov: NCT01545258 , first posted March 6, 2012.

Background: One of the big contributors to physical inactivity in the elderly population is osteoarthritis (OA) of the knee. Digital motivation seems to have a positive effect on individual physical inactivity level, but limited evidence exists on the effects of digital motivation on patients with knee OA., Objective: To investigate if motivational text messages reduce time spent physically inactive in patients with knee OA., Method: This study was designed as an unblinded pilot randomised controlled trial, randomising participants equally (1:1) to an intervention group (motivational text messages) or control group (no intervention). Participants were recruited from six physical therapy clinics in Denmark. Inclusion criteria were age ≥ 18, diagnosed with knee OA, owner of a smartphone or tablet, and participating or commencing participation in the GLA:D® program. The primary outcome was time spent physically inactive, measured with a tri-axial accelerometer mounted on the lateral side of the thigh. Data on OA symptoms were obtained using the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire., Results: A total of 49 participants were screened, and 38 participants were included and randomised to either the intervention group ( n  = 19) or the control group ( n  = 19). No statistically significant difference between the two groups was found in average change of time spent physically inactive (mean difference 13.2 min/day [95% CI - 41.0 to 67.3]; P  = 0.63), time spent standing (mean difference 3.0 min/day [95% CI - 22.7 to 28.7]; P  = 0.81), or time spent moving (mean difference - 20.4 min/day [95% CI - 63.0 to 22.3]; P  = 0.34) nor was there any difference in change between the two groups on KOOS., Conclusion: Motivational text messages have seemed to have no effect on overall time spent physically inactive., Trial Registration: clinicaltrials.gov, NCT03339011. Registered 9 November 2017., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: People with hand-related rheumatoid arthritis (RA) experience problems performing activities of daily living (ADL). Compensatory strategies to improve ADL ability have shown effective. Similarly, hand exercise has shown effect on pain, grip strength, and self-reported ability. A combination has shown positive effects based on self-report, but self-report and observation provide distinct information about ADL. The purpose of this study was to examine whether hand exercise as add on to compensatory intervention (CIP) will improve observed ADL ability in RA., Methods: Women (n = 55) with hand-related RA were randomized to CIP EXERCISE (intervention) or CIP only (control). CIP is focused on joint protection, assistive devices, and alternative ways of performing AD. The hand-exercise program addressed range of motion and muscle strength. Primary outcome was change in observed ADL motor ability measured by the Assessment of Motor and Process Skills (AMPS). Baseline measures were repeated after 8 weeks., Results: Improvements in ADL motor ability in CIP EXERCISE (mean change = 0.24 logits; 95% CI = 0.09 to 0.39) and CIP CONTROL (mean change =0.20 logits; 95% CI = 0.05 to 0.35) were statistically significant, with no differences between groups (mean difference = 0.04 logits; 95% CI = - 0.16 to 0.25). Thirteen (46.4%) participants in the CIP EXERCISE and 12 (44.4%) in the CIP CONTROL obtained clinically relevant improvements (≥ 0.30 logits) in ADL motor ability; this group difference was not significant (z = 0.15; p = 0.88)., Conclusion: Adding hand exercise to a compensatory intervention did not yield additional benefits in women with hand-related RA. The study was approved by the ethics committee 14th of April 2014 (H-3-2014-025) and registered at ClinicalTrials.gov 16th of May 2014 (NCT02140866).

Introduction: With an increasing prevalence of citizens of older age and with overweight, the health issues related to knee osteoarthritis (OA) will intensify. Weight loss is considered a primary management strategy in patients with concomitant overweight and knee OA. However, there are no widely available and feasible methods to sustain weight loss in patients with overweight and knee OA. The present protocol describes a randomised controlled trial evaluating the efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide in a 3 mg/day dosing in patients with overweight and knee OA., Methods and Analysis: 150 volunteer adult patients with overweight or obesity and knee OA will participate in a randomised, double-blind, placebo-controlled, parallel-group and single-centre trial. The participants will partake in a run-in diet intervention phase (week -8 to 0) including a low calorie diet and dietetic counselling. At week 0, patients will be randomised to either liraglutide 3 mg/day or liraglutide placebo 3 mg/day for 52 weeks as an add-on to dietetic guidance on re-introducing regular foods and a focus on continued motivation to engage in a healthy lifestyle. The co-primary outcomes are changes in body weight and the Knee Injury and Osteoarthritis Outcome Score pain subscale from week 0 to week 52., Ethics and Dissemination: The trial has been approved by the regional ethics committee in the Capital Region of Denmark, the Danish Medicines Agency and the Danish Data Protection Agency. An external monitoring committee (The Good Clinical Practice Unit at Copenhagen University Hospitals) will oversee the trial. The results will be presented at international scientific meetings and through publications in peer-reviewed journals., Trial Registration Numbers: 2015-005163-16, NCT02905864, U1111-1171-4970 BASED ON PROTOCOL VERSION: V.6; 30 January 2017, 15:30 hours., Competing Interests: Competing interests: HG has received speaker fees from Pfizer and MSD. MB has received speaker fees from Esaote, AbbVie and UCB. FKKK has received lecture fees from, participated in advisory boards of and/or consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD/Merck, Novo Nordisk, Sanofi and Zealand Pharma. AA is member of advisory boards/consultant for Acino, Switzerland, BioCare Copenhagen, DK, Gelesis, USA, Groupe Éthique et Santé, France, McCain Foods Limited, USA, Novo Nordisk, DK, Pfizer, USA, Saniona, DK, Weight Watchers, USA and Zaluvida, Switzerland. He is recipient of travel grants and honoraria as speaker for a wide range of Danish and international concerns. Commercial interests: co-owner and member of the Board of the consultancy company Dentacom Aps, Denmark (2005). Co-founder and co-owner of UCPH spin-outs Mobile Fitness A/S (2005), Flaxslim ApS (were also member of Board, 2015, and Personalized Weight Management Research Consortium ApS (Gluco-diet.dk, 2017). Co-inventor of a number of patents owned by UCPH, in accordance with Danish law. AA is not advocate or activist for specific diets, and is not strongly committed to any specific diet, for example, veganism, Atkins diet, gluten-free diet, high animal protein diet or dietary supplements. LEK has received fees for speaking and consultancy from Pfizer, AbbVie, Amgen, Sanofi, UCB, Celgene, BMS, Biogen, Novo Nordisk, MSD, Novartis, Eli Lilly and Janssen Pharmaceuticals., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the effect of quadriceps strengthening on quadriceps muscle force, power, and work and tibio-femoral compressive loads during walking in adults with knee osteoarthritis., Methods: Study design: Two-center, randomized, controlled trial., Intervention: Patients with knee osteoarthritis were randomly allocated to quadriceps strengthening program (3 times weekly) or no attention control group., Main Outcome Measures: Primary outcome was change from baseline in peak quadriceps force during walking at 12 weeks. Secondary outcomes included quadriceps power and work, knee compression forces during walking estimated with musculoskeletal modeling, muscle strength and pain and function. Outcomes were measured at baseline and 12 weeks., Results: 30 patients were randomized to receive either training (n = 15) or no attention (n = 15). At follow-up, there were no statistical differences between groups for maximum quadriceps force, quadriceps positive power, negative work, and positive work, and knee compressive force. Maximum negative quadriceps power in early stance was statistically significantly increased 36% in the training group compared to the control group which was most likely partially a response to faster walking velocity at follow-up. Muscle strength and patient reported pain and function were improved in the training group compared to the control group., Conclusions: Quadriceps strength training leads to increased muscle strength and improved symptomatic and functional outcomes but does not change quadriceps or knee joint biomechanics during walking. The biomechanical mechanism of improved health with strength training in knee osteoarthritis patients remains unknown. ClinicalTrials.gov Identifier: NCT01538407., (Copyright © 2018 Elsevier Ltd. All rights reserved.)