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Objective: Distraction treatment for severe osteoarthritis below the age of 65 successfully postpones arthroplasty. Most patients have been treated with a general external fixator or a device specifically intended for knee distraction. This study compares clinical efficacy of both devices in retrospect and their mechanical characteristics., Design: Clinical efficacy 2 years posttreatment was compared using retrospective data from patients with severe knee osteoarthritis treated with knee distraction; 63 with the Dynamic Monotube (Stryker GmbH, Switzerland) and 65 with the KneeReviver (ArthroSave BV, the Netherlands). Changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function, general well-being (SF-36), cartilage thickness by radiographic joint space widening, and adverse events during treatment were assessed. Axial stiffness of clinically feasible configurations was assessed by bench testing for the Dynamic Monotube triax system and the KneeReviver., Results: No differences were observed in clinical efficacy, nor in mechanical characteristics and adverse events between the two devices. Although with large variation, both showed a clinically relevant improvement. In mechanical testing, contact between articular surfaces was observed for both devices at physiological loading. Stiffness of applied configurations strongly varied and primarily depended on bone pin length., Conclusions: Patients treated with a general intended-use device or a distraction-specific device both experienced clinical and structural efficacy although with significant variation between patients. The latter may be the result of varying mechanical characteristics resulting from differences in clinical configurations of the devices and actual loading. The exact role of full/partial mechanical unloading of the joint during distraction treatment remains unclear., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SM was financially supported by the Dutch Arthritis Society (LLP-9). The funders nor the suppliers of the distraction devices had any role in the study design, data collection, analysis, or interpretation of the data, or in the writing of the manuscript.

The Imposter Phenomenon (IP) is gaining increasing attention in academia, not only as an overall attractive research topic but also as a concern that especially affects members of minority groups. Nevertheless, there is little evidence for the occurrence and socio-structural correlates of the IP. Against the backdrop of a pressing need to contextualize the IP, this paper provides (1) an overview of the existing empirical evidence on the IP from a perspective that incorporates the role of social contexts, (2) highlights shortcomings in both existing theoretical approaches and methodological tools, (3) introduces the Impostor Phenomenon Short Scale (IPSS-3) as a novel, time-efficient and universally applicable IP measure, and (4) underscores that the IP, in fact, does not occur in a social vacuum but is closely intertwined with socio-structural characteristics. To this end, the paper draws on three distinct data sets gathered among German adolescents and adults for the development of the IPSS-3 (Study 1: n  = 271), its validation (Study 2: n = 427), and to assess the IP's socio-structural correlates (Study 3: n  = 865). The findings demonstrate that the IPSS-3 represents the first time-efficient and universally applicable instrument suitable for capturing the IP in large-scale and longitudinal research designs, e.g., initiated in adolescence. Thus, the IPSS-3 can address key open questions related to age effects, the role of transitions in the life course, and systematic variations in IP intensity among different social groups., Competing Interests: The author declares 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 © 2024 Jansen.)

Objective: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA)., Methods: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components., Results: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R 2  = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R 2  = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R 2  = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R 2  = 0.12)., Conclusion: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure., (© 2024. The Author(s).)

Objective: To assess whether change of semiquantitatively magnetic resonance imaging (MRI)-defined bone marrow lesions (BMLs) and inflammatory markers is associated with change in quantitatively-assessed cartilage loss in the femorotibial joint (FTJ) in knees with radiographic osteoarthritis (OA) over 24 months., Design: Participants were included from the IMI-APPROACH and the Osteoarthritis Initiative FNIH studies. Semiquantitative MRI assessment was performed for BMLs, Hoffa- and effusion-synovitis. Quantitative cartilage thickness measurements were performed manually. Definitions of change included number of subregions with BMLs, change in sum and change in maximum increase in size. Change in Hoffa-synovitis and effusion-synovitis was categorized in addition. Between-group comparisons regarding cartilage loss in the FTJ, medial and lateral compartments were performed using analysis of variance (ANOVA)., Results: A total of 629 participants were included. Knees without any BMLs at baseline (BL) and follow-up (FU) had significantly less cartilage loss compared to the other subgroups. Change in both directions in the sum score of BMLs was associated with increased rates of cartilage loss. Maximum increase in size of BMLs was associated with increased rates of cartilage loss (FTJ increase by 2 grades -0.183 mm, 95% CI [-0.335, -0.031], by 3 grades -0.306 mm, [-0.511, -0.101]). Worsening of Hoffa-synovitis was associated with increased rates of cartilage loss., Conclusion: Knees without BMLs at BL and FU showed lowest rates of cartilage loss. Knees with an increase in BML size showed increased rates of concurrent cartilage loss. Approaches with the aim to inhibit BML development, avoidance of increase in size and avoidance of Hoffa-synovitis worsening may have beneficial effects on cartilage loss., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Scientific and financial support for the FNIH OA Biomarkers Consortium are made possible through grants, direct and in-kind contributions provided by: AbbVie; Amgen Inc.; Arthritis Foundation; Bioiberica S.A.; DePuy Mitek, Inc.; Flexion Therapeutics, Inc.; GlaxoSmithKline; Merck Serono; Rottapharm | Madaus; Sanofi; Stryker; The Pivotal OAI MRI Analyses (POMA) Study, NIH HHSN2682010000. We thank the Osteoarthritis Research Society International (OARSI) for their leadership and expertise on the FNIH OA Biomarker Consortium project. The OAI is a public-private partnership comprised of five contracts (N01-AR- 2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health. Funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc. Private sector funding for the Consortium and OAI is managed by the FNIH.The IMI-APPROACH study consortium received support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement no 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. See www.imi.europa.eu and www.approachproject.eu. The funding sources had no role in the design of this study.

Objectives: To compare inflammatory and structural differences in active Psoriatic Arthritis (PsA) between disease-modifying antirheumatic drug (DMARD)-naive and DMARD-failure patients using diverse imaging approaches for future analyses. Additionally, to explore the influence of patient characteristics (clinical and demographic variables) on imaging findings., Methods: Of the 80 patients included from the first cohort of the ongoing multicentre TOFA-PREDICT trial, 40 were DMARD-naive and 40 were DMARD-failure (csDMARD failure; 1 prior bDMARD excluding etanercept was allowed), all meeting classification criteria for PsA with a minimum disease duration of eight weeks. Baseline conventional radiographs of hands and feet, MRIs of both ankles, and whole-body 18F-FDG PET/CT were evaluated for inflammatory and structural imaging parameters, including Sharp-van der Heijde (SHS), Heel Enthesitis Magnetic Resonance Imaging Scoring System (HEMRIS) and Deauville synovitis scoring. Differences between groups and the influence of patient characteristics were examined with multiple linear regression., Results: At baseline, patient characteristics were similar between groups. Imaging parameters showed limited inflammation and structural damage. Inflammatory imaging parameters were not significantly different (p> 0.200). Among structural parameters, only HEMRIS Achilles tendon structural damage was significantly different (p= 0.024, R2=0.071) and, SHS Joint Space Narrowing was not statistically significant (p= 0.050, R2=0.048) with higher values for both in DMARD-failures. After correction of patient characteristics, these differences in imaging disappeared (both p> 0.600)., Conclusion: At baseline, PsA patient groups were comparable concerning structural and inflammatory imaging parameters, especially after correcting for patient characteristics. Thus, DMARD-naive and DMARD-failure patient groups may be combined in future PsA progression and treatment decision studies., Clinical Trial Registration Number: EudraCT: 2017-003900-28., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To investigate whether structural hand OA or its progression is associated with structural knee OA progression after two years in a population with symptomatic knee OA., Methods: We used baseline and two-year follow-up data from the IMI-APPROACH cohort. Symptomatic hand and knee OA were defined using ACR criteria. Radiographs of hands and knees were scored semi-quantitatively for osteophytes and joint space narrowing (JSN) following the OARSI atlas, and Kellgren-Lawrence (KL) scale. Knee images were also scored quantitatively with the Knee Image Digital Analysis (KIDA). Progression was defined as change above the minimal detectable change on patient level, except for KIDA (most affected knee compartment level). With logistic regression analyses the severity or progression of hand OA was associated with knee OA progression., Results: In 221 participants (mean age 66, 77% women, mean BMI 27.7, 19% hand OA), OA progression occurred in 18%-28%, and 9%-38% in hands and knees respectively, depending on features. Baseline structural hand OA features were not significantly associated with knee OA progression, except for hand osteophytes with KIDA osteophytes progression (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06). Progression of structural hand OA features was not significantly associated with knee OA progression, except for hand osteophyte or JSN progression, which was significantly associated with knee osteophyte progression (OR 0.44, 95%CI 0.22-0.84 and OR 0.43, 95%CI 0.18-0.94, respectively), and hand osteophyte progression for knee JSN (OR 2.51, 95%CI 1.15-5.48)., Conclusions: In patients with symptomatic knee OA, no consistent associations between baseline structural hand OA or hand OA progression and knee OA progression were shown., Competing Interests: F Berenbaum received consulting fees from Grunenthal, GSK, Eli lilly, Novartis, Pfizer and Servier, IKH received consulting fees from novartis, GSK and Grunenthal, SCM received a grant from the Dutch Arthritis Foundation, HW received financial support for the IMI-APPROACH cohort, and MK received financial support from the Dutch Arthritis Foundation, all paid to the institution. All other authors declare no competing interests., (© 2024 The Authors.)

Objectives: Ectopic bone deposition plays an important role in osteoarthritis (OA) and in arterial wall disease. We aimed to investigate the prevalence and progression of arterial calcifications on whole-body computed tomography (CT) in persons with knee OA., Methods: We included 118 (36 male) participants who satisfied the clinical American College of Rheumatology classification criteria for knee OA. Baseline investigations included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kellgren-Lawrence grading. At baseline and after two years, a whole-body CT was performed using the same scanner and protocol. Calcifications were quantified in the carotid, brachiocephalic, coronary, thoracic aortic, abdominal aortic, iliac, femoropopliteal and crural arteries. Multivariable linear and logistic regression modeling was used for analyses., Results: At baseline males were 66.9 ± 7.7 and females were 68.0 ± 5.6 years old. Calcifications were common, all participants except two females had some calcification, and prevalence ranged between 41.8% and 94.4% for various arterial beds. Baseline femoropopliteal calcifications were associated with a higher Kellgren-Lawrence grade (more severe knee OA). Median annual progression rate was 13.1% in males and 15.7% in females. Structural OA severity was not associated with progression, but a five points lower (worse) WOMAC was associated with 1% faster progression of arterial calcifications (p= 0.008)., Conclusion: Around age 70 nearly all persons with knee OA have arterial calcifications, which progress substantially. For further investigation into shared causality intervention studies are needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study aims at assessing approaches for generating high-resolution magnetic resonance imaging- (MRI-) based synthetic computed tomography (sCT) images suitable for orthopedic care using a deep learning model trained on low-resolution computed tomography (CT) data. To that end, paired MRI and CT data of three anatomical regions were used: high-resolution knee and ankle data, and low-resolution hip data. Four experiments were conducted to investigate the impact of low-resolution training CT data on sCT generation and to find ways to train models on low-resolution data while providing high-resolution sCT images. Experiments included resampling of the training data or augmentation of the low-resolution data with high-resolution data. Training sCT generation models using low-resolution CT data resulted in blurry sCT images. By resampling the MRI/CT pairs before the training, models generated sharper images, presumably through an increase in the MRI/CT mutual information. Alternatively, augmenting the low-resolution with high-resolution data improved sCT in terms of mean absolute error proportionally to the amount of high-resolution data. Overall, the morphological accuracy was satisfactory as assessed by an average intermodal distance between joint centers ranging from 0.7 to 1.2 mm and by an average intermodal root-mean-squared distances between bone surfaces under 0.7 mm. Average dice scores ranged from 79.8% to 87.3% for bony structures. To conclude, this paper proposed approaches to generate high-resolution sCT suitable for orthopedic care using low-resolution data. This can generalize the use of sCT for imaging the musculoskeletal system, paving the way for an MR-only imaging with simplified logistics and no ionizing radiation., (© 2023 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Background: Patients with psoriatic arthritis (PsA) have an increased risk of cardiovascular disease, possibly due to a chronic inflammatory state., Objectives: The main objective of this study was to investigate the difference in vascular inflammation, measured with 18-fluorodeoxyglucose positron emission tomography/CT (PET/CT), in PsA patients and controls. We conducted a secondary analysis to assess the association between clinical parameters of disease activity with vascular inflammation in PsA., Methods: We included a total of 75 PsA patients with active peripheral arthritis (defined as ≥2 tender and swollen joints) from an ongoing clinical trial (EudraCT 2017-003900-28) and a retrospective group of 40 controls diagnosed with melanoma, without distant metastases and not receiving immunotherapy. The main outcome measure was aortic vascular inflammation which was measured on PET/CT scans using target-to-background ratios. Clinical disease activity in PsA was assessed with joint counts, body surface area and the Disease Activity index for PsA. Laboratory assessments included C reactive protein and erythrocyte sedimentation rate., Results: Vascular inflammation was increased in patients with PsA in comparison with controls (mean target-to-background ratio for entire aorta, respectively, 1.63±0.17 vs 1.49±0.16; p=<0.001). This association remained significant after correction for gender, age, body mass index, mean arterial pressure and aortic calcification (p=0.002). Vascular inflammation was not associated with disease-related parameters., Conclusions: Aortic vascular inflammation was significantly increased in patients with active PsA compared with controls. This evidence supports the theory that inflammation in PsA is not limited to the skin and joints but also involves the vascular system., Competing Interests: Competing interests: KPMS: consulting/advisory relationship: Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, Sairopa. Honoraria received: Novartis, Roche, Merck Sharp and Dome. Research funding: TigaTx, Bristol Myers Squibb, Philips. All paid to the institution and outside the submitted work. PAdJ has a research collaboration with Vifor Pharma and Philips Healthcare. WF received research grants unrelated to the topic of the present study from Novo Nordisk and Pfizer, which were paid to the institution. HEV reports having received grants, consulting fees or honorarium from AbbVie, Boehringer Ingelheim, Novartis, Pfizer, UCB, Janssen and Galapagos; all outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Over the last few years, political advertisers have moved with their audiences: to social media platforms. Advertisers on these platforms aim to persuade voters by sending messages tailored to them based on their own data: political microtargeting (PMT). A considerable problem with PMT is that users are often unaware that they are being targeted, while current transparency advances do not seem to suffice in informing users. However, increasing transparency may have consequences on users' privacy perceptions. Thus, the current work investigates whether disclosures, as a measure to increase transparency, increase users' recognition of a microtargeted ad, and subsequently what this means for their perceived benefits, privacy concerns, and their likelihood of engaging in privacy protection behavior, based on the privacy calculus. In a preregistered online one-factorial between-subjects experiment (N = 450) we exposed participants to either an Instagram post containing a currently used disclosure or a more salient disclosure. Our results show that exposure to this disclosure increases recognition of the ad being microtargeted, and that this relates to perceived benefits but not privacy concerns. However, the results show that users' privacy concerns are related to their increased privacy protection behavior. Finally, we found that over four-fifths of our participants who were exposed to the more salient disclosure recalled it correctly., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jansen, Krämer. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Knee joint distraction (KJD) has been associated with clinical and structural improvement and SF marker changes. The current objective was to analyse radiographic changes after KJD using an automatic artificial intelligence-based measurement method and relate these to clinical outcome and SF markers., Methods: Twenty knee osteoarthritis patients were treated with KJD in regular care. Radiographs and WOMAC were collected before and ∼1 year post-treatment. SF was aspirated before, during and after treatment; biomarker levels were assessed by immunoassay. Radiographs were analysed to obtain compartmental minimum and standardized joint space width (JSW), Kellgren-Lawrence (KL) grades, compartmental joint space narrowing (JSN) scores, and osteophytosis and sclerosis scores. Results were analysed for the most affected compartment (MAC) and least affected compartment. Radiographic changes were analysed using the Wilcoxon signed rank test for categorical and paired t-test for continuous variables. Linear regression was used to calculate associations between changes in JSW, WOMAC pain and SF markers., Results: Sixteen patients could be evaluated. JSW, KL and JSN improved in around half of the patients, significant only for MAC JSW (P < 0.05). MAC JSW change was positively associated with WOMAC pain change (P < 0.04). Greater monocyte chemoattractant protein 1 (MCP-1) and lower TGFβ-1 increases were significantly associated with changes in MAC JSW (P < 0.05). MCP-1 changes were positively associated with WOMAC pain changes (P < 0.05)., Conclusion: Automatic radiographic measurements show improved joint structure in most patients after KJD in regular care. MAC JSW increased significantly and was associated with SF biomarker level changes and even with improvements in pain as experienced by these patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Diagnostic reasoning is an important topic in General Practitioners' (GPs) vocational training. Interestingly, research has paid little attention to the content of the cases used in clinical reasoning education. Malpractice claims of diagnostic errors represent cases that impact patients and that reflect potential knowledge gaps and contextual factors. With this study, we aimed to identify and prioritize educational content from a malpractice claims database in order to improve clinical reasoning education in GP training. With input from various experts in clinical reasoning and diagnostic error, we defined five priority criteria that reflect educational relevance. Fifty unique medical conditions from a malpractice claims database were scored on those priority criteria by stakeholders in clinical reasoning education in 2021. Subsequently, we calculated the mean total priority score for each condition. Mean total priority score (min 5-max 25) for all fifty diagnoses was 17,11 with a range from 13,89 to 19,61. We identified and described the fifteen highest scoring diseases (with priority scores ranging from 18,17 to 19,61). The prioritized conditions involved complex common (e.g., cardiovascular diseases, renal insufficiency and cancer), complex rare (e.g., endocarditis, ectopic pregnancy, testicular torsion) and more straightforward common conditions (e.g., tendon rupture/injury, eye infection). The claim cases often demonstrated atypical presentations or complex contextual factors. Including those malpractice cases in GP vocational training could enrich the illness scripts of diseases that are at high risk of errors, which may reduce diagnostic error and related patient harm., (© 2022. The Author(s).)

Objective: To gain better understanding of osteoarthritis (OA) heterogeneity and its predictors for distinguishing OA phenotypes. This could provide the opportunity to tailor prevention and treatment strategies and thus improve care., Design: Ten year follow-up data from CHECK (1002 early-OA subjects with first general practitioner visit for complaints ≤6 months before inclusion) was used. Data were collected on WOMAC (pain, function, stiffness), quantitative radiographic tibiofemoral (TF) OA characteristics, and semi-quantitative radiographic patellofemoral (PF) OA characteristics. Using functional data analysis, distinctive sets of trajectories were identified for WOMAC, TF and PF characteristics, based on model fit and clinical interpretation. The probabilities of knee membership to each trajectory were used in hierarchical cluster analyses to derive knee OA phenotypes. The number and composition of potential phenotypes was selected again based on model fit (silhouette score) and clinical interpretation., Results: Five trajectories representing different constant levels or changing WOMAC scores were identified. For TF and PF OA, eight and six trajectories respectively were identified based on (changes in) joint space narrowing, osteophytes and sclerosis. Combining the probabilities of knees belonging to these different trajectories resulted in six clusters ('phenotypes') of knees with different degrees of functional (WOMAC) and radiographic (PF) parameters; TF parameters were found not to significantly contribute to clustering. Including baseline characteristics as well resulted in eight clusters of knees, dominated by sex, menopausal status and WOMAC scores, with only limited contribution of PF features., Conclusions: Several stable and progressive trajectories of OA symptoms and radiographic features were identified, resulting in phenotypes with relatively independent symptomatic and radiographic features. Sex and menopausal status may be especially important when phenotyping knee OA patients, while radiographic features contributed less. Possible phenotypes were identified that, after validation, could aid personalized treatments and patients selection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Altamirano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Longitudinal weight-bearing radiographic joint space width (JSW) and non-weight-bearing MRI-based cartilage thickness changes often show weak correlations. The current objective was to investigate these correlations, and to explore the influence of different factors that could contribute to longitudinal differences between the two methods., Methods: The current study included 178 participants with medial osteoarthritis (OA) out of the 297 knee OA participants enrolled in the IMI-APPROACH cohort. Changes over 2 years in medial JSW (ΔJSWmed), minimum JSW (ΔJSWmin), and medial femorotibial cartilage thickness (ΔMFTC) were assessed using linear regression, using measurements from radiographs and MRI acquired at baseline, 6 months, and 1 and 2 years. Pearson R correlations were calculated. The influence of cartilage quality (T2 mapping), meniscal extrusion (MOAKS scoring), potential pain-induced unloading (difference in knee-specific pain scores), and increased loading (BMI) on the correlations was analyzed by dividing participants in groups based on each factor separately, and comparing correlations (slope and strength) between groups using linear regression models., Result: Correlations between ΔMFTC and ΔJSWmed and ΔJSWmin were statistically significant (p < 0.004) but weak (R < 0.35). Correlations were significantly different between groups based on cartilage quality and on meniscal extrusion: only patients with the lowest T2 values and with meniscal extrusion showed significant moderate correlations. Pain-induced unloading or BMI-induced loading did not influence correlations., Conclusions: While the amount of loading does not seem to make a difference, weight-bearing radiographic JSW changes are a better reflection of non-weight-bearing MRI cartilage thickness changes in knees with higher quality cartilage and with meniscal extrusion., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Objective: Knee distraction treatment for end-stage osteoarthritis successfully postpones arthroplasty for years. Studies performed thus far used general intended use, patient-personalised or custom-made devices. In this study, for the first time, a device specifically designed for knee distraction is evaluated., Design: 65 patients (≤65 years) with end-stage knee osteoarthritis indicated for arthroplasty received knee distraction. Before, 1-year and 2-year post-treatment, questionnaires were filled out and knee radiographs made. Adverse events and self-reported pain medication were registered., Results: Forty-nine patients completed 2-year follow-up: one patient did not complete treatment, three patients received arthroplasty in the first and four patients in the second year follow-up. Eight patients were lost to follow-up in the second year. The total Western Ontario and McMaster Universities Osteoarthritis Index score showed a clinically relevant improvement at 1 and 2 years (+26 and +24 points), as did all subscales (all p<0.001). The minimum radiographic joint space width improved over 1 (+0.5 mm; p<0.001) and 2 (+0.4 mm; p=0.015) years, as did the physical Short-Form 36 (+10 points; p<0.001). The most common adverse event was pin tract infection, experienced by 66% of patients, in 88% successfully treated with oral antibiotics. In two cases, hospitalisation and/or intravenous antibiotics were needed. Eight patients experienced device-related complications. None of the complications influenced 2-year outcomes. Before treatment, 42% of patients used pain medication, which had nearly been halved 1 (23%; p=0.02) and 2 years (29%; p=0.27) post-treatment., Conclusions: Patients treated with a general applicable, for knee distraction purpose-built device showed, despite adverse events, significant clinical and structural improvement over 2 years., Trial Registration Number: NL7986., Competing Interests: Competing interests: PE was supported for the current manuscript by the Dutch Arthritis Society, NWO, InSciTe, TKI and Marie Curie, received payment for lectures from Masterclass Episurf and Arthex, participated on the advisory board TETEC and has stock or stock options with Chondropeptix and Avalanche Medical., (© 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.)

The association between structural changes and pain sensation in osteoarthritis (OA) remains unclear. Joint deterioration in OA leads to the release of protein fragments that can either systemically (serum) or locally (synovial fluid; SF) be targeted as biomarkers and describe structural changes and potentially pain. Biomarkers of collagen type I (C1M), type II (C2M), type III (C3M), type X (C10C), and aggrecan (ARGS) degradation were measured in the serum and SF of knee OA patients. Spearman's rank correlation was used to assess the correlation of the biomarkers' levels between serum and SF. Linear regression adjusted for confounders was used to evaluate the associations between the biomarkers' levels and clinical outcomes. The serum C1M levels were negatively associated with subchondral bone density. The serum C2M levels were negatively associated with KL grade and positively associated with minimum joint space width (minJSW). The C10C levels in SF were negatively associated with minJSW and positively associated with KL grade and osteophyte area. Lastly, the serum C2M and C3M levels were negatively associated with pain outcomes. Most of the biomarkers seemed to mainly be associated with structural outcomes. The overall biomarkers of extracellular matrix (ECM) remodeling in serum and SF may provide different information and reflect different pathogenic processes.

In the Innovative Medicine's Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) knee osteoarthritis (OA) study, machine learning models were trained to predict the probability of structural progression (s-score), predefined as >0.3 mm/year joint space width (JSW) decrease and used as inclusion criterion. The current objective was to evaluate predicted and observed structural progression over 2 years according to different radiographic and magnetic resonance imaging (MRI)-based structural parameters. Radiographs and MRI scans were acquired at baseline and 2-year follow-up. Radiographic (JSW, subchondral bone density, osteophytes), MRI quantitative (cartilage thickness), and MRI semiquantitative [SQ; cartilage damage, bone marrow lesions (BMLs), osteophytes] measurements were obtained. The number of progressors was calculated based on a change exceeding the smallest detectable change (SDC) for quantitative measures or a full SQ-score increase in any feature. Prediction of structural progression based on baseline s-scores and Kellgren-Lawrence (KL) grades was analyzed using logistic regression. Among 237 participants, around 1 in 6 participants was a structural progressor based on the predefined JSW-threshold. The highest progression rate was seen for radiographic bone density (39%), MRI cartilage thickness (38%), and radiographic osteophyte size (35%). Baseline s-scores could only predict JSW progression parameters (most P>0.05), while KL grades could predict progression of most MRI-based and radiographic parameters (P<0.05). In conclusion, between 1/6 and 1/3 of participants showed structural progression during 2-year follow-up. KL scores were observed to outperform the machine-learning-based s-scores as progression predictor. The large amount of data collected, and the wide range of disease stage, can be used for further development of more sensitive and successful (whole joint) prediction models. Trial Registration: Clinicaltrials.gov number NCT03883568., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-949/coif). WW reports serving as an employee and shareholder of Chondrometrics GmbH and receiving consulting fees from Galapagos NV; MK reports consulting fees from Abbvie, Pfizer, Kiniksa, Flexion, Galapagos, Jansen, CHDR, Novartis, UCB, all paid to institution; FJB reports Funding from Gedeon Richter Plc., Bristol-Myers Squibb International Corporation (BMSIC), Sun Pharma Global FZE, Celgene Corporation, Janssen Cilag International N.V, Janssen Research & Development, Viela Bio, Inc., Astrazeneca AB, UCB BIOSCIENCES GMBH, UCB BIOPHARMA SPRL, AbbVie Deutschland GmbH & Co.KG, Merck KGaA, Amgen, Inc., Novartis Farmacéutica, S.A., Boehringer Ingelheim España, S.A, CSL Behring, LLC, Glaxosmithkline Research & Development Limited, Pfizer Inc, Lilly S.A., Corbus Pharmaceuticals Inc., Biohope Scientific Solutions for Human Health S.L., Centrexion Therapeutics Corp., Sanofi, TEDEC-MEIJI FARMA S.A., Kiniksa Pharmaceuticals, Ltd; IKH reports Research grant (ADVANCE) from Pfizer (payment to institution) and consulting fees from Novartis, outside of the submitted work; FB reports Institutional grants from TRB Chemedica and Pfizer. Consulting fees from AstraZeneca, Boehringer Ingelheim, Bone Therapeutics, Cellprothera, Galapagos, Gilead, Grunenthal, GSK, Eli Lilly, MerckSerono, MSD, Nordic Bioscience, Novartis, Pfizer, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4P Pharma. Honoraria for lectures from Expanscience, Pfizer, Viatris. Payment for expert testimony from Pfizer and Eli Lilly. Travel support from Nordic Pharma, Pfizer, Eli Lilly, Novartis. Stock owner of 4Moving Biotech and Peptinov; CHL reports employee of Merck KGaA at start of the study; FWR reports serving as a shareholder of Boston Imaging Core Lab (BICL), LLC and consultant to Calibr and Grünenthal. The other authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences., Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function., Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters., Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed., Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Objective: Osteoarthritis (OA) is a highly prevalent chronic condition. The subchondral bone plays an important role in onset and progression of OA making it a potential treatment target for disease-modifying therapeutic approaches. However, little is known about changes of periarticular bone mineral density (BMD) in OA and its relation to meniscal coverage and meniscal extrusion at the knee. Thus, the aim of this study was to describe periarticular BMD in the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort at the knee and to analyze the association with structural disease severity, meniscal coverage and meniscal extrusion., Design: Quantitative CT (QCT), MRI and radiographic examinations were acquired in 275 patients with knee osteoarthritis (OA). QCT was used to assess BMD at the femur and tibia, at the cortical bone plate (Cort) and at the epiphysis at three locations: subchondral (Sub), mid-epiphysis (Mid) and adjacent to the physis (Juxta). BMD was evaluated for the medial and lateral compartment separately and for subregions covered and not covered by the meniscus. Radiographs were used to determine the femorotibial angle and were evaluated according to the Kellgren and Lawrence (KL) system. Meniscal extrusion was assessed from 0 to 3., Results: Mean BMD differed significantly between each anatomic location at both the femur and tibia (p < 0.001) in patients with KL0. Tibial regions assumed to be covered with meniscus in patients with KL0 showed lower BMD at Sub (p < 0.001), equivalent BMD at Mid (p = 0.07) and higher BMD at Juxta (p < 0.001) subregions compared to regions not covered with meniscus. Knees with KL2-4 showed lower Sub (p = 0.03), Mid (p = 0.01) and Juxta (p < 0.05) BMD at the medial femur compared to KL0/1. Meniscal extrusion grade 2 and 3 was associated with greater BMD at the tibial Cort (p < 0.001, p = 0.007). Varus malalignment is associated with significant greater BMD at the medial femur and at the medial tibia at all anatomic locations., Conclusion: BMD within the epiphyses of the tibia and femur decreases with increasing distance from the articular surface. Knees with structural OA (KL2-4) exhibit greater cortical BMD values at the tibia and lower BMD at the femur at the subchondral level and levels beneath compared to KL0/1. BMD at the tibial cortical bone plate is greater in patients with meniscal extrusion grade 2/3., Competing Interests: Declaration of competing interest FWR is shareholder of Boston Imaging Core Lab. (BICL), LLC. He is consultant to Calibr and Grünenthal; RH is a member of the speakers bureau and a consultant of Siemens Healthineers, outside the submitted work. MK reports grants from IMI-APPROACH, during the conduct of the study; consulting fees from GlaxoSmithKline, Pfizer, Merck-Serono, Kiniksa, Abbvie, Flexion, Galapagos, Jansen, CHDR, UCB, Novartis outside the submitted work and all paid to institution; FJB funding from Gedeon Richter Plc., Bristol-Myers Squibb International Corporation (BMSIC), Sun Pharma Global FZE, Celgene Corporation, Janssen Cilag International N·V, Janssen Research & Development, Viela Bio, Inc., Astrazeneca AB, UCB BIOSCIENCES GMBH, UCB BIOPHARMA SPRL, AbbVie Deutschland GmbH & Co.KG, Merck KGaA, Amgen, Inc., Novartis Farmacéutica, S.A., Boehringer Ingelheim España, S.A, CSL Behring, LLC, Glaxosmithkline Research & Development Limited, Pfizer Inc., Lilly S.A., Corbus Pharmaceuticals Inc., Biohope Scientific Solutions for Human Health S.L., Centrexion Therapeutics Corp., Sanofi, MEIJI FARMA S.A., Kiniksa Pharmaceuticals, Ltd. Grunenthal, Asofarma Mexico, Gebro Pharma, Roche, Galapagos, Regeneron; FB is shareholder of 4Moving Biotech and 4P,Pharma, reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Novartis, Pfizer, Roche, Sanofi, Servier, Peptinov, TRB Chemedica, Viatris. WW is employee and shareholder of Chondrometrics GmbH. AL is employee of Servier. The other authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next-generation sequencing (NGS). Circulating cell-free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre-treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre-treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre-treatment ctDNA detection had a sensitivity of 47% (95% CI 24-71) (8/17), specificity of 85% (95% CI 42-99) (6/7), positive predictive value (PPV) of 89% (95% CI 51-99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17-67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post-nCRT ctDNA detection had a sensitivity of 21% (95% CI 6-51) (3/14), specificity of 100% (95% CI 56-100) (7/7), PPV of 100% (95% CI 31-100) (3/3), and NPV of 39% (95% CI 18-64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre-treatment and post-nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Objectives: The IMI-APPROACH knee osteoarthritis study used machine learning (ML) to predict structural and/or pain progression, expressed by a structural (S) and pain (P) predicted-progression score, to select patients from existing cohorts. This study evaluates the actual 2-year progression within the IMI-APPROACH, in relation to the predicted-progression scores., Methods: Actual structural progression was measured using minimum joint space width (minJSW). Actual pain (progression) was evaluated using the Knee injury and Osteoarthritis Outcomes Score (KOOS) pain questionnaire. Progression was presented as actual change (Δ) after 2 years, and as progression over 2 years based on a per patient fitted regression line using 0, 0.5, 1 and 2-year values. Differences in predicted-progression scores between actual progressors and non-progressors were evaluated. Receiver operating characteristic (ROC) curves were constructed and corresponding area under the curve (AUC) reported. Using Youden's index, optimal cut-offs were chosen to enable evaluation of both predicted-progression scores to identify actual progressors., Results: Actual structural progressors were initially assigned higher S predicted-progression scores compared with structural non-progressors. Likewise, actual pain progressors were assigned higher P predicted-progression scores compared with pain non-progressors. The AUC-ROC for the S predicted-progression score to identify actual structural progressors was poor (0.612 and 0.599 for Δ and regression minJSW, respectively). The AUC-ROC for the P predicted-progression score to identify actual pain progressors were good (0.817 and 0.830 for Δ and regression KOOS pain, respectively)., Conclusion: The S and P predicted-progression scores as provided by the ML models developed and used for the selection of IMI-APPROACH patients were to some degree able to distinguish between actual progressors and non-progressors., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03883568., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that affects up to 30% of patients with psoriasis. Current challenges in clinical care and research include personalised treatment, understanding the divergence of therapy response and unravelling the multifactorial pathophysiology of this complex disease. Moreover, there is an urgent clinical need to predict, assess and understand the cellular and molecular pathways underlying the response to disease-modifying antirheumatic drugs (DMARDs). The TOFA-PREDICT clinical trial addresses this need. Our primary objective is to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in PsA., Methods and Analysis: In this investigator-initiated, phase III, multicentre, open-label, four-arm randomised controlled trial, we plan to integrate clinical, molecular and imaging parameters of 160 patients with PsA. DMARD-naïve patients are randomised to methotrexate or tofacitinib. Additionally, patients who are non-responsive to conventional synthetic (cs)DMARDs continue their current csDMARD and are randomised to etanercept or tofacitinib. This results in four arms each with 40 patients. Patients are followed for 1 year. Treatment response is defined as minimal disease activity at week 16. Clinical data, biosamples and images are collected at baseline, 4 weeks and 16 weeks; at treatment failure (treatment switch) and 52 weeks. For the first 80 patients, we will use a systems medicine approach to assess multiomics biomarkers and develop a prediction model for treatment response. Subsequently, data from the second 80 patients will be used for validation., Ethics and Dissemination: The study was approved by the Medical Research Ethics Committee in Utrecht, Netherlands, is registered in the European Clinical Trials Database and is carried out in accordance with the Declaration of Helsinki. The study's progress is monitored by Julius Clinical, a science-driven contract research organisation., Trial Registration Number: EudraCT: 2017-003900-28., 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.)

Knee joint distraction (KJD) is a novel technique for relatively young knee osteoarthritis (OA) patients. With KJD, an external distraction device creates temporary total absence of contact between cartilage surfaces, which results in pain relief and possibly limits the progression of knee OA. Recently, KJD showed similar clinical outcomes compared with high tibial osteotomy (HTO). Yet, no comparative data exist regarding return to sport (RTS) and return to work (RTW) after KJD. Therefore, our aim was to compare RTS and RTW between KJD and HTO. We performed a cross-sectional follow-up study in patients <65 years who previously participated in a randomized controlled trial comparing KJD and HTO. Out of 62 eligible patients, 55 patients responded and 51 completed the questionnaire (16 KJDs and 35 HTOs) at 5-year follow-up. The primary outcome measures were the percentages of RTS and RTW. Secondary outcome measures included time to RTS/RTW, and pre- and postoperative Tegner's (higher is more active), and Work Osteoarthritis or Joint-Replacement Questionnaire (WORQ) scores (higher is better work ability). Patients' baseline characteristics did not differ. Total 1 year after KJD, 79% returned to sport versus 80% after HTO (not significant [n.s.]). RTS <6 months was 73 and 75%, respectively (n.s.). RTW 1 year after KJD was 94 versus 97% after HTO (n.s.), and 91 versus 87% <6 months (n.s.). The median Tegner's score decreased from 5.0 to 3.5 after KJD, and from 5.0 to 3.0 after HTO (n.s.). The mean WORQ score improvement was higher after HTO (16 ± 16) than after KJD (6 ± 13; p  = 0.04). Thus, no differences were found for sport and work participation between KJD and HTO in our small, though first ever, cohort. Overall, these findings may support further investigation into KJD as a possible joint-preserving option for challenging "young" knee OA patients. The level of evidence is III., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Increased subchondral cortical bone plate thickness and trabecular bone density are characteristic of knee osteoarthritis (OA). Knee joint distraction (KJD) is a joint-preserving knee OA treatment where the joint is temporarily unloaded. It has previously shown clinical improvement and cartilage regeneration, indicating reversal of OA-related changes. The purpose of this research was to explore 3D subchondral bone changes after KJD treatment using CT imaging., Design: Twenty patients were treated with KJD and included to undergo knee CT imaging before, one, and two years after treatment. Tibia and femur segmentation and registration to canonical surfaces were performed semi-automatically. Cortical bone thickness and trabecular bone density were determined using an automated algorithm. Statistical parametric mapping (SPM) with two-tailed F-tests was used to analyze whole-joint changes., Results: Data was available of 16 patients. Subchondral cortical bone plate thickness and trabecular bone density were higher in the weight-bearing region of the most affected compartment (MAC; mostly medial). Especially the MAC showed a decrease in thickness and density in the first year after treatment, which was sustained towards the second year., Conclusions: KJD treatment results in bone changes that include thinning of the subchondral cortical bone plate and decrease of subchondral trabecular bone density in the first two years after treatment, potentially indicating a partial normalization of subchondral bone., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: Knee joint distraction (KJD) has been shown to result in long-term clinical improvement and short-term cartilage restoration in young OA patients. The objective of the current study was to evaluate MRI cartilage thickness up to 10 years after KJD treatment, using a 3D surface-based approach., Methods: Twenty end-stage knee OA patients were treated with KJD. MRI scans (1.5 T) were performed before and at 1, 2, 5, 7, and 10 years after treatment. Tibia and femur cartilage segmentation and registration to a canonical surface were performed semi-automatically. Statistical parametric mapping with linear mixed models was used to analyse whole-joint changes. The influence of baseline patient characteristics was analysed with statistical parametric mapping using linear regression. Relevant weight-bearing parts of the femur were selected to obtain the average cartilage thickness in the femur and tibia of the most- (MAC) and least-affected compartment. These compartmental changes over time were analysed using repeated measures ANOVA; missing data was imputed. In all cases, P <0.05 was considered statistically significant., Results: One and 2 years post-treatment, cartilage in the MAC weight-bearing region was significantly thicker than pre-treatment, gradually thinning after 5 years, but still increased at 10 years post-treatment. Long-term results showed that areas in the least-affected compartment were significantly thicker than pre-treatment. Male sex and more severe OA at baseline somewhat predicted shorter-term benefit (P >0.05). Compartmental analyses showed significant short- and long-term thickness increase in the tibia and femur MAC (all P <0.05)., Conclusion: KJD results in significant short- and long-term cartilage regeneration, up to 10 years post-treatment., Trial Registration: Netherlands Trial Register, https://www.trialregister.nl, NL419., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Joint distraction, the prolonged mechanical separation of the bones at a joint, has emerged as a joint-preserving treatment for end-stage osteoarthritis, with the gradually growing promise of implementation in regular clinical practice. Joint distraction of the knee has been most extensively studied, with these studies showing prolonged symptomatic improvement in combination with repair of cartilage tissue in degenerated knee joints, supporting the concept that cartilage repair can translate into real clinical benefit. The reversal of tissue degeneration observed with joint distraction could be the result of one or a combination of various proposed mechanisms, including partial unloading, synovial fluid pressure oscillation, mechanical and biochemical changes in subchondral bone, adhesion and chondrogenic commitment of joint-derived mesenchymal stem cells or a change in the molecular milieu of the joint. The overall picture that emerges from the combined evidence is relevant for future research and treatment-related improvements of joint distraction and for translation of the insights gained about tissue repair to other joint-preserving techniques. It remains to be elucidated whether optimizing the biomechanical conditions during joint distraction can actually cure osteoarthritis rather than only providing temporary symptomatic relief, but even temporary relief might be relevant for society and patients, as it will delay joint replacement with a prosthesis at an early age and thereby avert revision surgery later in life. Most importantly, improved insights into the underlying mechanisms of joint repair might provide new leads for more targeted treatment options., (© 2021. Springer Nature Limited.)

Objective: Knee joint distraction (KJD) is a joint-preserving osteoarthritis treatment that may postpone a total knee arthroplasty (TKA) in younger patients. This systematic review and meta-analysis evaluates short- and long-term clinical benefit and tissue structure changes after KJD., Design: MEDLINE, EMBASE, and Web of Science were searched for eligible clinical studies evaluating at least one of the primary parameters: WOMAC, VAS-pain, KOOS, EQ5D, radiographic joint space width or MRI cartilage thickness after KJD. Random effects models were applied on all outcome parameters and outcomes were compared with control groups found in the included studies., Results: Eleven articles reporting on 7 different KJD cohorts with in total 127 patients and 5 control groups with multiple follow-up moments were included, of which 2 were randomized controlled trials. Significant improvements in all primary parameters were found and benefit lasted up to at least 9 years. Overall, outcomes were comparable with control groups, including high tibial osteotomy, although TKA showed better clinical response., Conclusions: Current, still limited, evidence shows KJD causes clear benefit in clinical and structural parameters, both short- and long-term. Longer follow-up with more patients is necessary, to validate outcome and to potentially improve patient selection for this intensive treatment. Thus far, for younger knee osteoarthritis patients, KJD may be an option to consider.

Objectives: Osteoarthritis (OA) patients with a neuropathic pain (NP) component may represent a specific phenotype. This study compares joint damage, pain and functional disability between knee OA patients with a likely NP component, and those without a likely NP component., Methods: Baseline data from the Innovative Medicines Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway knee OA cohort study were used. Patients with a painDETECT score ≥19 (with likely NP component, n=24) were matched on a 1:2 ratio to patients with a painDETECT score ≤12 (without likely NP component), and similar knee and general pain (Knee Injury and Osteoarthritis Outcome Score pain and Short Form 36 pain). Pain, physical function and radiographic joint damage of multiple joints were determined and compared between OA patients with and without a likely NP component., Results: OA patients with painDETECT scores ≥19 had statistically significant less radiographic joint damage (p≤0.04 for Knee Images Digital Analysis parameters and Kellgren and Lawrence grade), but an impaired physical function (p<0.003 for all tests) compared with patients with a painDETECT score ≤12. In addition, more severe pain was found in joints other than the index knee (p≤0.001 for hips and hands), while joint damage throughout the body was not different., Conclusions: OA patients with a likely NP component, as determined with the painDETECT questionnaire, may represent a specific OA phenotype, where local and overall joint damage is not the main cause of pain and disability. Patients with this NP component will likely not benefit from general pain medication and/or disease-modifying OA drug (DMOAD) therapy. Reserved inclusion of these patients in DMOAD trials is advised in the quest for successful OA treatments.Trial registration numberThe study is registered under clinicaltrials.gov nr: NCT03883568., Competing Interests: Competing interests: The IMI-APPROACH project received a grant from Innovative Medicines Institute, grant agreement 115770. Outside the submitted work: EMvH has nothing to disclose; PMJW has nothing to disclose; MPJ has nothing to disclose; WPG has nothing to disclose; ML has nothing to disclose; MK reports grants from IMI-APPROACH, grants from Dutch Arthritis Association, during the conduct of the study; other from GlaxoSmithKline, Pfizer, Merck-Serono, Kiniksa, Abbvie, outside the submitted work; FBl reports grants from Gebro Pharma, grants from BIOIBERICA, grants from AB Science, grants from Abbvie, grants from Ablynx N.V., grants from Amgen, grants from Archigen Biotech, grants from Boehringer, grants from Bristol-Myers, grants from Celgene, grants from Eli Lilly and Company, grants from F. Hoffmann- La Roche., grants from Galapagos, grants from Gedeon, grants from Genentech, grants from Gideal Sciences, NC, grants from Glaxosmithkline, grants from Hospira, grants from INC Research UK, grants from Inventiv Health Clinical, grants from Janssen, grants from Lilly, grants from Nichi-IKO Pharmaceutical, grants from Novartis, grants from ONO Pharma, grants from Pfizer, grants from Pharmaceutical Research, grants from Regeneron, grants from Roche, grants from SA UCB Pharma, grants from Sanofi, grants from TRB Chemedica, grants from UCB Biosciences, outside the submitted work; In addition, FB has a patent Molecular block-matching method for gel image analysis issued, a patent Targeting A Specific Receptor On Cells With A Specific Compound For Use In The Treatment And/Or The Prevention Of Osteoarthritis And Rheumatoid Arthritis pending, a patent Genetic markers for osteoarthritis issued, a patent Method for the diagnosis of osteoarthritis issued, a patent Genetic markers for osteoarthritis pending, a patent Method for the diagnosing Arthrosis pending, a patent Method for diagnosing Arthrosis pending, a patent Method for the diagnosis of osteoarthritis pending, and a patent Anti-connexin compounds for use in the prevention and/or treatment of degenerative joint diseases. pending; IKH reports personal fees from AbbVie, grants from Pfizer, outside the submitted work; FBe reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma; A-CB-J reports non-financial support from Nordic Bioscience, personal fees from Nordic Bioscience, during the conduct of the study; CHL reports other from Merck KGaA, during the conduct of the study; AL is employee of Institut de Recherches Internationales Servier; JLa reports personal fees and other from GlaxoSmithKline, outside the submitted work; JLo has nothing to disclose; AM has nothing to disclose; HHW has nothing to disclose; FL has nothing to disclose; NE has nothing to disclose; SM has nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Knee Image Digital Analysis (KIDA) is standardized radiographic analysis software for measuring osteoarthritis (OA) characteristics. It was validated in mild OA, but used for severe OA as well. The current goal was to evaluate the performance of KIDA in severe OA., Design: Of 103 patients, standardized radiographs were performed before and one and 2 years after treatment for severe OA. All radiographs were evaluated on subchondral bone density, joint space width (JSW), osteophytes, eminence height, and joint angle, twice within years by the same observer. Part of the radiographs were randomly selected for reevaluation twice within 1 month and evaluation by another observer. The intraclass correlation coefficient (ICC), smallest detectable difference (SDD) and coefficient of variation (CV) were calculated; the SDD and CV were compared to those in mild OA. The relation of severity with KIDA parameters and with observer differences was calculated with linear regression., Results: Intra-observer ICCs were higher in the 98 severe radiographs reanalyzed within 1 month (all >0.8) than the 293 reanalyzed within years (all >0.5; most >0.8) and than inter-observer ICCs (all >0.7). SDDs and CVs were smaller when reanalyzed within a month and comparable to those in mild OA. Some parameters showed bias between readings. Severity showed significant relation with osteophytes and JSW parameters, and with the observer variation in these parameters (all P < 0.04)., Conclusions: KIDA is a well-performing tool also for severe OA. In order to decrease variability and SDDs, images should be analyzed in a limited time frame and randomized order., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In knee osteoarthritis, radiographic joint space width (JSW) is frequently used as a surrogate marker for cartilage thickness; however, longitudinal changes in radiographic JSW have shown poor correlations with those of magnetic resonance imaging (MRI) cartilage thickness. There are fundamental differences between the techniques: radiographic JSW represents two-dimensional (2D), weight-bearing, bone-to-bone distance, while on MRI three-dimensional (3D) non-weight-bearing cartilage thickness is measured. In this exploratory study, computed tomography (CT) was included as a third technique, as it can measure bone-to-bone under non-weight-bearing conditions. The objective was to use CT to compare the impact of weight-bearing versus non-weight-bearing, as well as bone-to-bone JSW versus actual cartilage thickness, in the knee., Methods: Osteoarthritis patients ( n  = 20) who were treated with knee joint distraction were included. Weight-bearing radiographs, non-weight-bearing MRIs and CTs were acquired before and 2 years after treatment. The mean radiographic JSW and cartilage thickness of the most affected compartment were measured. From CT, the 3D median JSW was calculated and a 2D projectional image was rendered, positioned similarly and measured identically to the radiograph. Pearson correlations between the techniques were derived, both cross-sectionally and longitudinally., Results: Fourteen patients could be analyzed. Cross-sectionally, all comparisons showed moderate to strong significant correlations (R = 0.43-0.81; all p  < 0.05). Longitudinal changes over time were small; only the correlations between 2D CT and 3D CT (R = 0.65; p  = 0.01) and 3D CT and MRI (R = 0.62; p  = 0.02) were statistically significant., Conclusion: The poor correlation between changes in radiographic JSW and MRI cartilage thickness appears primarily to result from the difference in weight-bearing, and less so from measuring bone-to-bone distance versus cartilage thickness., Competing Interests: Conflict of interest statement: FE declares personal consultancy to Merck KGaA, Samumed, Bioclinica, Galapagos, Servier and Novartis, employment and stock (options) at Chrondrometrics, development of educational presentations at Medtronic, and expense reimbursement at Merck, Galapagos, Servier, and KolonTissuegene outside the submitted work. FPJGL was co-founder of ArthroSave BV with no further relation and is consultant for SynerkinePharma BV. The other authors declare no potential conflicts of interest., (© The Author(s), 2021.)

Objective: Both, knee joint distraction (KJD) and high tibial osteotomy (HTO) are joint-preserving surgeries that postpone total knee arthroplasty (TKA) in younger osteoarthritis (OA) patients. Here we evaluate the 2-year follow-up of KJD versus TKA and KJD versus HTO in 2 noninferiority studies., Design: Knee OA patients indicated for TKA were randomized to KJD ( n = 20; KJD TKA ) or TKA ( n = 40). Medial compartmental knee OA patients considered for HTO were randomized to KJD ( n = 23; KJD HTO ) or HTO ( n = 46). Patient-reported outcome measures were assessed over 2 years of follow-up. The radiographic joint space width (JSW) was measured yearly. In the KJD groups, serum-PIIANP and urinary-CTXII levels were measured as collagen type-II synthesis and breakdown markers. It was hypothesized that there was no clinically important difference in the primary outcome, the total WOMAC, when comparing KJD with HTO and with TKA., Results: Both trials were completed, with 114 patients (19 KJD TKA ; 34 TKA; 20 KJD HTO ; 41 HTO) available for 2-year analyses. At 2 years, the total WOMAC score (KJDTKA: +30.4 [95% CI 23.0-37.9] points; TKA: +42.4 [95% CI 38.1-46.8]; KJDHTO: +21.6 [95% CI 13.8-29.4]; HTO: +29.2 [95% CI 23.6-34.8]; all: P < 0.05) and radiographic minimum JSW (KJDTKA: +0.9 [95% CI 0.2-1.6] mm; KJDHTO: +0.9 [95% CI 0.5-1.4]; HTO: +0.6 [95% CI 0.3-0.9]; all: P < 0.05) were still increased for all groups. The net collagen type-II synthesis 2 years after KJD was increased ( P < 0.05). Half of KJD patients experienced pin tract infections, successfully treated with oral antibiotics., Conclusions: Sustained improvement of clinical benefit and (hyaline) cartilage thickness increase after KJD is demonstrated. KJD was clinically noninferior to HTO and TKA in the primary outcome.

High tibial osteotomy (HTO) and knee joint distraction (KJD) are joint-preserving treatments that unload the more affected compartment (MAC) in knee osteoarthritis. This post-hoc study compares two-year cartilage-thickness changes after treatment with KJD vs. HTO, and identifies factors predicting cartilage restoration. Patients indicated for HTO were randomized to KJD (KJD HTO ) or HTO treatment. Patients indicated for total knee arthroplasty received KJD (KJD TKA ). Outcomes were the MRI mean MAC cartilage thickness and percentage of denuded bone area (dABp) change two years after treatment, using radiographic joint space width (JSW) as the reference. Cohen's d was used for between-group effect sizes. Post-treatment, KJD HTO patients ( n = 18) did not show significant changes. HTO patients ( n = 33) displayed a decrease in MAC cartilage thickness and an increase in dABp, but an increase in JSW. KJD TKA ( n = 18) showed an increase in MAC cartilage thickness and JSW, and a decrease in dABp. Osteoarthritis severity was the strongest predictor of cartilage restoration. Kellgren-Lawrence grade ≥3 showed significant restoration ( p < 0.01) after KJD; grade ≤2 did not. Effect sizes between severe KJD and HTO patients were large for MAC MRI cartilage thickness (d = 1.09; p = 0.005) and dABp (d = 1.13; p = 0.003), but not radiographic JSW (d = 0.28; p = 0.521). This suggests that in knee osteoarthritis patients with high disease severity, KJD may be more efficient in restoring cartilage thickness.

Purpose: Knee joint distraction (KJD) is a joint-preserving treatment for younger osteoarthritis patients. KJD has shown positive results in regular care, but the external fixation frame often caused pin tract skin infections. Therefore, the use of cadexomer iodine was included in the wound care protocol. The goal of this cross-sectional study was to evaluate whether use of this ointment reduced the number of patients with infections during KJD treatment., Methods: Patients treated with KJD in regular care were included if they gave consent for use of their data and completed treatment with the newest distraction device before 2020. All patients followed a wound care protocol, which since March 2019 included using cadexomer iodine ointment. The number of patients experiencing pin tract infections was compared between patients who did (March 2019-December 2019) and did not (November 2017-March 2019) use the ointment., Results: Sixty-seven patients were included; 34 patients used cadexomer iodine and 33 patients did not. Patient who did not use cadexomer iodine experienced twice as many infections (64% vs 32%;p = 0.010). There was a significant difference in the number of patients with serious infections, requiring more antibiotics than the standard 7-day oral antibiotics (30% without vs 6% with cadexomer iodine; p = 0.009)., Conclusions: The use of cadexomer iodine ointment during KJD results in a significant reduction of the number of patients experiencing pin tract infections during treatment. Use of this ointment should be considered standard protocol during KJD treatment and could be of value in general external fixator usage as well.

Purpose: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, and biochemical markers, to support OA drug development., Participants: APPROACH is a prospective cohort study including 297 patients with tibiofemoral OA, according to the American College of Rheumatology classification criteria. Patients were (pre)selected from existing cohorts using machine learning models, developed on data from the CHECK cohort, to display a high likelihood of radiographic joint space width (JSW) loss and/or knee pain progression., Findings to Date: Selection appeared logistically feasible and baseline characteristics of the cohort demonstrated an OA population with more severe disease: age 66.5 (SD 7.1) vs 68.1 (7.7) years, min-JSW 2.5 (1.3) vs 2.1 (1.0) mm and Knee injury and Osteoarthritis Outcome Score pain 31.3 (19.7) vs 17.7 (14.6), except for age, all: p<0.001, for selected versus excluded patients, respectively. Based on the selection model, this cohort has a predicted higher chance of progression., Future Plans: Patients will visit the hospital again at 6, 12 and 24 months for physical examination, pain and general health questionnaires, collection of blood and urine, MRI scans, radiographs of knees and hands, CT scan of the knee, low radiation whole-body CT, HandScan, motion analysis and performance-based tests.After two years, data will show whether those patients with the highest probabilities for progression experienced disease progression as compared to those wit lower probabilities (model validation) and whether phenotypes/endotypes can be identified and predicted to facilitate targeted drug therapy., Trial Registration Number: NCT03883568., Competing Interests: Competing interests: EMvH has nothing to disclose; WEvS reports grants from The Innovative Medicines Initiative Joint Undertaking under Grant Agreement no 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution, during the conduct of the study; MPJ has nothing to disclose; PMJW has nothing to disclose. MK reports grants from IMI-APPROACH, grants from Dutch Arthritis Association, during the conduct of the study; other from GlaxoSmithKline, Pfizer, Merck-Serono, Kiniksa, Abbvie, outside the submitted work; ML reports grants from Inovative Medicines Initative, during the conduct of the study; FJB reports grants from Gebro Pharma, grants from BIOIBERICA, grants from AB Science, grants from Abbvie, grants from Ablynx N.V., grants from Amgen, grants from Archigen Biotech, grants from Boehringer, grants from Bristol-Myers, grants from Celgene Int., grants from Eli Lilly and Company, grants from F. Hoffmann- La Roche, grants from Galapagos, grants from Gedeon, grants from Genentech, grants from Gideal Sciences, NC, grants from Glaxosmithkline, grants from Hospira, grants from INC Research UK, grants from Inventiv Health Clinical, grants from Janssen, grants from Lilly, grants from Nichi-IKO Pharmaceutical, grants from Novartis, grants from ONO Pharma, grants from Pfizer, grants from Pharmaceutical Research, grants from Regeneron, grants from Roche, grants from SA UCB Pharma, grants from Sanofi, grants from TRB Chemedica, grants from UCB Biosciences GMBH, outside the submitted work; In addition, FJB has a patent Molecular block-matching method for gel image analysis issued, a patent Targeting A Specific Receptor On Cells With A Specific Compound For Use In The Treatment And/Or The Prevention Of Osteoarthritis And Rheumatoid Arthritis pending, a patent Genetic markers for osteoarthritis issued, a patent Method for the diagnosis of osteoarthritis issued, a patent Genetic markers for osteoarthritis pending, a patent Method for the diagnosing Arthrosis pending, a patent Method for diagnosing Arthrosis pending, a patent Method for the diagnosis of osteoarthritis pending, and a patent Anti-connexin compounds for use in the prevention and/or treatment of degenerative joint diseases. pending; IKH reports personal fees from AbbVie, grants from Pfizer, outside the submitted work; FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, outside the submitted work; CHL reports other from Merck KGaA, during the conduct of the study; JLo has nothing to disclose; ACB-J reports non-financial support from Nordic Bioscience, personal fees from Nordic Bioscience, during the conduct of the study; AM has nothing to disclose; JLa reports personal fees and other from GlaxoSmithKline, outside the submitted work; and Current employee and shareholder of GlaxoSmithKline; JBo reports grants from Innovative Medicines Initiative (IMI-1), during the conduct of the study; and one of Lygature's other project receives part of its funding directly from Merck KgaA. This project is in the field of schistosomiasis and has no relationship whatsoever with the APPROACH project; HHW has nothing to disclose; ACAM has nothing to disclose; FPJGL has nothing to disclose., (© 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.)

Objective: Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response., Method: 20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS 4 ) was collected at baseline, 3, 6 and 12 months., Results: 13/20 (65%) were male with mean age 54°±°5yrs. All had Kellgren-Lawrence grade ≥2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGFβ-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS 4 over 6 months showed greater increases in FGF-2 and TGFβ-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS 4 over 12 months., Conclusion: Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Knee joint distraction (KJD) has been evaluated as a joint-preserving treatment to postpone total knee arthroplasty in knee osteoarthritis patients in three clinical trials. Since 2014 the treatment is used in regular care in some hospitals, which might lead to a deviation from the original indication and decreased treatment outcome. In this study, baseline characteristics, complications and clinical benefit are compared between patients treated in regular care and in clinical trials., Methods: In our hospital, 84 patients were treated in regular care for 6 weeks with KJD. Surgical details, complications, and range of motion were assessed from patient hospital charts. Patient-reported outcome measures were evaluated in regular care before and one year after treatment. Trial patients (n = 62) were treated and followed as described in literature., Results: Patient characteristics were not significantly different between groups, except for distraction duration (regular care 45.3±4.3; clinical trials 48.1±8.1 days; p = 0.019). Pin tract infections were the most occurring complication (70% regular care; 66% clinical trials), but there was no significant difference in treatment complications between groups (p>0.1). The range of motion was recovered within a year after treatment for both groups. WOMAC questionnaires showed statistically and clinically significant improvement for both groups (both p<0.001 and >15 points in all subscales) and no significant differences between groups (all differences p>0.05). After one year, 70% of patients were responders (regular care 61%, trial 75%; p = 0.120). Neither regular care compared to clinical trial, nor any other characteristic could predict clinical response., Conclusions: KJD as joint-preserving treatment in clinical practice, to postpone arthroplasty for end-stage knee osteoarthritis patient below the age of 65, results in an outcome similar to that thus far demonstrated in clinical trials. Longer follow-up in regular care is needed to test whether also long-term results remain beneficial and comparable to trial data., Competing Interests: FPJG Lafeber is co-founder, co-director, and shareholder of ArthroSave BV, a medical device company involved in marketing a user-friendly knee joint distraction device. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The current study examined the effectiveness of respiratory biofeedback in lowering subjective and objective arousal after stress. Participants were presented with a meditation session in virtual reality while subjective and objective arousal were measured, the latter measured through ECG and EEG. Three conditions were used: (a) a respiratory biofeedback condition, in which visual feedback was paired to breathing; (b) a control feedback placebo condition, in which visual feedback was not paired to breathing; and (c) a control no-feedback condition, in which no visual feedback was used. Subjective and objective arousal decreased during meditation after stress in all conditions, demonstrating recovery after stress during meditation in virtual reality. However, the reduction in arousal (on all outcome measures combined and heart rate specifically) was largest in the control feedback placebo condition, in which no biofeedback was used, indicating that respiratory biofeedback had no additional value in reducing arousal. The findings of the current study highlight the importance of including a control feedback placebo condition in order to establish the exact additional value of biofeedback and offer insights in applying cost-effective virtual reality meditation training.

Objective: Knee joint distraction (KJD), a joint-preserving surgery for severe osteoarthritis (OA), provides clinical and structural improvement and postpones the need for total knee arthroplasty (TKA). This study evaluates 9-year treatment outcome and identifies characteristics predicting long-term treatment success., Design: Patients with severe tibiofemoral OA (n = 20; age<60 years) indicated for TKA were treated with KJD. Questionnaires, radiographs, and magnetic resonance imaging (MRI) were used for evaluation. Survival after treatment was analyzed, where 'failure' was defined by TKA over time., Results: 9-year survival was 48%, and 72% for men (compared to 14% for women; P = 0.035) and 73% for those with a first-year minimum joint space width (JSW) increase of >0.5 mm (compared to 0% for <0.05 mm; P = 0.002). Survivors still reported clinical improvement compared to baseline (ΔWOMAC +29.9 points (95%CI 16.9-42.9; P = 0.001), ΔVAS -46.8 mm (-31.6-61.9; P < 0.001)). Surprisingly, patients getting TKA years after KJD still reported clinical improvement although less pronounced (ΔWOMAC +20.5 points (-1.8-42.8; P = 0.067), ΔVAS -25.4 mm (-3.2-47.7; P = 0.030)). Survivors showed long-lasting minimum JSW increase (baseline 0.3 mm (IQR 1.9), follow-up 1.3 mm (2.5); P = 0.017) while 'failures' did not (baseline 0.4 mm (1.8), follow-up 0.2 mm (1.5); P = 0.161). First-year minimum JSW on radiographs and cartilage thickness increase on MRI predict 9-year survival (HR 0.05 and 0.12, respectively; both P < 0.026). Male gender was associated with survival (HR 0.24; P = 0.050)., Conclusions: KJD shows long-lasting clinical and structural improvement. In addition to a greater survival rate for males (>two out of three), the initial cartilage repair activity appears to be important for long-term clinical success., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Progressive realisation is invoked as the guiding principle for countries on their own path to universal health coverage (UHC). It refers to the governmental obligations to immediately and progressively move towards the full realisation of UHC. This paper provides procedural guidance for countries, that is, how they can best organise their processes and evidence collection to make decisions on what services to provide first under progressive realisation. We thereby use 'evidence-informed deliberative processes', a generic value assessment framework to guide decision making on the choice of health services. We apply this to the concept of progressive realisation of UHC. We reason that countries face two important choices to achieve UHC. First, they need to define which services they consider as high priority, on the basis of their social values, including cost-effectiveness, priority to the worse off and financial risk protection. Second, they need to make tough choices whether they should first include more priority services, first expand coverage of existing priority services or first reduce co-payments of existing priority services. Evidence informed deliberative processes can facilitate these choices for UHC, and are also essential to the progressive realisation of the right to health. The framework informs health authorities on how they can best organise their processes in terms of composition of an appraisal committee including stakeholders, of decision-making criteria, collection of evidence and development of recommendations, including their communication. In conclusion, this paper fills in an important gap in the literature by providing procedural guidance for countries to progressively realise UHC., Competing Interests: Competing interests: None declared.

Circulating tumor DNA (ctDNA) has emerged as a potential new biomarker with diagnostic, predictive, and prognostic applications for various solid tumor types. Before beginning large prospective clinical trials to prove the added value of utilizing ctDNA in clinical practice, it is essential to investigate the effects of various preanalytical conditions on the quality of cell-free DNA (cfDNA) in general and of ctDNA in particular in order to optimize and standardize these conditions. Whole blood samples were collected from patients with metastatic cancer bearing a known somatic variant. The following preanalytical conditions were investigated: (a) different time intervals to plasma isolation (1, 24, and 96 h) and (b) different preservatives in blood collection tubes (EDTA, CellSave, and BCT). The quality of cfDNA/ctDNA was assessed by DNA quantification, digital polymerase chain reaction (dPCR) for somatic variant detection and a β-actin fragmentation assay for DNA contamination from lysed leukocytes. In 11 (69%) of our 16 patients, we were able to detect the known somatic variant in ctDNA. We observed a time-dependent increase in cfDNA concentrations in EDTA tubes, which was positively correlated with an increase in wild-type copy numbers and large DNA fragments (> 420 bp). Using different preservatives did not affect somatic variant detection ability, but did stabilize cfDNA concentrations over time. Variant allele frequency was affected by fluctuations in cfDNA concentration only in EDTA tubes at 96 h. Both CellSave and BCT tubes ensured optimal ctDNA quality in plasma processed within 96 h after blood collection for downstream somatic variant detection by dPCR., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Jan Hontelez and colleagues argue that the cost-effectiveness studies of HIV treatment scale-up need to include health system constraints to be more informative.

Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet activation exacerbates acute kidney injury. However, the mechanism of platelet activation during ischemia reperfusion injury and how platelet activation leads to tissue injury are largely unknown. Here we found that renal ischemia reperfusion injury in mice leads to increased platelet activation in immediate proximity of necrotic cell casts. Furthermore, platelet inhibition by clopidogrel decreased cell necrosis and inflammation, indicating a link between platelet activation and renal tissue damage. Necrotic tubular epithelial cells were found to release extracellular DNA, which, in turn, activated platelets, leading to platelet-granulocyte interaction and formation of neutrophil extracellular traps ex vivo. Renal ischemia reperfusion injury resulted in increased DNA-platelet and DNA-platelet-granulocyte colocalization in tissue and elevated levels of circulating extracellular DNA and platelet factor 4 in mice. After renal ischemia reperfusion injury, neutrophil extracellular traps were formed within renal tissue, which decreased when mice were treated with the platelet inhibitor clopidogrel. Thus, during renal ischemia reperfusion injury, necrotic cell-derived DNA leads to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Embedding health technology assessment (HTA) in a fair process has great potential to capture societal values relevant to public reimbursement decisions on health technologies. However, the development of such processes for priority setting has largely been theoretical. In this paper, we provide further practical lead ways on how these processes can be implemented. We first present the misconception about the relation between facts and values that is since long misleading the conduct of HTA and underlies the current assessment-appraisal split. We then argue that HTA should instead be explicitly organized as an ongoing evidence-informed deliberative process, that facilitates learning among stakeholders. This has important consequences for whose values to consider, how to deal with vested interests, how to consider all values in the decision-making process, and how to communicate decisions. This is in stark contrast to how HTA processes are implemented now. It is time to set the stage for HTA as learning., (© 2017 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background: The negative consequences of sleep-wake disorders in the general population and in children with an autism spectrum disorder (ASD) are well-established. However, little is known about sleep-wake disorders in adults with ASD.
AIM: To study and measure sleep-wake disorders and sleep-wake patterns in adults in a clinical facility who have been diagnosed primarily as having ASD without any comorbid intellectual disability.
METHOD: We assessed the sleep patterns of 19 patients in a residential facility. We asked patients to provide their sleep history, answer questionnaires and keep a sleep diary (subjective measurement). We also asked patients to collect actigraphy data (objective measurement) for seven days and to provide information about comorbid symptoms of anxiety and depression and use of medication.
RESULTS: Nine patients (47%) had undiagnosed comorbid sleep-wake disorders. Patients in our study overrated their sleep efficiency (diary) compared to objective data (actigraphy). However, patients' subjective sleep quality did match patients' sleep efficiency. Only two out of 14 patients with symptoms of anxiety and/or depression were diagnosed with a comorbid depressive disorder, 15 patients were treated with medication.
CONCLUSION: Sleep-wake disorders and comorbid symptoms of anxiety and depression might be more prevalent in adults with ASD in a residential facility than reported so far. This possibility needs to be considered more carefully during the diagnostic process and during treatment.

Background: PIK3CA is the most frequent somatic mutated oncogene in estrogen receptor (ER) positive breast cancer. We previously observed an association between PIK3CA genotype and aromatase inhibitors (AI) treatment outcome. This study now evaluates whether expression of mRNAs and miRs are linked to PIK3CA genotype and are independently related to AI therapy response in order to define potential expressed biomarkers for treatment outcome., Materials and Methods: The miR and mRNA expression levels were evaluated for their relationship with the PIK3CA genotype in two breast tumor datasets, i.e. 286 luminal cancers from the TCGA consortium and our set of 84 ER positive primary tumors of metastatic breast cancer patients who received first line AI. BRB Array tools class comparison was performed to define miRs and mRNAs whose expression associate with PIK3CA exon 9 and 20 status. Spearman correlations established miR-mRNA pairs and mRNAs with related expression. Next, a third dataset of 25 breast cancer patients receiving neo-adjuvant letrozole was evaluated, to compare expression levels of identified miRs and mRNAs in biopsies before and after treatment. Finally, to identify potential biomarkers miR and mRNA levels were related with overall survival (OS) and progression free survival (PFS) after first-line AI therapy., Results: Expression of 3 miRs (miR-449a, miR-205-5p, miR-301a-3p) and 9 mRNAs (CCNO, FAM81B, LRG1, NEK10, PLCL1, PGR, SERPINA3, SORBS2, VTCN1) was related to the PIK3CA status in both datasets. All except miR-301a-3p had an increased expression in tumors with PIK3CA mutations. Validation in a publicly available dataset showed that LRG1, PGR, and SERPINA3 levels were decreased after neo-adjuvant AI-treatment. Six miR-mRNA pairs correlated significantly and stepdown analysis of all 12 factors revealed 3 mRNAs (PLCL1, LRG1, FAM81B) related to PFS. Further analyses showed LRG1 and PLCL1 expression to be unrelated with luminal subtype and to associate with OS and with PFS, the latter independent from traditional predictive factors., Conclusion: We showed in two datasets of ER positive and luminal breast tumors that the expression of 3 miRs and 9 mRNAs associate with the PIK3CA status. Expression of LRG1 is independent of luminal (A or B) subtype, decreased after neo-adjuvant AI-treatment, and is proposed as potential biomarker for AI therapy outcome., (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)