Exercise for knee osteoarthritis pain: Association or causation?

Exercise is universally recommended as a primary strategy for the management of knee osteoarthritis (OA) pain. The recommendations are based on results from more than 100 randomized controlled trials (RCTs) that compare exercise to no-attention control groups. However, due to the inherent difficulties with adequate placebo control, participant blinding and the use of patient-reported outcomes, the existing RCT evidence is imperfect. To better understand the evidence used to support a causal relationship between exercise and knee OA pain relief, we examined the existing evidence through the Bradford Hill considerations for causation. The Bradford Hill considerations, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework for assessment of possible causal relationships. There are 9 considerations by which the evidence is reviewed: Strength of association, Consistency, Specificity, Temporality, Biological Gradient (Dose-Response), Plausibility, Coherence, Experiment, and Analogy. Viewing the evidence from these 9 viewpoints did neither bring forward indisputable evidence for nor against the causal relationship between exercise and improved knee OA pain. Rather, we conclude that the current evidence is not sufficient to support claims about (lack of) causality. With our review, we hope to advance the continued global conversation about how to improve the evidence-based management of patients with knee OA.

Diagnostic Accuracy of Candidate Magnetic Resonance Imaging Knee Osteoarthritis Definitions Versus Radiograph in an Acute Anterior Cruciate Ligament Injury Cohort.

OBJECTIVE: We tested the diagnostic accuracy of previously proposed magnetic resonance imaging (MRI) osteoarthritis (OA) definitions in a cohort after acute anterior cruciate ligament (ACL) injury. METHODS: We studied participants with posteroanterior and lateral knee radiographs and MRI 5 years after ACL injury, scored using the Anterior Cruciate Ligament Osteoarthritis Score. Radiographic OA (ROA) was defined using Osteoarthritis Research Society International scoring of osteophytes and joint space narrowing considering medial/lateral tibiofemoral and patellofemoral compartments. We tested three candidate MRI OA definitions that performed well in an older adult cohort. "Multicenter Osteoarthritis Study (MOST) simple" required cartilage score ≥2 (range 0-6) and osteophyte score ≥2 (0-7); "MOST optional" included cartilage score ≥2, osteophyte score ≥2, and either bone marrow lesions (BMLs) ≥1 (0-3) or synovitis ≥2 (0-3). The third, a Delphi panel definition, included nonzero scores for cartilage, osteophyte, BMLs, meniscus, and other structures. We calculated sensitivity and specificity with 95% confidence intervals (95% CIs) for each MRI definition versus ROA. RESULTS: We included 113 participants (mean age 26 years, 26% female). At 5 years, 29 participants (26%) had ROA. "MOST simple" had a sensitivity of 52% (95% CI 33%-71%), and specificity of 76% (95% CI 66%-85%). Sensitivity and specificities for "MOST optional" were 28% (95% CI 29%-67%) and 83% (95% CI 74%-91%), respectively. The Delphi panel definition had a sensitivity of 48% (95% CI 29%-67%) and specificity of 77% (95% CI 67%-86%). CONCLUSION: Simple MRI-based OA definitions requiring at least cartilage damage and an osteophyte have low sensitivity and high specificity in young persons after knee injury.

Genetic Influence on Osteoarthritis Versus Other Rheumatic Diseases.

OBJECTIVE: We aimed to compare the genetic contribution to osteoarthritis (OA) versus other rheumatic/musculoskeletal diseases (RMDs) in the same population and to explore the role for any shared genetics between OA and other RMDs. METHODS: In 59,970 Swedish twins aged 35 years or older, we estimated the heritability (the variance explained by genetic factors) of OA in peripheral joints, back and neck pain, shoulder pain (adhesive capsulitis, impingement syndrome, etc), rheumatoid arthritis, spondyloarthritis (SpA) and psoriatic arthritis, myalgia, and osteoporosis diagnosed in specialist and inpatient care. We also studied how much covariance between OA and each of the RMDs could be explained by genetics by studying phenotypic correlations in bivariate classical twin models. RESULTS: Any-site OA and hip OA (50% and 64%) were among the most heritable RMDs (as compared with 23% for fibromyalgia [lowest] and 63% for SpA [highest]). The highest phenotypic correlations were between OA (any joint site) and shoulder pain in the same individual (r = 0.33, 95% confidence interval 0.31-0.35), of which 70% (95% confidence interval 52-88) could be explained by shared genetics. The phenotypic correlation between OA and back/neck pain was r = 0.25, with 25% to 75% explained by genetics. Phenotypic correlations between OA and each of the other RMDs were lower (r ~ 0.1 to r ~ 0.2), with inconclusive sources of variation. CONCLUSION: OA has relatively large heritability as compared with other RMDs. The coexistence of OA and shoulder pain, as well as back pain, was common and could often be explained by genetic factors. Findings imply similar etiologies of OA and several pain conditions.

Proteomic profiling of human menisci from mild joint degeneration and end-stage osteoarthritis versus healthy controls.

Objective: To gain new insight into the molecular changes of the meniscus by comparing the proteome profiles of healthy controls with mild degeneration and end-stage osteoarthritis (OA). Method: We obtained tissue plugs from lateral and medial menisci of 37 individuals (central part of the posterior horn) classified as healthy (n â€‹= â€‹12), mild signs of joint damage (n â€‹= â€‹13) and end-stage OA (n â€‹= â€‹12). The protein profile was analysed by nano-liquid chromatography-mass spectrometry using data-independent acquisition and quantified by Spectronaut. Linear-mixed effects modelling was applied to extract the between-group comparisons. Results: A similar protein profile was observed for the mild group as compared to healthy controls while the most different group was end-stage OA mainly for the medial compartment. When a pattern of gradual change in protein levels from healthy to end-stage OA was required, a 42-proteins panel was identified, suggesting a potential role in OA development. The levels of QSOX1 were lower and G6PD higher in the mild group following the proposed protein abundance pattern. Qualitative protein changes suggest lower levels of CYTL1 as a potential biomarker of early joint degradation. Conclusion: For future targeted proteomic approaches, we propose a candidate panel of 42 proteins based on gradually altered meniscal posterior horn protein abundance patterns associated with joint degradation.

Use of non-surgical treatments on the journey to knee replacement in patients with knee osteoarthritis: a 10-year population-based case-control study.

AIM: To investigate temporal trends in primary care visits, physiotherapy visits, dispensed non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in knee osteoarthritis (OA) patients who have and have not undergone knee replacement. METHODS: We analysed 5665 OA patients from the Skåne Healthcare Register, Sweden, who underwent knee replacement between 2015 and 2019. Controls were OA patients without knee replacement, matched 1:1 by sex, age, time and healthcare level of initial OA diagnosis, and assigned a pseudo-index date corresponding to their case's knee replacement date. Annual prevalence and prevalence ratio of primary care and physiotherapy visits, dispensed NSAIDs and opioids (all for any cause) in the 10 years before knee replacement were estimated using Poisson regression. RESULTS: The annual prevalence of all-cause primary care visits, physiotherapy visits and opioid use was similar between cases and controls until 3 years before the index date when it started to increase among the cases. The year before the index date, the prevalence ratio (cases vs controls) for physiotherapy use was 1.8 (95% CI 1.7, 1.8), while for opioid use 1.6 (1.5, 1.7). NSAID use was consistently higher among cases, even 10 years before the index date when the prevalence ratio versus controls was 1.3 (1.2, 1.3), increasing to 1.8 (1.7, 1.9) in the year preceding the index date. CONCLUSIONS: Management of OA patients who have and have not undergone knee replacement appears largely similar except for higher use of NSAIDs in knee replacement cases. Symptomatic treatments start to increase a few years before the surgery in knee replacement cases.

Identifying Non-Steroidal Anti-Inflammatory Drug (NSAID) Users Among People with Osteoarthritis Through Administrative and Clinician-Reported Data - A Validation Study of 116,162 Patients.

Purpose: (i) To report the prevalence of participants to a first-line intervention for OA in Sweden using over-the-counter (OTC) and/or prescribed NSAIDs; (ii) To estimate the accuracy of dispensed prescriptions of NSAIDs recorded in a Swedish health-care register to capture the use of NSAID considering clinician-report as reference standard. Methods: Register-based study. We used data from OA individuals who participated in the Swedish first-line intervention recorded in the Swedish Osteoarthritis Register (SOAR). SOAR includes clinician-reported use of NSAIDs in the three months preceding the intervention. We used the Prescribed Drug Register to retrieve data on NSAID prescriptions dispensed in the same period. We estimated the prevalence of OTC users (individuals with clinicians-reported use of NSAID but no prescription dispensed), prescription users (individuals with clinicians-reported use of NSAID and a prescription dispensed) and non-users (neither of the previous). We calculated sensitivity, specificity, positive predictive value, and negative predictive value of dispensed prescriptions of NSAIDs vs clinician-report. Results: We included 116,162 individuals (mean age [Standard Deviation]: 66 [9.6] years, 79% women, 77% knee OA). Overall, 24.7% (95% Confidence Intervals [CI] 24.5%; 25.0%) used OTC NSAIDs only, 18.2% (18.0%; 18.5%) used prescribed NSAIDs, 6.6% (6-4%; 6.7%) reported not using NSAIDs while having an NSAID prescription dispensed. Of the 49,913 individuals with clinician-reported use of NSAIDs, 21,190 had a prescription dispensed (sensitivity: 42.5% [95% CI 42.0%, 42.9%]; positive predictive value: 73.5% [73.0%, 74.0%]). Of the 66,249 individuals reporting not using NSAIDs, 58,617 did not have a prescription dispensed (specificity: 88.5% [88.2%, 88.7%]; negative predictive value: 67.1% [66.8%, 67.4%]). Conclusion: Overall, 24.7% of participants in a first-line intervention for OA used OTC NSAIDs only while 18.2% used prescribed NSAIDs. Dispensed prescriptions of NSAIDs have high specificity but low sensitivity and can correctly identify about 70% of both the non-users and users in this population.

A human meniscus explant model for studying early events in osteoarthritis development by proteomics.

Degenerative meniscus lesions have been associated with both osteoarthritis etiology and its progression. We, therefore, sought to establish a human meniscus ex vivo model to study the meniscal response to cytokine treatment using a proteomics approach. Lateral menisci were obtained from five knee-healthy donors. The meniscal body was cut into vertical slices and further divided into an inner (avascular) and outer region. Explants were either left untreated (controls) or stimulated with cytokines. Medium changes were conducted every 3 days up to Day 21 and liquid chromatography-mass spectrometry was performed at all the time points for the identification and quantification of proteins. Mixed-effect linear regression models were used for statistical analysis to estimate the effect of treatments versus control on protein abundance. Treatment by IL1ß increased release of cytokines such as interleukins, chemokines, and matrix metalloproteinases but a limited catabolic effect in healthy human menisci explants. Further, we observed an increased release of matrix proteins (collagens, integrins, prolargin, tenascin) in response to oncostatin M (OSM) + tumor necrosis factor (TNF) and TNF+interleukin-6 (IL6) + sIL6R treatments, and analysis of semitryptic peptides provided additional evidence of increased catabolic effects in response to these treatments. The induced activation of catabolic processes may play a role in osteoarthritis development.

Identification and quantification of degradome components in human synovial fluid reveals an increased proteolytic activity in knee osteoarthritis patients vs controls.

Synovial fluid (SF) may contain cleavage products of proteolytic activities. Our aim was to characterize the degradome through analysis of proteolytic activity and differential abundance of these components in a peptidomic analysis of SF in knee osteoarthritis (OA) patients versus controls (n = 23). SF samples from end-stage knee osteoarthritis patients undergoing total knee replacement surgery and controls, that is, deceased donors without known knee disease were previously run using liquid chromatography mass spectrometry (LC-MS). This data was used to perform new database searches generating results for non-tryptic and semi-tryptic peptides for studies of degradomics in OA. We used linear mixed models to estimate differences in peptide-level expression between the two groups. Known proteolytic events (from the MEROPS peptidase database) were mapped to the dataset, allowing the identification of potential proteases and which substrates they cleave. We also developed a peptide-centric R tool, proteasy, which facilitates analyses that involve retrieval and mapping of proteolytic events. We identified 429 differentially abundant peptides. We found that the increased abundance of cleaved APOA1 peptides is likely a consequence of enzymatic degradation by metalloproteinases and chymase. We identified metalloproteinase, chymase, and cathepsins as the main proteolytic actors. The analysis indicated increased activity of these proteases irrespective of their abundance.

Prevalence of long COVID complaints in persons with and without COVID-19.

We studied the prevalence and patterns of typical long COVID complaints in ~ 2.3 million individuals aged 18-70 years with and without confirmed COVID-19 in a Nation-wide population-based prospective cohort study in Norway. Our main outcome measures were the period prevalence of single-occurring or different combinations of complaints based on medical records: (1) Pulmonary (dyspnea and/or cough), (2) Neurological (concentration problems, memory loss), and/or (3) General complaints (fatigue). In persons testing positive (n = 75 979), 64 (95% confidence interval: 54 to 73) and 122 (111 to 113) more persons per 10 000 persons had pulmonary complaints 5-6 months after the test compared to 10 000 persons testing negative (n = 1 167 582) or untested (n = 1 084 578), respectively. The corresponding difference in prevalence of general complaints (fatigue) was 181 (168 to 195) and 224 (211 to 238) per 10 000, and of neurological complaints 5 (2 to 8) and 9 (6-13) per 10 000. Overlap between complaints was rare. Long COVID complaints were only slightly more prevalent in persons with than without confirmed COVID-19. Still, long COVID may pose a substantial burden to healthcare systems in the future given the lasting high incidence of symptomatic COVID-19 in both vaccinated and unvaccinated individuals.

Sick leave after arthroscopic meniscus repair vs. arthroscopic partial meniscectomy.

Objective: To evaluate sick leave after meniscal repair vs arthroscopic partial meniscectomy (APM) and, for comparison, vs the general population. Method: Using Swedish register data we included all employed persons aged 19-49 years in the general population of Skåne region and identified those having had meniscus repair or APM in the period of 2005-2012. We retrieved data on sick leave during 1 year before until 2 years after surgery. We used logistic regression to estimate the risk differences of being on sick leave and negative binomial model to analyze differences in the number of days on sick leave. Results: We included 192 persons with meniscus repair, 2481 with APM, and 376 â€‹345 references without meniscus surgery. Of these, 55% of meniscus repair group, 43% of APM group had any sick leave in the 2-year period following the surgery, while 17% of the references were on sick leave in the corresponding period. The mean (SD) number of days of sick leave after meniscus repair was 55 (77) days and for APM 37 (86) days. Meniscus repair was associated with higher probability of sick leave compared to APM with an adjusted risk difference of 0.13 (95% CI 0.07-0.19). Conclusion: Persons undergoing meniscus repair have more frequent and 37% longer periods of sick leave in the short term than persons undergoing APM. However, sick leave in the long-term warrant further attention as successful repair may be associated with less knee osteoarthritis development than APM.

Does lower educational attainment increase the risk of osteoarthritis surgery? a Swedish twin study.

BACKGROUND: Previous studies have reported an inverse association between educational attainment and different osteoarthritis (OA) outcomes. However, none of the previous studies have accounted for potential confounding by early-life environment and genetics. Thus, we aimed to examine the association between educational attainment and knee and hip OA surgery using twin data. METHODS: From the Swedish Twin Registry (STR), we identified dizygotic (DZ) and monozygotic (MZ) twins. All twins in the STR aged 35 to 64 years were followed from January the 1st 1987 or the date they turned 35 years until OA surgery, relocation outside Sweden, death or the end of 2016 (18,784 DZ and 8,657 MZ complete twin pairs). Associations between educational attainment and knee and hip OA surgery were estimated in models matched on twin pairs, using Weibull within-between (WB) shared frailty model. RESULTS: For knee OA surgery, the analysis matched on MZ twins yielded a within-estimate hazard ratio (HR) per 3 years of education, of 1.06 (95% CI: 0.81, 1.32), suggesting no association between the outcome and the individual´s education. Rather, there seemed to be a so called familial effect of education, with a between-pair estimate of HR = 0.71 (95% CI: 0.41, 1.01). For hip OA surgery, the within- and between-pair estimates for MZ twins were 0.92 (95% CI: 0.69, 1.14) and 1.15 (95% CI: 0.87, 1.42), respectively. CONCLUSIONS: Our results suggest that the inverse associations between education and knee/hip OA surgery observed in cohort studies are potentially confounded by unobserved familial factors like genetics and/or early life exposures.

Evidence of ACL healing on MRI following ACL rupture treated with rehabilitation alone may be associated with better patient-reported outcomes: a secondary analysis from the KANON trial.

OBJECTIVES: Evaluate the natural course of anterior cruciate ligament (ACL) healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group. METHODS: Secondary analysis of 120 Knee Anterior Cruciate Ligament Nonsurgical vs Surgical Treatment (KANON) trial participants randomised to rehabilitation and optional delayed ACL reconstruction (ACLR) or early ACLR and rehabilitation. ACL continuity on MRI (Anterior Cruciate Ligament OsteoArthritis Score 0-2) was considered evidence of ACL healing. Outcomes included Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS patient acceptable symptomatic state (PASS) and treatment failure criteria. Linear mixed models were used to estimate adjusted mean differences (95% CIs) in patient-reported sport and recreational function (KOOS-Sport/Rec) and quality of life (KOOS-QOL) at 2 and 5 years, between participants with MRI evidence of ACL healing and those who had (1) no evidence of ACL healing, (2) delayed ACLR or (3) early ACLR. RESULTS: MRI evidence of ACL healing at 2-year follow-up was observed in 16 of 54 (30%, 95% CI 19 to 43%) participants randomised to optional delayed ACLR. Excluding participants who had delayed ACLR, 16 of 30 (53%, 36-70%) participants managed with rehabilitation-alone displayed MRI evidence of ACL healing. Two-year outcomes were better in the healed ACL group (n=16) compared with the non-healed (n=14) (mean difference (95% CI) KOOS-Sport/Rec: 25.1 (8.6-41.5); KOOS-QOL: 27.5 (13.2-41.8)), delayed ACLR (n=24) (KOOS-Sport/Rec: 24.9 (10.2-39.6); KOOS-QOL: 18.1 (5.4-30.8)) and early ACLR (n=62) (KOOS-Sport/Rec: 17.4 (4.1-30.7); KOOS-QOL: 11.4 (0.0-22.9)) groups. Five-year KOOS-QOL was better in the healed versus non-healed group (25.3 (9.4-41.2)). Of participants with MRI evidence of ACL healing, 63-94% met the PASS criteria for each KOOS subscale, compared with 29-61% in the non-healed or reconstructed groups. CONCLUSIONS: MRI appearance of ACL healing after ACL rupture occurred in one in three adults randomised to initial rehabilitation and one in two who did not cross-over to delayed ACLR and was associated with favourable outcomes. The potential for spontaneous healing of the ACL to facilitate better clinical outcomes may be greater than previously considered. TRIAL REGISTRATION NUMBER: ISRCTN84752559.

Road to Total Knee Replacement: Utilization of Knee Surgeries Up to Ten Years Before Total Knee Replacement in England and Sweden.

OBJECTIVE: To compare the prevalence and timing of knee surgery (including meniscal, ligamentous, synovial, and osteotomy) in the 10 years prior to primary total knee replacement (TKR) between England and Sweden. METHODS: This was a population-based, case-control study within England and southern Sweden using electronic health care databases. Patients underwent primary TKR between 2015 and 2019. Risk-set sampling showed that general population controls matched 1:1 by age, sex, and practice/municipality. The annual prevalence and prevalence ratio of having at least 1 recorded surgery in each of the 10 years preceding TKR was estimated using Poisson regressions. RESULTS: We included 6,308 and 47,010 TKR cases in Sweden and England, respectively. Meniscal surgeries were the most frequent procedure prior to TKR in both countries; prevalence was higher in England across all time points. The prevalence of meniscal surgery increased in both countries in the years approaching TKR, reaching 33.2 (95% confidence interval [95% CI] 31.6-34.9) per 1,000 persons in England, and 9.83 (95% CI 7.66-12.61) in Sweden. In England, we observed a decrease from 2014 to 2018 in the utilization of this procedure in the 4 years preceding a TKR. The prevalence of all analyzed surgeries was consistently lower in controls. CONCLUSION: There are comparable trends in the use of knee surgery in the years preceding TKR across England and Sweden. Of note, meniscal surgeries remain common, even within the year prior to TKR, highlighting that these patients may experience low-value care. Careful consideration of knee surgery in those with late-stage disease is required.

Does osteoarthritis modify the association between NSAID use and risk of comorbidities and adverse events?

Objectives: To investigate the role of osteoarthritis (OA) in the incidence of musculoskeletal, metabolic, cardiovascular, digestive, neuro-psychological, kidney and other comorbidities/adverse events after (i) incident non-steroidal anti-inflammatory drug (NSAID) initiation and (ii) NSAID discontinuation. Methods: We used register data for the population of Skåne, Sweden. For (i), we analysed the association between starting NSAIDs and the risk of incident outcome events in the 6 years following NSAID dispensation among people with prevalent OA vs no OA. For (ii) we studied the effect of discontinuing NSAIDs among people with and without OA up to 120 days. We used flexible parametric models to estimate adjusted differences in cumulative incidence with NSAIDs as time-varying exposure in the presence of non-proportional hazards. Results: For (i) we included between 243,832 and 409,749 persons. In the whole cohort, over the 6 years of follow-up, NSAID initiation was associated with a 3% (metabolic) to 16% (musculoskeletal) higher cumulative incidence of outcomes compared to non-users. The difference between those initiating NSAIDs vs non-users was similar in those with and without OA for most outcomes, but in those with OA the increase was lower for neuro-psychological (95%CI: 3.7%-4.6% vs 7.1%-7.9%) and musculoskeletal comorbidities (12%-14.5% vs 16.2%-17.2%).In (ii), we found no interaction between OA and NSAID discontinuation. NSAID discontinuation was associated with decreased risks for most of the outcomes, from -1.3% for musculoskeletal to -0.4% for cardiovascular comorbidities. Conclusions: OA appears to have little influence on the increased risk of comorbidities observed after NSAID initiation or decrease after discontinuation.

The association between preexisting conditions and osteoarthritis development in peripheral joints: A population based nested case-control study.

Aim: To study the risk of receiving a new (incident) osteoarthritis (OA) diagnosis in different joint sites based on conditions diagnosed in the 20 years prior the OA diagnosis. Methods: We used register data for the entire population of the Skåne region (Sweden) to perform a nested case-control study. The outcome was newly diagnosed (incident) OA in peripheral joints, i.e. knee (ICD-10 code M17), hip (M16) and other joints (M15, M18, M19), diagnosed in 2018 or 2019 in persons aged 45+ years with 20 years of register coverage. For each OA case, we sampled 1 control matched on age (1-year strata), sex and residential area in the year of index date using incidence density sampling. The exposures of interest comprised 50 comorbidities. We used adjusted conditional logistic regression for analysis. Results: Between January 1st, 2018 and December 31st, 2019, we identified 7 201, 2 895, and 7863 persons, respectively, with newly diagnosed knee, hip and other OA. Hypertension, back pain, gout, allergy, depression, anxiety and migraine were all associated with increased risk of knee OA diagnosis, while only gastroesophageal reflux disease and back pain were associated with newly diagnosed hip OA. Interestingly, many of the analysed conditions were associated with increased risk of OA diagnosis in other peripheral joints, including diagnosed generalised OA. Conclusions: The risk of being diagnosed with OA increases with the presence of multimorbidity earlier in life, but the associations seem to differ between weight-bearing and non-weight-bearing joints.

Associations of human femoral condyle cartilage structure and composition with viscoelastic and constituent-specific material properties at different stages of osteoarthritis.

The relationships between structure and function in human knee femoral cartilage are not well-known at different stages of osteoarthritis. Thus, our aim was to characterize the depth-dependent composition and structure (proteoglycan content, collagen network organization and collagen content) of normal and osteoarthritic human femoral condyle cartilage (n = 47) and relate them to their viscoelastic and constituent-specific mechanical properties that are obtained through dynamic sinusoidal testing and fibril-reinforced poroelastic material modeling of stress-relaxation testing, respectively. We characterized the proteoglycan content using digital densitometry, collagen network organization (orientation angle and anisotropy) using polarized light microscopy and collagen content using Fourier transform infrared spectroscopy. In the superficial cartilage (0-10 % of thickness), the collagen network disorganization and proteoglycan loss were associated with the smaller initial fibril network modulus - a parameter representing the pretension of the collagen network. Furthermore, the proteoglycan loss was associated with the greater strain-dependent fibril network modulus - a measure of nonlinear mechanical behavior. The proteoglycan loss was also associated with greater cartilage viscosity at a low loading frequency (0.005 Hz), while the collagen network disorganization was associated with greater cartilage viscosity at a high loading frequency (1 Hz). Our results suggest that proteoglycan loss and collagen network disorganization reduce the pretension of the collagen network while proteoglycan degradation also increases the nonlinear mechanical behavior of the collagen network. Further, the results also highlight that proteoglycan loss and collagen disorganization increase the viscosity of femoral cartilage, but their contribution to increased viscosity occurs in completely different loading frequencies.

Post-covid medical complaints following infection with SARS-CoV-2 Omicron vs Delta variants.

The SARS-CoV-2 Omicron (B.1.1.529) variant has been associated with less severe acute disease, however, concerns remain as to whether long-term complaints persist to a similar extent as for earlier variants. Studying 1 323 145 persons aged 18-70 years living in Norway with and without SARS-CoV-2 infection in a prospective cohort study, we found that individuals infected with Omicron had a similar risk of post-covid complaints (fatigue, cough, heart palpitations, shortness of breath and anxiety/depression) as individuals infected with Delta (B.1.617.2), from 14 to up to 126 days after testing positive, both in the acute (14 to 29 days), sub-acute (30 to 89 days) and chronic post-covid (≥90 days) phases. However, at ≥90 days after testing positive, individuals infected with Omicron had a lower risk of having any complaint (43 (95%CI = 14 to 72) fewer per 10,000), as well as a lower risk of musculoskeletal pain (23 (95%CI = 2-43) fewer per 10,000) than individuals infected with Delta. Our findings suggest that the acute and sub-acute burden of post-covid complaints on health services is similar for Omicron and Delta. The chronic burden may be lower for Omicron vs Delta when considering musculoskeletal pain, but not when considering other typical post-covid complaints.

A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects.

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.