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Background: Feline osteoarthritis (OA) leads to chronic pain and somatosensory sensitisation. In humans, sensory exposure can modulate chronic pain. Recently, electroencephalography (EEG) revealed a specific brain signature to human OA. However, EEG pain characterisation or its modulation does not exist in OA cats, and all EEG were conducted in sedated cats, using intradermal electrodes, which could alter sensory (pain) perception., New Method: Cats (n=11) affected by OA were assessed using ten gold-plated surface electrodes. Sensory stimuli were presented in random orders: response to mechanical temporal summation, grapefruit scent and mono-chromatic wavelengths (500 nm-blue, 525 nm-green and 627 nm-red light). The recorded EEG was processed to identify event-related potentials (ERP) and to perform spectral analysis (z-score)., Results: The procedure was well-tolerated. The ERPs were reported for both mechanical (F3, C3, Cz, P3, Pz) and olfactory stimuli (Cz, Pz). The main limitation was motion artifacts. Spectral analysis revealed a significant interaction between the power of EEG frequency bands and light wavelengths (p<0.001). All wavelengths considered, alpha band proportion was higher than that of delta and gamma bands (p<0.044), while the latter was lower than the beta band (p<0.016). Compared to green and red, exposure to blue light elicited distinct changes in EEG power over time (p<0.001)., Comparison With Existing Method: This is the first demonstration of EEG feasibility in conscious cats with surface electrodes recording brain activity while exposing them to sensory stimulations., Conclusion: The identification of ERPs and spectral patterns opens new avenues for investigating feline chronic pain and its potential modulation through sensory interventions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated M ontreal I nduction of R at A rthritis T esting (MI-RAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations., Methods: Functional biomechanical, somatosensory sensitization (peripheral-via tactile paw withdrawal threshold; central-via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA ( n = 12) and Naïve ( n = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56)., Results: The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group ( P < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from -55.61% ± 8.50% (D7) to -26.29% ± 8.50% (D35) ( P < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 ( P < 0.008); central sensitization was evident at D21 ( P = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate ( P < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b ( P = 0.029) at D56., Conclusion: The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Reviewer NA declared a shared committee group ( Non-Human Pain Special Interest Group of the IASP) with the author ET to the handling Editor., (Copyright © 2024 Otis, Cristofanilli, Frezier, Delsart, Martel-Pelletier, Pelletier, Beaudry, Lussier, Boyer and Troncy.)

Ancylostoma caninum is a widely prevalent parasitic nematode in dogs across the world. There has been a notable increase in reports of anthelmintic resistance in A. caninum within the United States of America in recent years, which has led us to investigate the potential of this scenario in Canada. The study objectives were to assess the prevalence of A. caninum in two different groups, including a colony of rescued dogs in Canada and three imported Greyhound dogs from USA, and to evaluate the efficacy of two benzimidazole (BZ) anthelmintics against A. caninum, complemented with a molecular genetic analysis adapted to low prevalence. Fecal samples were collected at pre- and post-treatment with fenbendazole for the native shelters-origin group, and a combination of anthelmintic formulations, including the pro-BZ febantel for the USA-origin group. The coprology analyses found several genera of internal parasites. Canine ancylostomiasis was the most prevalent parasitosis with 30.77% in the native group and 100% in the USA group, but with overall low average of A. caninum eggs per gram. Through the fecal egg count reduction test (FECRT), applying a cut-off at 90% as baseline of egg reduction for successful efficacy, BZ showed variable efficacy. Furthermore, molecular analysis confirmed the presence of A. caninum in both groups of dogs and found differences in the genetics linked to BZ resistance on the A. caninum β-tubulin isotype 1 gene. In the isolate from the native group, both codons 167 and 200 were homozygous without the presence of single nucleotide polymorphism (SNP). In contrast, the selected isolate from the USA group, showed a homozygous allele at position 200 and a heterozygous SNP at position 167. The latter was congruent with the low efficacy in FECRT and agrees with the recent findings of USA A. caninum isolate resistant phenotype to the BZ anthelmintics. The limitations of the study include an overall low eggs-per-gram in both canine groups, and the shortage of additional fecal samples from the USA group, restraining the molecular analysis only to one out of the three Greyhounds. This study provided some insights on the efficacy of BZs against A. caninum and revealed the presence of BZ resistant isolates in imported dogs in Quebec, Canada. All this information should be considered, for choosing the best strategy in the control of A. caninum using anthelmintic drugs., Competing Interests: Declaration of competing interest Authors declare no conflict of interest in the development of this research project., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Since 2000, advanced therapies (AT) have revolutionized the treatment of moderate to severe rheumatoid arthritis (RA). Randomized control trials as well as observational studies together with medication availability often determine second-line choices after the failure of first Tumor Necrosis Factor inhibitors (TNFi). This led to the observation that specific sequences provide better long-term effectiveness. We investigated which alternative medication offers the best long-term sustainability following the first TNFi failure in RA., Methods: Data were extracted from RHUMADATA from January2007. Patients were followed until treatment discontinuation, loss to follow-up, or November 25, 2022. Kaplan-Meier and Cox regression models were used to compare discontinuation between groups. Missing data were imputed, and propensity scores were computed to reduce potential attribution bias. Complete, unadjusted, and propensity score-adjusted imputed data analyses were produced., Results: 611 patients (320 treated with a TNFi and 291 treated with molecules having another mechanism of action (OMA)) were included. The mean age at diagnosis was 44.5 and 43.9 years, respectively. The median retention was 2.84 and 4.48 years for TNFi and OMAs groups. Using multivariable analysis, the discontinuation rate of the OMA group was significantly lower than TNFi (adjHR: 0.65; 95% CI: 0.44-0.94). This remained true for the PS-adjusted MI Cox models. In a stratified analysis, rituximab (adjHR: 0.39; 95% CI: 0.18-0.84) had better retention than TNFi after adjusting for patient characteristics., Conclusion: Switching to an OMA, especially rituximab, in patients with failure to a first TNFi appears to be the best strategy as a second line of therapy., (© 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.)

Background: Allergen testing is used to select antigens included in the desensitisation vaccine. Intradermal skin test (IDT) is the gold standard in cats, yet allergen-specific immunoglobulin (Ig)E serological testing (ASIS) is often used. Feline data are lacking regarding the agreement between IDT and ASIS results., Hypothesis/objectives: The first objective of the study was to establish a colony of cats with naturally acquired feline atopic syndrome (FAS). Further objectives were to define their hypersensitivity disorder to detail the allergen tests results, and to assess similarity between the allergen tests., Animals: Thirty-five cats with FAS and 10 control cats., Materials and Methods: Enrolled cats went through a five phase-screening and quarantine process before joining the colony. An elimination diet trial was performed on all FAS cats. ASIS and IDT were consecutively performed on all cats under sedation., Results: Reactions to 34 allergens were compiled for the 45 cats. Global sensitivity and specificity of ASIS were 34.7% and 78.9%, respectively. Only flea (ICC = 0.26, p = 0.040) and Dermatophagoides pteronyssinus (ICC = 0.48, p < 0.001) allergens had a significant intraclass correlation (weak agreement). Two FAS cats had negative tests including one cat with a concomitant food allergy., Conclusions and Clinical Relevance: This study depicts the first reported colony of cats with naturally acquired FAS. This is the first feline study to compare and show the poor agreement between allergen tests with a panel of 34 allergens. This colony also harbours two cats with FAS with negative allergen tests. These may represent the first described cats with an intrinsic form of atopic syndrome., (© 2024 ESVD and ACVD.)

Care-coordination platforms may optimize ST-elevation myocardial infarction (STEMI) treatment delays. This study aimed to assess the impact of Stenoa use on treatment delays in STEMI patients. We conducted a retrospective cohort study on local STEMI cases for the period between September 2020 and March 2023, comparing the times from first medical contact to device, before vs after the implementation of the Stenoa platform by the catheterization laboratory (cath-lab) and emergency department. A total of 180 patients were included. Significant reductions were found in times from first medical contact to electrocardiogram, from electrocardiogram to cath-lab activation, and from cath-lab activation to cath-lab arrival ( P  = 0.02, P  = 0.04, and P  = 0.02, respectively), after the platform was implemented. These findings suggest that use of Stenoa reduces STEMI door-to-balloon-time components., (© 2024 The Authors.)

Veterinarians face the lack of a rapid, reliable, inexpensive, and treatment-sensitive metrological instrument reflecting feline osteoarthritis (OA) pain. The Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians (MI-CAT(V)) has been refined in 4 sub-sections, and we proposed its concurrent validation. Cats naturally affected by OA ( n = 32) were randomly distributed into 4 groups of firocoxib analgesic (Gr. A: 0.40; B: 0.25; C: 0.15, and P: 0.00 mg/kg bodyweight). They were assessed during Baseline, Treatment, and Recovery periods using MI-CAT(V) and objective outcomes (effort path, stairs assay compliance, and actimetry). The MI-CAT(V) total score correlated to the effort path and actimetry (Rho S = -0.501 to -0.453; p < 0.001), also being sensitive to treatment responsiveness. The pooled treatment group improved its total, gait, and body posture scores during Treatment compared to the Baseline, Recovery, and placebo group ( p < 0.05). The MI-CAT(V) suggested a dose-(especially for Gr. B) and cluster-response. Cats in the moderate and severe MI-CAT(V) clusters responded to firocoxib with a remaining analgesic effect, while the mild cluster seemed less responsive and experienced a negative rebound effect. The MI-CAT(V) was validated for its OA pain severity discriminatory abilities and sensitivity to firocoxib treatment, providing a new perspective for individualized care.

Objective and Design: 15-Lipoxygenase-1 (15-LOX-1) catalyzes the biosynthesis of many anti-inflammatory and immunomodulatory lipid mediators and was reported to have protective properties in several inflammatory conditions, including osteoarthritis (OA). This study was designed to evaluate the expression of 15-LOX-1 in cartilage from normal donors and patients with OA, and to determine whether it is regulated by DNA methylation., Methods: Cartilage samples were obtained at autopsy from normal knee joints and from OA-affected joints at the time of total knee joint replacement surgery. The expression of 15-LOX-1 was evaluated using real-time polymerase chain reaction (PCR). The role of DNA methylation in 15-LOX-1 expression was assessed using the DNA methyltransferase inhibitor 5-Aza-2'-desoxycytidine (5-Aza-dC). The effect of CpG methylation on 15-LOX-1 promoter activity was evaluated using a CpG-free luciferase vector. The DNA methylation status of the 15-LOX-1 promoter was determined by pyrosequencing., Results: Expression of 15-LOX-1 was upregulated in OA compared to normal cartilage. Treatment with 5-Aza-dC increased 15-LOX-1 mRNA levels in chondrocytes, and in vitro methylation decreased 15-LOX-1 promoter activity. There was no difference in the methylation status of the 15-LOX-1 gene promoter between normal and OA cartilage., Conclusion: The expression level of 15-LOX-1 was elevated in OA cartilage, which may be part of a repair process. The upregulation of 15-LOX-1 in OA cartilage was not associated with the methylation status of its promoter, suggesting that other mechanisms are involved in its upregulation., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

D prostanoid receptor 1 (DP1), a prostaglandin D2 receptor, plays a central role in the modulation of inflammation and cartilage metabolism. We have previously shown that activation of DP1 signaling downregulated catabolic responses in cultured chondrocytes and was protective in mouse osteoarthritis (OA). However, the mechanisms underlying its transcriptional regulation in cartilage remained poorly understood. In the present study, we aimed to characterize the human DP1 promoter and the role of DNA methylation in DP1 expression in chondrocytes. In addition, we analyzed the expression level and methylation status of the DP1 gene promoter in normal and OA cartilage. Deletion and site-directed mutagenesis analyses identified a minimal promoter region (-250/-120) containing three binding sites for specificity protein 1 (Sp1). Binding of Sp1 to the DP1 promoter was confirmed using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays . Treatment with the Sp1 inhibitor mithramycin A reduced DP1 promoter activity and DP1 mRNA expression. Inhibition of DNA methylation by 5-Aza-2'-deoxycytidine upregulated DP1 expression, and in vitro methylation reduced the DP1 promoter activity. Neither the methylation status of the DP1 promoter nor the DP1 expression level were different between normal and OA cartilage. In conclusion, our results suggest that the transcription factor Sp1 and DNA methylation are important determinants of DP1 transcription regulation. They also suggest that the methylation status and expression level of DP1 are not altered in OA cartilage. These findings will improve our understanding of the regulatory mechanisms of DP1 transcription and may facilitate the development of intervention strategies involving DP1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Najar, Alsabri, Guedi, Merimi, Lavoie, Grabs, Pelletier, Martel-Pelletier, Benderdour and Fahmi.)

Validating animal pain models is crucial to enhancing translational research and response to pharmacological treatment. This study investigated the effects of a calibrated slight exercise protocol alone or combined with multimodal analgesia on sensory sensitivity, neuroproteomics, and joint structural components in the MI-RAT model. Joint instability was induced surgically on day (D) 0 in female rats ( N = 48) distributed into sedentary-placebo, exercise-placebo, sedentary-positive analgesic (PA), and exercise-PA groups. Daily analgesic treatment (D3-D56) included pregabalin and carprofen. Quantitative sensory testing was achieved temporally (D-1, D7, D21, D56), while cartilage alteration (modified Mankin's score (mMs)) and targeted spinal pain neuropeptide were quantified upon sacrifice. Compared with the sedentary-placebo (presenting allodynia from D7), the exercise-placebo group showed an increase in sensitivity threshold ( p < 0.04 on D7, D21, and D56). PA treatment was efficient on D56 ( p = 0.001) and presented a synergic anti-allodynic effect with exercise from D21 to D56 ( p < 0.0001). Histological assessment demonstrated a detrimental influence of exercise (mMs = 33.3%) compared with sedentary counterparts (mMs = 12.0%; p < 0.001), with more mature transformations. Spinal neuropeptide concentration was correlated with sensory sensitization and modulation sites (inflammation and endogenous inhibitory control) of the forced mobility effect. The surgical MI-RAT OA model coupled with calibrated slight exercise demonstrated face and predictive validity, an assurance of higher clinical translatability.

Background: For one of the most chronic medical conditions, osteoarthritis, uncertainties remain on the impact of injury chronology, the role of repeat injury on the incidence/progression of this disease and the need for knee arthroplasty., Objectives: To explore, in an older adult population, how nonsurgical knee injuries relate to osteoarthritis incidence/progression and the weight of independent risk factors for arthroplasty., Design: A cohort study design evaluates the long-term impact of injuries on knee osteoarthritis outcomes., Methods: Knees with no prior injury ( n  = 6358) and with at least one injury ( n  = 819) ⩽20 years before study inclusion were from the Osteoarthritis Initiative cohort. Sociodemographic, clinical and structural [X-ray, magnetic resonance imaging (MRI)] data at study inclusion and changes within 96 months were analysed. Statistics included a mixed model for repeated measurements, generalized estimating equations and multivariable Cox regression with covariates., Results: At inclusion, knees with prior injury demonstrated greater incidence and severity of osteoarthritis ( p  ⩽ 0.001). At 96 months, there was a greater increase in symptoms [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, p  = 0.002], joint space width (JSW, p  = 0.039) loss, medial cartilage volume loss (CVL, p  ⩽ 0.001) and bone marrow lesion size (BML, p  ⩽ 0.049). Knees with/without injury at inclusion but with new ones over time had a pronounced increase in symptoms (all WOMAC scores, p  ⩽ 0.001), JSW loss, lateral (without) and medial CVL, lateral (without) and medial meniscal extrusion and medial BML (without; all p  ⩽ 0.030). Levels of lateral and medial meniscal extrusion (without) and symptoms (with/without; all WOMAC scores, p  ⩽ 0.001) were all accentuated with a repeated new injury. Risk factors associated with the highest knee arthroplasty occurrence are new meniscal extrusion and new injury ( p  ⩽ 0.001)., Conclusion: This study highlights the importance of nonsurgical knee injury in older adults as an independent risk factor for knee osteoarthritis and arthroplasty. These data will be beneficial in clinical practice as they will help identify individuals at greater risk of significant disease progression and worst disease outcomes for a customized therapeutic approach., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: J.-P.P. and J.M.-P. are shareholders in ArthroLab Inc., (© The Author(s), 2023.)

Objectives: To determine the feasibility of a randomized controlled trial (RCT) examining outdoor walking on knee osteoarthritis (KOA) clinical outcomes and magnetic resonance imaging (MRI) structural changes., Method: This was a 24-week parallel two-arm pilot RCT in Tasmania, Australia. KOA participants were randomized to either a walking plus usual care group or a usual care control group. The walking group trained 3 days/week. The primary outcome was feasibility assessed by changes being required to the study design, recruitment, randomization, program adherence, safety, and retention. Exploratory outcomes were changes in symptoms, physical performance/activity, and MRI measures., Results: Forty participants (mean age 66 years (SD 1.4) and 60% female) were randomized to walking (n = 24) or usual care (n = 16). Simple randomization resulted in a difference in numbers randomized to the two groups. During the study, class sizes were reduced from 10 to 8 participants to improve supervision, and exclusion criteria were added to facilitate program adherence. In the walking group, total program adherence was 70.0% and retention 70.8% at 24 weeks. The walking group had a higher number of mild adverse events and experienced clinically important improvements in symptoms (e.g., visual analogue scale (VAS) knee pain change in the walking group: - 38.7 mm [95% CI - 47.1 to - 30.3] versus usual care group: 4.3 mm [- 4.9 to 13.4])., Conclusions: This study supports the feasibility of a full-scale RCT given acceptable adherence, retention, randomization, and safety, and recruitment challenges have been identified. Large symptomatic benefits support the clinical usefulness of a subsequent trial., Trial Registration Number: 12618001097235. Key Points • This pilot study is the first to investigate the effects of an outdoor walking program on knee osteoarthritis clinical outcomes and MRI joint structure, and it indicates that a full-scale RCT is feasible. • The outdoor walking program (plus usual care) resulted in large improvements in self-reported knee osteoarthritis symptoms compared to usual care alone. • The study identified recruitment challenges, and the manuscript explores these in more details and provides recommendations for future studies., (© 2023. The Author(s).)

The metrological properties of two performance-based outcome measures of feline osteoarthritis (OA), namely Effort Path (Path) and Stairs Assay Compliance (Stairs), were tested. Cats naturally affected by OA (n = 32) were randomly distributed into four groups (A: 0.40, B: 0.25, C: 0.15, or D: 0.00 mg firocoxib/kg bodyweight) and assessed during baseline, treatment, and recovery periods. For Path, from an elevated walking platform, the cats landed on a pressure-sensitive mattress and jumped up onto a second elevated platform. Analysis included velocity, time to completion, peak vertical force (PVF), and vertical impulse. For Stairs, the number of steps and time to completion were recorded for 16 steps up and down in a 4 min period. Reliability was moderate to very good for Path and poor to good for Stairs. Different normalization methods are described in the manuscript. The placebo group remained stable within-time in Path, whereas treated cats trotted faster on the ramp (p < 0.0001), improved their PVF (p < 0.018) and completed the task quicker (p = 0.003). The percentage of cats completing the Stairs finish line was higher under treatment (p < 0.036), with huge effect size, the placebo group results being stable within-time. Both are promising performance-based outcome measures to better diagnose and manage feline OA pain.

Background: Knee osteoarthritis is the most prevalent chronic musculoskeletal debilitating disease. Current treatments are only symptomatic, and to improve this, we need a robust prediction model to stratify patients at an early stage according to the risk of joint structure disease progression. Some genetic factors, including single nucleotide polymorphism (SNP) genes and mitochondrial (mt)DNA haplogroups/clusters, have been linked to this disease. For the first time, we aim to determine, by using machine learning, whether some SNP genes and mtDNA haplogroups/clusters alone or combined could predict early knee osteoarthritis structural progressors., Methods: Participants (901) were first classified for the probability of being structural progressors. Genotyping included SNP genes TP63, FTO, GNL3, DUS4L, GDF5, SUPT3H, MCF2L, and TGFA; mtDNA haplogroups H, J, T, Uk, and others; and clusters HV, TJ, KU, and C-others. They were considered for prediction with major risk factors of osteoarthritis, namely, age and body mass index (BMI). Seven supervised machine learning methodologies were evaluated. The support vector machine was used to generate gender-based models. The best input combination was assessed using sensitivity and synergy analyses. Validation was performed using tenfold cross-validation and an external cohort (TASOAC)., Results: From 277 models, two were defined. Both used age and BMI in addition for the first one of the SNP genes TP63, DUS4L, GDF5, and FTO with an accuracy of 85.0%; the second profits from the association of mtDNA haplogroups and SNP genes FTO and SUPT3H with 82.5% accuracy. The highest impact was associated with the haplogroup H, the presence of CT alleles for rs8044769 at FTO, and the absence of AA for rs10948172 at SUPT3H. Validation accuracy with the cross-validation (about 95%) and the external cohort (90.5%, 85.7%, respectively) was excellent for both models., Conclusions: This study introduces a novel source of decision support in precision medicine in which, for the first time, two models were developed consisting of (i) age, BMI, TP63, DUS4L, GDF5, and FTO and (ii) the optimum one as it has one less variable: age, BMI, mtDNA haplogroup, FTO, and SUPT3H. Such a framework is translational and would benefit patients at risk of structural progressive knee osteoarthritis., (© 2022. The Author(s).)

Knee osteoarthritis (OA) is one of the most common and disabling medical conditions. In the case of moderate to severe pain, a single intervention may not be sufficient to allay symptoms and improve quality of life. Examples include first-line, background therapy with symptomatic slow-acting drugs for OA (SYSADOAs) or non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) performed a review of a multimodal/multicomponent approach for knee OA therapy. This strategy is a particularly appropriate solution for the management of patients affected by knee OA, including those with pain and dysfunction reaching various thresholds at the different joints. The multimodal/multicomponent approach should be based, firstly, on different combinations of non-pharmacological and pharmacological interventions. Potential pharmacological combinations include SYSADOAs and NSAIDs, NSAIDs and weak opioids, and intra-articular treatments with SYSADOAs/NSAIDs. Based on the available evidence, most combined treatments provide benefit beyond single agents for the improvement of pain and other symptoms typical of knee OA, although further high-quality studies are required. In this work, we have therefore provided new, patient-centered perspectives for the management of knee OA, based on the concept that a multimodal, multicomponent, multidisciplinary approach, applied not only to non-pharmacological treatments but also to a combination of the currently available pharmacological options, will better meet the needs and expectations of patients with knee OA, who may present with various phenotypes and trajectories., (© 2022. The Author(s).)

Elite athletes are at greater risk of joint injuries linked to the subsequent risk of developing osteoarthritis (OA). Genetic factors such as mitochondrial (mt) DNA haplogroups have been associated with the incidence/progression of OA and athletic performance. This review highlights an area not yet addressed: is there a common pattern in the mtDNA haplogroups for OA occurrence in individuals and elite athletes of populations of the same descent? Haplotypes J and T confer a decreased risk of OA in Caucasian/European descent, while H and U increase this risk. Both J and T haplogroups are under-represented in Caucasian/European individuals and endurance athletes with OA, but power athletes showed a greater percentage of the J haplogroup. Caucasian/European endurance athletes had a higher percentage of haplogroup H, which is associated with increased athletic performance. In a Chinese population, haplogroup G appears to increase OA susceptibility and is over-represented in Japanese endurance athletes. In contrast, in Koreans, haplogroup B had a higher frequency of individuals with OA but was under-represented in the endurance athlete population. For Caucasian endurance athletes, it would be interesting to evaluate if those carrying haplotype H would be at an increased risk of accelerated OA, as well as the haplogroup G in Chinese and Japanese endurance athletes. The reverse might be studied for the Korean descent for haplogroup B. Knowledge of such genetic data could be used as a preliminary diagnosis to identify individuals at high risk of OA, adding prognostic information and assisting in personalising the early management of both populations., 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.)

Hand osteoarthritis is the most common joint condition and is associated with significant morbidity. It is of paramount importance that patients are thoroughly assessed and examined when complaining of hand stiffness, pain, deformity or disability and that the patient's concerns and expectations are addressed by the healthcare professional. In 2019 the American College of Rheumatology and Arthritis Foundation (ACR/AF) produced guidelines which included recommendations for the treatment of hand osteoarthritis. An ESCEO expert working group (including patients) was convened and composed this paper with the aim to assess whether these guidelines were appropriate for the treatment of hand osteoarthritis therapy in Europe and whether they met with the ESCEO patient-centered approach. Indeed, patients are the key stakeholders in healthcare and eliciting the patient's preference is vital in the context of an individual consultation but also for informing research and policy-making. The patients involved in this working group emphasised the often-neglected area of aesthetic changes in hand osteoarthritis, importance of developing pharmacological therapies which can alleviate pain and disability and the need of the freedom to choose which approach (out of pharmacological, surgical or non-pharmacological) they wished to pursue. Following robust appraisal, it was recommended that the ACR/AF guidelines were suitable for a European context (as described within the body of the manuscript) and it was emphasised that patient preferences are key to the success of individual consultations, future research and future policy-making., (© 2022. Crown.)

The relationship between knee moments and markers of knee osteoarthritis progression has not been examined in different knee osteoarthritis subtypes. The objective was to examine relationships between external knee moments during gait and tibiofemoral cartilage thickness in patients with nontraumatic and posttraumatic knee osteoarthritis. For this cross-sectional study, participants with knee osteoarthritis were classified into two groups: nontraumatic (n = 22; mean age 60 years) and posttraumatic (n = 19; mean age 56 years, history of anterior cruciate ligament rupture). Gait data were collected with a three-dimensional motion capture system sampled at 100 Hz and force plates sampled at 2000 Hz. External knee moments were calculated using inverse dynamics. Cartilage thickness was determined with magnetic resonance imaging (T1-weighted, 3D sagittal gradient-echo sequence). Linear regression analyses examined relationships between cartilage thickness with knee moments, group, and their interaction. A higher knee adduction moment impulse was negatively associated with medial to lateral cartilage thickness ratio (B = -1.97). This relationship differed between participants in the nontraumatic osteoarthritis group (r = -0.56) and posttraumatic osteoarthritis group (r = -0.30). A higher late stance knee extension moment was associated with greater medial femoral condyle cartilage thickness (B = -0.86) and medial to lateral cartilage thickness (B = -0.73). These relationships also differed between participants in the nontraumatic osteoarthritis group (r = -0.61 and r = -0.51, respectively) and posttraumatic osteoarthritis group (r = 0.10 and r = 0.25, respectively). Clinical Significance: The relationship between knee moments with tibiofemoral cartilage thickness differs between patients with nontraumatic and posttraumatic knee osteoarthritis. The potential influence of mechanical knee loading on articular cartilage may also differ between these subtypes., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Given that von Willebrand disease (VWD) is one of the most common bleeding disorders, the diagnosis or the exclusion is essential in the workup of individuals that have unexplained bleeding. For the clinical laboratory, the challenge is highlighted by the variable presentations of this disorder and the multiple assays that are available from different vendors. This review will give a brief overview of primary hemostasis with a detailed explanation of the biosynthesis, structure, and mechanics of von Willebrand factor (VWF). The final sections will focus on the distinguishing characteristics of the different types of VWD and the array of clinical laboratory tests currently available to assist in the diagnosis.

Purpose: Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague-Dawley rat model of surgically induced osteoarthritis (OA)., Methods: Female rats were ovariectomized and pre-emptive 17β-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17β-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC-MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A)., Results: Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (- 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17β-estradiol. Interestingly, the 17β-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018)., Conclusion: These results clearly indicate that 17β-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Vastus medialis intramuscular fat has been proposed to be a modifiable determinant of knee cartilage loss in patients with knee osteoarthritis. The objective was to determine whether vastus medialis intramuscular fat relates to osteoarthritis severity and quadriceps muscle strength in patients with non-traumatic and post-traumatic knee osteoarthritis., Methods: For this cross-sectional study, participants with knee osteoarthritis were classified into two groups: non-traumatic (n = 22; mean age = 60 years) and post-traumatic (n = 19; mean age = 56 years). Healthy adults were included (n = 22; mean age = 59 years). A 3-Tesla magnetic resonance imaging was used to measure vastus medialis cross-sectional area and intramuscular fat. Isometric knee extensor muscle torque was assessed using an isokinetic dynamometer and normalized to body mass (Nm/kg). Knee osteoarthritis severity was assessed using standing antero-posterior radiographs (Kellgren-Lawrence scores). Regression analyses examined relationships between 1) vastus medialis intramuscular fat with knee osteoarthritis severity and osteoarthritis group, after accounting for sex and body mass index, and 2) knee extensor muscle torque with vastus medialis intramuscular fat, after accounting for sex and vastus medialis cross-sectional area., Findings: Vastus medialis intramuscular fat was positively associated with body mass index (B = 0.321, P < 0.001), but not with osteoarthritis severity or group (P > 0.05). Higher vastus medialis intramuscular fat was associated with reduced knee extensor muscle torque (B = -0.040, P = 0.018)., Interpretation: Greater vastus medialis intramuscular fat was associated with lower quadriceps muscle strength in patients with knee OA. It is unclear whether this is due to the accumulation of vastus medialis intramuscular fat or other potential factors, such as diet and physical inactivity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The hallmark of osteoarthritis (OA), the most prevalent musculoskeletal disease, is the loss of cartilage. By using machine learning (ML), we aimed to assess if baseline knee bone curvature (BC) could predict cartilage volume loss (CVL) at one year, and to develop a gender-based model. BC and cartilage volume were assessed on 1246 participants using magnetic resonance imaging. Variables included age, body mass index, and baseline values of eight BC regions. The outcome consisted of CVL at one year in 12 regions. Five ML methods were evaluated. Validation demonstrated very good accuracy for both genders (R ≥ 0.78), except the medial tibial plateau for the woman. In conclusion, we demonstrated, for the first time, that knee CVL at one year could be predicted using five baseline BC region values. This would benefit patients at risk of structural progressive knee OA.

Background: Osteoarthritis (OA) is a slowly developing and debilitating disease, and there are no validated specific biomarkers for its early detection. To improve therapeutic approaches, identification of specific molecules/biomarkers enabling early determination of this disease is needed. This study aimed at identifying, with the use of proteomics/mass spectrometry, novel OA-specific serum biomarkers. As obesity is a major risk factor for OA, we discriminated obesity-regulated proteins to target only OA-specific proteins as biomarkers., Methods: Serum from the Osteoarthritis Initiative cohort was used and divided into 3 groups: controls (n=8), OA-obese (n=10) and OA-non-obese (n=10). Proteins were identified and quantified from the liquid chromatography-tandem mass spectrometry analyses using MaxQuant software. Statistical analysis used the Limma test followed by the Benjamini-Hochberg method. To compare the proteomic profiles, the multivariate unsupervised principal component analysis (PCA) followed by the pairwise comparison was used. To select the most predictive/discriminative features, the supervised linear classification model sparse partial least squares regression discriminant analysis (sPLS-DA) was employed. Validation of three differential proteins was performed with protein-specific assays using plasma from a cohort derived from the Newfoundland Osteoarthritis., Results: In total, 509 proteins were identified, and 279 proteins were quantified. PCA-pairwise differential comparisons between the 3 groups revealed that 8 proteins were differentially regulated between the OA-obese and/or OA-non-obese with controls. Further experiments using the sPLS-DA revealed two components discriminating OA from controls (component 1, 9 proteins), and OA-obese from OA-non-obese (component 2, 23 proteins). Proteins from component 2 were considered related to obesity. In component 1, compared to controls, 7 proteins were significantly upregulated by both OA groups and 2 by the OA-obese. Among upregulated proteins from both OA groups, some of them alone would not be a suitable choice as specific OA biomarkers due to their rather non-specific role or their strong link to other pathological conditions. Altogether, data revealed that the protein CRTAC1 appears to be a strong OA biomarker candidate. Other potential new biomarker candidates are the proteins FBN1, VDBP, and possibly SERPINF1. Validation experiments revealed statistical differences between controls and OA for FBN1 (p=0.044) and VDPB (p=0.022), and a trend for SERPINF1 (p=0.064)., Conclusion: Our study suggests that 4 proteins, CRTAC1, FBN1, VDBP, and possibly SERPINF1, warrant further investigation as potential new biomarker candidates for the whole OA population., (© 2022. The Author(s).)

Objectives: The aim of this study was to investigate changes over time in osteoarthritis risk factors most closely associated with the occurrence of total knee arthroplasty (TKA). We hypothesize that the robustness of a longitudinal case-control study will provide new information on the association between changes in various clinical and structural parameters in different time frames before TKA., Methods: Cases (195; TKA after cohort entry) and controls (468) matched for age, gender, income, WOMAC pain, Kellgren-Lawrence grade and follow-up duration were from the Osteoarthritis Initiative cohort. Associations between changes in sociodemographic, clinical, imaging and osteoarthritis therapies with the occurrence of TKA were performed using conditional logistic regression analyses., Results: Worsening of WOMAC scores (cOR 1.02-1.20, p  ⩽ 0.012), KOOS (1.02-1.04, p  ⩽ 0.014), knee injuries sustained in the previous 30-40 years (women 2.70, p  = 0.034) and valgus alignment (1.10, p  = 0.052) were associated with the occurrence of TKA. Also associated with TKA was cartilage volume loss in the lateral (overall 1.76, p  = 0.025; women 1.93, p  = 0.047) and medial compartments (⩾10%, overall 1.54, p  = 0.027; men 2.34, p  = 0.008), occurrence of medial meniscal extrusion (overall 1.77, p  = 0.046; men 2.86, p  = 0.028), and increase in bone marrow lesions (BMLs) for women (1.09, p  = 0.048). The association of risk factors with TKA was reinforced when both an increase in WOMAC pain and cartilage volume loss (1.85, p  = 0.001) were combined. Pain medication usage, mainly narcotics and intra-articular steroid injections (IASI), was also associated with TKA, with no impact on changes in cartilage loss or structure., Conclusion: This study provides new information about gender differences in risk factors associated with the occurrence of TKA. Worsening of valgus alignment, cartilage volume loss in the lateral compartment, BMLs and older injuries are important risk factors in women, while medial compartment cartilage loss and meniscal extrusion are in men. The use of pain medication and IASI although associated was found not causal with TKA., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J-P.P. and J.M-P. are shareholders in ArthroLab Inc. J-P.R. and M.D. are consultants for ArthroLab Inc. P.P. is an employee of ArthroLab Inc. None of the authors are part of the Osteoarthritis Initiative (OAI) investigative team., (© The Author(s), 2022.)

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m 2 , and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10 -4 ), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Introduction: Knee osteoarthritis (OA) is a disease affecting all the neighboring articular tissues including the infrapatellar fat pad (IPFP). Although not yet as widely studied as other tissues in the knee, the IPFP has been recognized to have important metabolic activities and is a key player in OA., Methods: In this commentary, we will briefly describe the different methodologies employed for the MRI morphological measurement of this tissue and depict the findings in regard to OA., Results: The morphology of this tissue, monitored mainly with the use of magnetic resonance imaging (MRI), demonstrates changes during OA. However, studies of the IPFP morphological alterations and their association with the OA process have shown conflicting results, including a detrimental or beneficial role or no role at all. Although many reasons could explain such mixed findings, one might be the different methodologies used for the MRI measurement of area, volume, or signal intensity. In addition, several techniques are also employed for measuring the volume and signal intensity. An additional level of complexity is related to the presence within the IPFP of two different types of signal intensities, hyper-intensity, and hypo-intensity., Conclusion: A consensus of a procedure to measure the morphology of the IPFP is urgently needed to fully appreciate the role of this tissue in the pathology of OA, as well as its uses for clinical decision-making., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)