Search

To determine the incidence and worsening of lumbar spine structure and low back pain (LBP) and whether they are predicted by demographic characteristics or clinical characteristics or appendicular joint osteoarthritis (OA).Paired baseline (2003-2004) and follow-up (2006-2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for osteophytes (OST), disc space narrowing (DSN), spondylolisthesis, and presence of facet joint OA (FOA). Spine OA was defined as at least mild OST and mild DSN at the same level for any level of the lumbar spine. LBP, comorbidities, and back injury were self-reported. Weibull models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of spine phenotypes accounting for potential predictors including demographic characteristics, clinical characteristics, comorbidities, obesity, and appendicular OA.Obesity was a consistent and strong predictor of incidence of DSN (HR 1.80 [95% CI 1.09-2.98]), spine OA (HR 1.56 [95% CI 1.01-2.41]), FOA (HR 4.99 [95% CI 1.46-17.10]), spondylolisthesis (HR 1.87 [95% CI 1.02-3.43]), and LBP (HR 1.75 [95% CI 1.19-2.56]), and worsening of DSN (HR 1.51 [95% CI 1.09-2.09]) and LBP (HR 1.51 [95% CI 1.12-2.06]). Knee OA was a predictor of incident FOA (HR 4.18 [95% CI 1.44-12.2]). Spine OA (HR 1.80 [95% CI 1.24-2.63]) and OST (HR 1.85 [95% CI 1.02-3.36]) were predictors of incidence of LBP. Hip OA (HR 1.39 [95% CI 1.04-1.85]) and OST (HR 1.58 [95% CI 1.00-2.49]) were predictors of LBP worsening.Among the multiple predictors of spine phenotypes, obesity was a common predictor for both incidence and worsening of lumbar spine degeneration and LBP.

To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression.The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models).Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832.The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

Background Several guidelines have suggested alternative glycemic markers for hemoglobin A1c among older adults with limited life expectancy or multiple coexisting chronic illnesses. We evaluated associations between fructosamine, albumin-corrected fructosamine (AlbF), fasting plasma glucose (FPG), and mortality in the diabetic and nondiabetic subpopulations, and compared which marker better predicts mortality among participants aged 80 and older. Methods Included were 2 238 subjects from the Healthy Ageing and Biomarkers Cohort Study (2012–2018) and 207 participants had diabetes at baseline. Multivariable Cox proportional hazards regression models investigated the associations of fructosamine, AlbF, FPG, and all-cause, cardiovascular disease (CVD), and non-CVD mortality in the diabetic and nondiabetic subpopulations. Restricted cubic splines explored potential nonlinear relations. C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) evaluated the additive value of different glycemic markers to predict mortality. Results Overall, 1 191 deaths were documented during 6 793 person-years of follow-up. In the linear model, per unit increases of fructosamine, AlbF, and FPG were associated with a higher risk of mortality in nondiabetic participants, with hazard ratios of 1.02 (1.00, 1.05), 1.27 (1.14, 1.42), and 1.04 (0.98, 1.11) for all-cause mortality, and 1.04 (1.00, 1.07), 1.38 (1.19, 1.59), and 1.10 (1.01, 1.19) for non-CVD mortality, respectively. Comparisons indicated that AlbF better predicts all-cause and non-CVD mortality in nondiabetic participants with significant improvement in IDI and NRI. Conclusions Higher concentrations of fructosamine, AlbF, and FPG were associated with a higher risk of all-cause or non-CVD mortality among the very elderly where AlbF may constitute an alternative prospective glycemic predictor of mortality.

Objective To examine the association of incident type 2 diabetes (T2D) risk with sleep factors, genetic risk, and their combination effects. Design Large prospective population-based cohort study. Methods This population-based prospective cohort study included 360 403 (mean (s.d.) age: 56.6 (8.0) years) participants without T2D at baseline from the UK Biobank. Genetic risk was categorised as high (highest quintile), intermediate (quintiles: 2–4), and low (lowest quintile) based on a polygenic risk score for T2D. Sleep scores, including long or short sleep duration, insomnia, snoring, late chronotype, and excessive daytime sleepiness, were categorized as an unfavourable, intermediate, or favourable sleep and circadian pattern. Results During a median follow-up of 9.0 years, 13 120 incident T2D cases were recorded. Among the participants with an unfavourable sleep and circadian pattern, 6.96% (95% CI: 6.68–7.24%) developed T2D vs 2.37% (95% CI: 2.28–2.46%) of participants with a favourable sleep and circadian pattern (adjusted hazard ratio (HR): 1.53, 95% CI: 1.45–1.62). Of participants with a high genetic risk, 5.53% (95% CI: 5.36–5.69%) developed T2D vs 2.01% (95% CI: 1.91–2.11%) of participants with a low genetic risk (adjusted HR: 2.89, 95% CI: 2.72–3.07). The association with sleep and circadian patterns was independent of genetic risk strata. Participants in the lowest quintile with an unfavourable sleep and circadian pattern were 3.97-fold more likely to develop T2D than those in the lowest quintile with a favourable sleep and circadian pattern. Conclusions Sleep and circadian patterns and genetic risk were independently associated with incident T2D. These results indicate the benefits of adhering to a healthy sleep and circadian pattern in entire populations, independent of genetic risk.

Purpose of the review Osteoarthritis (OA) is a painful disease for which drug development has proven difficult. One major reason for this is the heterogeneity of the disease and the current lack of operationalized means to distinguish various disease endotypes (molecular subtypes). Biomarkers measured in blood or urine, reflecting joint tissue turnover, have been developed and tested during the last decades. In this narrative review, we provide highlights on biomarkers derived from the two most studied and abundant cartilage proteins - type II collagen and aggrecan. Recent findings Multiple biomarkers assessing type II collagen degradation and formation, and aggrecan turnover have been developed. Several markers, such as uCTX-II, have been validated for their association with disease severity and prognosis, as well as pharmacodynamically used to describe the mode of action and efficacy of drugs in development. There is a great need for biomarkers for subdividing patients (i.e., endotyping) and recent scientific advances have not yet come closer to achieving this goal. Summary There is strong support for using biomarkers for understanding OA, reflecting degradation and formation of the joint tissues, focused on type II collagen and aggrecan. There is still a lack of in vitro diagnostics, in all contexts of use.

Objective To compare C-reactive protein (CRP) and matrix metalloproteinase-generated neoepitope of CRP (CRPM) as biomarkers of inflammation and radiographic severity in patients with knee osteoarthritis. Methods Participants with symptomatic osteoarthritis (n=25) of at least one knee underwent knee radiographic imaging and radionuclide etarfolatide imaging to quantify inflammation of the knees and other appendicular joints. For purposes of statistical analysis, semi-quantitative etarfolatide and radiographic imaging scores were summed across the knees; etarfolatide scores were also summed across all joints to provide a multi-joint synovitis measure. Multiple inflammation and collagen-related biomarkers were measured by ELISA including CRP, CRPM, MMP-generated neoepitopes of type I collagen and type III collagen in serum (n=25), and CD163 in serum (n=25) and synovial fluid (n=18). Results BMI was associated with CRP (p=0.001), but not CRPM (p=0.753). Adjusting for BMI, CRP was associated with radiographic knee osteophyte score (p=0.002), while CRPM was associated with synovitis of the knee (p=0.017), synovitis of multiple joints (p=0.008), and macrophage marker CD163 in serum (p=0.009) and synovial fluid (p=0.03). CRP correlated with MMP-generated neoepitope of type I collagen in serum (p=0.045), and CRPM correlated with MMP-generated neoepitope of type III collagen in serum (p Conclusions To our knowledge, this is the first time that CRPM has been shown to be associated with knee and multi-joint inflammation based on objective imaging (etarfolatide) and biomarker (CD163) measures. These results demonstrate the capability of biomarker measurements to reflect complex biological processes and for neoepitope markers to more distinctly reflect acute processes than their precursor proteins. CRPM is a promising biomarker of local and systemic inflammation in knee OA that is associated with cartilage degradation and is independent of BMI. CRPM is a potential molecular biomarker alternative to etarfolatide imaging for quantitative assessment of joint inflammation.

Background Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. Materials and methods The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. Results In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4–8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011). Conclusion Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. Level of evidence Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.

Posttraumatic arthritis (PTA) occurs commonly after articular fracture and may arise, in part, from joint surface incongruity after injury. MRL/MpJ (MRL) "super-healer" mice are protected from PTA compared to C57BL/6 (B6) mice following articular fracture. However, the relationship between the initial displacement of the articular surface, biologic response, and susceptibility to PTA after fracture remains unclear. The objective of this study was to assess whether joint incongruity after articular fracture, as measured by in vivo micro-computed tomography (microCT), could predict pathomechanisms of PTA in mice. B6 and MRL mice (n = 12/strain) received a closed articular fracture (fx) of the left tibial plateau. Articular incongruity was quantified as bone surface deviations (BSD) for each in vivo microCT scan obtained from pre-fx to 8 weeks post-fx, followed by histologic assessment of arthritis. Serum concentrations of bone formation (PINP) and bone resorption (CTX-I) biomarkers were quantified longitudinally. Both strains showed increases in surface incongruity over time, as measured by increases in BSD. In B6 mice, acute surface incongruity was significantly correlated to the severity of PTA (R 2 = 0.988; p = .0006), but not in MRL mice (R 2 = 0.224; p = .220). PINP concentrations significantly decreased immediately post-fx in B6 mice (p = .023) but not in MRL mice, indicating higher bone synthesis in MRL mice. MRL/MpJ mice demonstrate a unique biologic response to articular fracture such that the observed articular bone surface displacement does not correlate with the severity of subsequent PTA. Clinical Relevance: Identifying therapies to enhance acute biologic repair following articular fracture may mitigate the risk of articular surface displacement for PTA.

The inflammatory response to joint injury, specifically intra-articular fracture, has been implicated in post-traumatic arthritis development. However, the role of T cells in regulating the development of post-traumatic arthritis is unclear. We hypothesized that the absence of T cells would lead to less severe post-traumatic arthritis following intra-articular fracture. T cell-deficient, athymic Nude and wild-type C57BL/6NJ mice were assessed at 8 weeks following closed articular fracture. Joints were assessed using histologic scores of arthritis, synovitis, and bone morphology via microCT. Cells were profiled in whole blood via flow cytometry, and plasma and synovial fluid derived cytokines quantified by multiplex analysis. Compared to C57BL/6NJ mice, Nude mice had significantly greater histologic evidence of arthritis and synovitis. Whole blood immune cell profiling revealed a lower percentage of dendritic cells but higher natural killer (NK) cells in Nude mice. Concurrently, Nude mice had significantly higher levels of NK cells in synovial tissue. Concentrations of plasma IL-1β and TNF-α, and synovial fluid IL-12, IL-17, and IL-6 in both knees were greater in Nude mice. Outcomes of this study suggest that T cells may play a protective regulatory role against the development of post-traumatic arthritis. Statement of Clinical Significance: Lack of functional T cells exacerbated the development of post-traumatic arthritis following intra-articular fracture suggesting that critical regulators of the immune responses, contained within the T cell population, are required for protection. Future research identifying the specific T cell subsets responsible for modulating disease immunopathogenesis will lead to new therapeutic targets to mitigate post-traumatic arthritis. This article is protected by copyright. All rights reserved.

Summary Objective To evaluate whether joint hypermobility modifies the association between knee joint injury and knee osteoarthritis (OA) among adults. Methods Data were from three studies: Genetics of Generalized Osteoarthritis (GOGO; N = 2341), Genetics of Osteoarthritis (GO; N = 1872), and the population-based Johnston County Osteoarthritis Project (JoCoOA; N = 1937). Knee injury was defined as a self-report of prior fracture or severe injury to either knee. OA was defined using three variables: knee pain (pain, aching, or stiffness of the knee on most days), radiographic OA (rOA; Kellgren-Lawrence grade 2–4), and symptomatic OA (sxOA; knee rOA with knee pain). Joint hypermobility was defined as Beighton score ≥4. For each study, separate logistic regression models, stratified by joint hypermobility, were used to estimate the association of knee injury with knee pain, rOA, and sxOA, adjusting for age, sex, body mass index, and race (JoCoOA only); statistical interactions between injury and hypermobility were assessed (p-value Results In all three studies, knee injury was associated with OA variables of knee pain, rOA, and sxOA (adjusted odds ratios [aOR] range 1.83–3.75). The association of knee injury with rOA and sxOA was magnified among individuals with vs. without joint hypermobility in GOGO: rOA aOR 11.0, 95% confidence interval [CI] 4.0–30.1 vs. 2.7, 95% CI 2.0–3.6, p = 0.009; sxOA aOR 9.2, 95% CI 3.5–24.3 vs. 3.3, 95% CI 2.4–4.4, p = 0.032. Interactions were not statistically significant in GO or JoCoOA. Conclusions In a general adult population, the presence of joint hypermobility may not modify the strong association between knee injury and OA.

Objective To evaluate the role of immune cells and their effector cytokines in the pathogenesis and progression of knee osteoarthritis (OA) in matched OA synovial fluid (SF) and synovial tissue samples. Methods Cells from matched samples of synovial tissue and SF acquired from individuals undergoing total knee replacement for OA (n = 39) were characterized for immune cell-associated surface markers and intracellular cytokine expression using polychromatic flow cytometry. Additional individuals with radiographic knee OA (Kellgren/Lawrence severity grades ≥1) who had available etarfolatide (inflammatory cell) imaging (n = 26) or baseline and 3-year data on progression of radiographic knee OA (n = 85) were also assessed. SF cytokine concentrations in all cohorts were evaluated for associations with synovial tissue and SF cell phenotypes and severity of radiographic knee OA. Results Macrophages (predominant in the synovial tissue, 53% of total cells) and neutrophils (predominant in the SF, 26% of total cells) were the major immune cell populations identified in the OA knee joints, exhibiting expression of or association with transforming growth factor β1 (TGFβ1) and elastase, respectively, in the SF. Expression levels of TGFβ1 and elastase were significantly associated with severity of radiographic knee OA. Baseline SF concentrations of TGFβ1 and elastase along with radiographic knee OA severity scores were predictive of knee OA progression, with areas under the receiver operating characteristic curves of 0.810 (for TGFβ1), 0.806 (for elastase), and 0.846 (for both TGFβ1 and elastase combined), with greater stability of prediction when both markers were utilized. Conclusion Our findings demonstrate the hitherto underappreciated role of neutrophils in the sterile inflammatory process and progression of OA. Two soluble mediators, SF elastase and TGFβ1, are strong predictors of knee OA progression, reflecting a synergistic role of neutrophil and macrophage populations in the pathogenesis and worsening of OA that could potentially be utilized to identify patients who may have a greater risk of more rapid disease progression.

The ultimate hope of researchers and patients is a pathway to development of treatments for osteoarthritis to modify the disease process in addition to the symptoms. However, development of disease modifying drugs requires objective endpoints such as measures of joint structure, joint tissue homeostasis and/or joint survival-measures such as provided by imaging biomarkers, molecular biomarkers and joint replacement frequency, respectively. Although biomarkers supporting investigational drug use and drug approval include surrogate endpoints that may not necessarily reflect or directly correlate with the clinical outcome of interest, a formal biomarker qualification process currently exists that is a rigorous three stage process that yields biomarker approvals (or denials) for specific contexts of use. From a cost perspective, biochemical biomarkers are the 'ones to beat'; however, even well-validated biomarkers may not cross the translation gaps for eventual use in healthcare unless they offer an advantage in terms of cost per quality adjusted life year. This review summarizes the case FOR and AGAINST biomarkers in drug development and highlights the current data for a subset of biomarkers in the osteoarthritis research field informing on cartilage homeostasis, joint inflammation and altered subchondral bone remodeling.

ObjectivesTo evaluate the associations of regular glucosamine use with all-cause and cause-specific mortality in a large prospective cohort.MethodsThis population-based prospective cohort study included 495 077 women and men (mean (SD) age, 56.6 (8.1) years) from the UK Biobank study. Participants were recruited from 2006 to 2010 and were followed up through 2018. We evaluated all-cause mortality and mortality due to cardiovascular disease (CVD), cancer, respiratory and digestive disease. HRs and 95% CIs for all-cause and cause-specific mortality were calculated using Cox proportional hazards models with adjustment for potential confounding variables.ResultsAt baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years (IQR 8.3–9.7 years), 19 882 all-cause deaths were recorded, including 3802 CVD deaths, 8090 cancer deaths, 3380 respiratory disease deaths and 1061 digestive disease deaths. In multivariable adjusted analyses, the HRs associated with glucosamine use were 0.85 (95% CI 0.82 to 0.89) for all-cause mortality, 0.82 (95% CI 0.74 to 0.90) for CVD mortality, 0.94 (95% CI 0.88 to 0.99) for cancer mortality, 0.73 (95% CI 0.66 to 0.81) for respiratory mortality and 0.74 (95% CI 0.62 to 0.90) for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers (p for interaction=0.00080).ConclusionsRegular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases.

Background Cognitive impairment is a major contributor to mortality among the elderly. However, the relationship between cognitive impairment evaluated by educational levels and mortality and the trend between cognitive impairment and mortality with time are unclear. We aim to evaluate the differences in associations of cognitive impairment, taking the stratification by educational levels into account, with all-cause mortality and further explore the relationship of cognitive impairment with mortality in different age and sex groups in two cohorts ascertained 6 years apart in China. Methods A total of 13,906 and 13,873 Chinese elderly aged 65 years and older were included in the 2002–2008 and 2008–2014 cohorts from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Mortality data was ascertained from interviews with family members or relatives of participants. Cognitive function, evaluated by the Mini-Mental State Examination (MMSE), were defined by different cut-offs taking educational background into account. Cox models were used to explore the relationship of cognitive impairment with mortality. Results For the 2002–2008 and 2008–2014 cohorts, 55,277 and 53,267 person-years were followed up, and the mean (SD) age were 86.5 (11.6) and 87.2 (11.3) years, respectively. Compared to normal cognition, cognitive impairment was independently associated with higher mortality risk after controlling for potential confounders, with hazard ratios (HRs) of 1.32 (95% confidence interval [CI], 1.25–1.39) in 2002–2008 cohort and 1.26 (95% CI, 1.19–1.32) in 2008–2014 cohort, stratified by educational levels. The trend of cognitive impairment with all-cause mortality risk decreased from 2002 to 2008 to 2008–2014 cohort, while no significant interaction of cognitive impairment with cohort for all-cause mortality was observed. The associations of cognitive impairment and mortality were decreased with age in the two cohorts. Conclusions Cognitive impairment evaluated by different cut-offs were associated with increased risk of mortality, especially among those aged 65–79 years in the two cohorts; this advocates that periodic screening for cognitive impairment among the elderly is warranted.

ObjectiveIn these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA).MethodsOver 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case–control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA.ResultsCarriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)).ConclusionCarriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous ‘anti-inflammatory’ mechanisms.

Background: Intra-articular ankle fracture (IAF) causes posttraumatic osteoarthritis (PTOA), but the exact mechanism is unknown. Proinflammatory mediators have been shown to be present in the synovial fluid fracture hematoma (SFFH) but have not been linked to cartilage damage. The purpose of this study was to determine if the SFFH causes cartilage damage and whether this damage can be attenuated by commercially available therapeutic agents. Methods: Synovial fluid was obtained from 54 IAFs and cultured with cartilage discs from the dome of fresh allograft human tali and randomly assigned to one of the following groups: (A) control—media only, (B) SFFH from days 0 to 2 after fracture, (C) SFFH from days 3 to 9, (D) SFFH from days 10 to 14, (E) group B + interleukin 1 receptor antagonist (IL-1Ra), and (F) group B + doxycycline. The cartilage discs underwent histological evaluation for cell survival and cartilage matrix components. The spent media were analyzed for inflammatory mediators. Results: Cartilage discs cultured with SFFH in groups B, C, and D demonstrated significantly increased production of cytokines, metalloproteinases (MMPs), and extracellular matrix breakdown products. Safranin O staining was significantly decreased in group B. The negative effects on cartilage were partially attenuated with the addition of either IL-1RA or doxycycline. There was no difference in chondrocyte survival among the groups. Conclusion: Exposure of uninjured cartilage to IAF SFFH caused activation of cartilage damage pathways evident through cartilage disc secretion of inflammatory cytokines, MMPs, and cartilage matrix fragments. The addition of IL-1Ra or doxycycline to SFFH culture partially attenuated this response. Clinical Relevance: IAFs create an adverse intra-articular environment consisting of significantly increased levels of inflammatory cytokines and MMPs able to damage cartilage throughout the joint. These data suggest that the acute addition of specific inflammatory inhibitors may decrease the levels of these proinflammatory mediators.

ObjectivesTo identify plasma extracellular vesicles (EVs) associated with radiographic knee osteoarthritis (OA) progression.MethodsEVs of small (SEV), medium (MEV) and large (LEV) sizes from plasma of OA participants (n=30) and healthy controls (HCs, n=22) were profiled for surface markers and cytokine cargo by high-resolution flow cytometry. The concentrations of cytokines within (endo-) and outside (exo-) EVs were quantified by multiplex ELISA. EV associations with knee radiographic OA (rOA) progression were assessed by multivariable linear regression (adjusted for baseline clinical variables of age, gender, BMI and OA severity) and receiver operating characteristic (ROC) curve analysis.ResultsBased on integrated mean fluorescence intensity (iMFI), baseline plasma MEVs carrying CD56 (corresponding to natural killer cells) predicted rOA progression with highest area under the ROC curve (AUC) 0.714 among surface markers. Baseline iMFI of TNF-α in LEVs, MEVs and SEVs, and the total endo-EV TNF-α concentration, predicted rOA progression with AUCs 0.688, 0.821, 0.821, 0.665, respectively. In contrast, baseline plasma exo-EV TNF-α (the concentration in the same unit of plasma after EV depletion) did not predict rOA progression (AUC 0.478). Baseline endo-EV IFN-γ and exo-EV IL-6 concentrations were also associated with rOA progression, but had low discriminant capacity (AUCs 0.558 and 0.518, respectively).ConclusionsPlasma EVs carry pro-inflammatory cargo that predict risk of knee rOA progression. These findings suggest that EV-associated TNF-α may be pathogenic in OA. The sequestration of pathogenic TNF-α within EVs may provide an explanation for the lack of success of systemic TNF-α inhibitors in OA trials to date.

Calorie restriction (CR) slows aging and increases healthy lifespan in model organisms. We tested if CR slowed biological aging in humans using DNA methylation analysis of blood samples from N=197 participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) randomized controlled trial. We quantified CR effects on biological aging by comparing change scores for six epigenetic-clock and Pace-of-Aging measures between n=128 CR-group and n=69 ad-libitum-control-group participants at 12- and 24-month follow-ups. CR effects were strongest for DunedinPACE Pace of Aging (12-month Cohen’s d=0.3; 24-month Cohen’s d=0.2, p0.08). CR effects for other epigenetic clocks were in the opposite direction (all p>0.15). CALERIE intervention slowed Pace of Aging but showed minimal effect on epigenetic clocks hypothesized to reflect longer term accumulation of aging burden.

Chronic inflammation exerts pleiotropic effects in the aetiology and progression of chronic obstructive pulmonary disease (COPD). Glucosamine is widely used in many countries and may have anti-inflammatory properties. We aimed to prospectively evaluate the association of regular glucosamine use with incident COPD risk and explore whether such association could be modified by smoking in the UK Biobank cohort, which recruited more than half a million participants aged 40–69 years from across the UK between 2006 and 2010. Cox proportional hazards models with adjustment for potential confounding factors were used to calculate hazard ratios (HR) as well as 95 % CI for the risk of incident COPD. During a median follow-up of 8·96 years (interquartile range 8·29–9·53 years), 9016 new-onset events of COPD were documented. We found that the regular use of glucosamine was associated with a significantly lower risk of incident COPD with multivariable adjusted HR of 0·80 (95 % CI, 0·75, 0·85; P < 0·001). When subgroup analyses were performed by smoking status, the adjusted HR for the association of regular glucosamine use with incident COPD were 0·84 (0·73, 0·96), 0·84 (0·77, 0·92) and 0·71 (0·62, 0·80) among never smokers, former smokers and current smokers, respectively. No significant interaction was observed between glucosamine use and smoking status (Pfor interaction = 0·078). Incident COPD could be reduced by 14 % to 84 % through a combination of regular glucosamine use and smoking cessation.

We provide a detailed account of the origin and establishment of the Osteoarthritis Research Society International (OARSI) and celebrate its history from inception to the current day. We discuss the mission, vision and strategic objectives of OARSI and how these have developed and evolved over the last 3 decades. We celebrate the achievements of the society as we approach its 30th birthday, honor the entire presidential line and respectfully pay tribute to the past presidents who are no longer with us. We reflect on the strong foundations of our society, OARSI’s efforts to disseminate understanding of the health, disability and economic burdens of osteoarthritis (OA) to policymakers, and the exciting initiatives to make the society inclusive and international. We thank our corporate and industrial sponsors, who have supported us over many years, without whom our annual congresses would not have been possible. We celebrate our longstanding strategic partnership with our publisher, Elsevier, and the successful launch of our new journal Osteoarthritis and Cartilage Open, the most significant new development in our dissemination toolbox. For the first time in the history of the organization, our annual congress was cancelled in April 2020 and the 2021 meeting will be virtual. Despite the numerous challenges posed by the ongoing COVID-19 pandemic and the need to adapt quickly to a rapidly changing landscape, we must remain optimistic about the future. We will take advantage of new exciting opportunities to advance our mission and vision to enhance the quality of life of persons with OA.

Background Inflammatory markers, such as high sensitivity C-reactive protein (hs-CRP), and cognitive impairment (CI) are associated with mortality; CRP is related to the deterioration of CI. However, it is still unknown whether these two indices predict mortality independent of each other. Furthermore, their joint effect on all-cause mortality has not been well established, especially in oldest-old adults. Methods Based on data from the 2012 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), we included 1447 oldest-old adults (mean age 84.7 years and 58.7% were female, weighted) with information on hs-CRP (stratified by a cutoff value of 3.0 mg/L) and cognition (quantified by Mini-Mental Status Examination (MMSE) scored according to the personal educational level) at baseline. Mortality was assessed in followed 2014 and 2017 waves. Cox proportional hazards regression models were used, with adjustment for hs-CRP and cognition (mutually controlled) and several traditional mortality risk factors. Results During a median follow-up period of 32.8 months (Q1-Q3, 9.7–59.0 months), 826 participants died. Hs-CRP [HR > 3.0 mg/L vs ≤ 3.0 mg/L: 1.64 (95% CI, 1.17, 2.30)] and cognition [HR CI vs normal: 2.30 (95% CI, 1.64, 3.21)] each was independent predictor of all-cause mortality, even after accounting for each other and other covariates. Monotonic and positive associations were observed in combined analyses, in which the highest mortality risk was obtained in elders with both high hs-CRP> 3.0 mg/L and CI [HR: 3.56 (95% CI, 2.35, 5.38)].The combined effects were stronger in male and younger oldest-old (aged 80–89 years). Conclusion High hs-CRP and CI, both individually and jointly, were associated with increased all-cause mortality risks in Chinese oldest-old. Intervention strategies for preventing inflammation and maintaining adequate cognitive function may be more important in male and younger oldest-old for reducing mortality risk.

Background Evidence of the trend of the incidence of activities of daily living (ADL) disability among Chinese older people is limited. We aimed to investigate the time trends and potential risk factors for the incidence of ADL disability among Chinese older people (≥65 years). Methods We established two consecutive and nonoverlapping cohorts (6,857 participants in the 2002 cohort and 5,589 participants in the 2008 cohort) from the Chinese Longitudinal Healthy Longevity Survey. ADL disability was defined as the need for assistance with at least one essential activity (dressing, bathing, toileting, eating, indoor activities, and continence). Cox proportional hazards models were used to identify factors associated with the trend in the incidence of ADL disability from 2002 to 2014. Results The incidence (per 1,000 person-years) of ADL disability decreased significantly from 64.2 in the 2002 cohort to 46.6 in the 2008 cohort (p < .001), and decreasing trends in the incidence of ADL disability were observed for all sex, age, and residence subgroups (all p < .001), even after adjusting for multiple potential confounding factors. Moreover, we found that adjustment for sociodemographic, lifestyle information, and cardiovascular risk factors (hypertension, diabetes, heart disease, and stroke) explained less of the decline in ADL disability during the period from 2002 to 2014. Conclusion The incidence of ADL disability among the older adults in China appears to have decreased during the study period, and this finding cannot be explained by existing sociodemographic and lifestyle information and cardiovascular risk factors.

PURPOSE Elevated synovial fluid (SF) concentrations of proinflammatory cytokines, degradative enzymes, and cartilage breakdown markers at the time of anterior cruciate ligament (ACL) reconstruction are associated with worse postoperative patient-reported outcomes and cartilage quality. However, it remains unclear if this is due to a more robust or dysregulated inflammatory response or is a function of a more severe injury. The objective of this study was to evaluate the association of the molecular composition of the SF, patient demographics, and injury characteristics to cartilage degradation after acute ACL injury. METHODS We performed a cluster analysis of SF concentrations of proinflammatory and anti-inflammatory cytokines, and biomarkers of cartilage degradation, bony remodeling, and hemarthrosis. We evaluated the association of biomarker clusters with patient demographics, days between injury, Visual Analogue Scale pain, SF aspirate volumes, and bone bruise volumes measured on magnetic resonance imaging. RESULTS Two clusters were identified from the 35 patients included in this analysis, dysregulated inflammation and low inflammation. The dysregulated inflammation cluster consisted of 10 patients and demonstrated significantly greater concentrations of biomarkers of cartilage degradation (P < 0.05) as well as a lower ratio of anti-inflammatory to proinflammatory cytokines (P = 0.053) when compared with the low inflammation cluster. Patient demographics, bone bruise volumes, SF aspirate volumes, pain, and concomitant injuries did not differ between clusters. CONCLUSIONS A subset of patients exhibited dysregulation of the inflammatory response after acute ACL injury which may increase the risk of posttraumatic osteoarthritis. This response does not appear to be a function of injury severity.

BACKGROUND: High concentrations of plasma 25-hydroxyvitamin D [25(OH)D], a marker of circulating vitamin D, have been associated with a lower risk of mortality in epidemiologic studies of multiple populations, but the association for Chinese adults aged ≥80 y (oldest old) remains unclear. OBJECTIVE: We investigated the association between plasma [25(OH)D] concentration and all-cause mortality among Chinese adults aged ≥80 y. DESIGN: The present study is a prospective cohort study of 2185 Chinese older adults (median age: 93 y). Prospective all-cause mortality data were analyzed for survival in relation to plasma 25(OH)D using Cox proportional hazards regression models, with adjustments for potential sociodemographic and lifestyle confounders and biomarkers. The associations were measured with HR and 95% CIs. RESULTS: The median plasma 25(OH)D concentration was 34.4 nmol/L at baseline. Over the 5466 person-year follow-up period, 1100 deaths were identified. Men and women were analyzed together as no effect modification by sex was found. After adjusting for multiple potential confounders, the risk of all-cause mortality decreased as the plasma 25(OH)D concentration increased (P-trend

Background: Little is known about the role of specific leisure activities in affecting cognitive functions. We aim to examine the associations of specific leisure activities with the risk of cognitive impairment among oldest-old people in China. Methods: This community-based prospective cohort study included 10,741 cognitively normal Chinese individuals aged 80 years or older (median age 88 years) from the Chinese Longitudinal Healthy Longevity Survey. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Cox proportional hazards models were utilized to estimate the effects of specific leisure activities on cognitive impairment outcome. Results: During a median follow-up time of 3.4 years (41,760 person-years), 2,894 participants developed cognitive impairment. Compared to those who “never” engaged in watching TV or listening to radio, reading books or newspapers, and playing cards or mah-jong, those who engaged in such activities “almost every day” reduced their risk of cognitive impairment, the fully-adjusted hazard ratios were 0.56 (0.51–0.61), 0.64 (0.53–0.78), and 0.70 (0.56–0.86), respectively. The association between the risk of cognitive impairment and watching TV and listening to the radio, playing cards or mah-jong, and reading books or newspapers were stronger among those who had two or more years of education. Moreover, the association between risk of cognitive impairment and watching TV and listening to radio was stronger in men than in women. Conclusions: In conclusion, a greater frequency of TV watching or radio listening, reading books or newspapers, and playing cards or mah-jong may decrease the risk of cognitive impairment among the oldest-old.

In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post-marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA.

Objective To explore associations of joint hypermobility (a condition where range of motion is greater than normal) with ankle and foot radiographic osteoarthritis (OA) and symptoms in a large community-based cohort of African American and white adults ages 55-94 years old. Methods Ankle and foot radiographs and joint hypermobility data (Beighton score for joint hypermobility criteria) were available for 848 participants (from 2003 to 2010) in this cross-sectional study. General joint hypermobility was defined as a Beighton score ≥4 (range 0-9); knee hypermobility was defined as hyperextension of at least 1 knee. Standing anteroposterior and lateral foot radiographs were read with standard atlases for Kellgren-Lawrence grade, osteophytes, and joint space narrowing (JSN) at the tibiotalar joint, and for osteophytes and JSN to define OA at 5 foot joints. Ankle or foot symptoms were self-reported. Separate person-based logistic regression models were used to estimate associations of ankle and foot OA and symptom outcomes with hypermobility measures, adjusting for age, sex, race, body mass index, and history of ankle/foot injury. Results This sample cohort included 577 women (68%) and 280 African Americans (33%). The mean age of the participants was 71 years, with a mean body mass index of 31 kg/m2 . The general joint hypermobility of the participants was 7% and knee hypermobility was 4%. Having a history of ankle injury was 11.5%, and foot injury was 3.8%. Although general joint hypermobility was not associated with ankle and foot outcomes, knee hypermobility was associated with ankle symptoms, foot symptoms, and talonavicular OA (adjusted odds ratios of 4.4, 2.4, and 3.0, respectively). Conclusion Knee joint hypermobility may be related to talonavicular OA and to ankle and foot symptoms.

Context The patterns of associations between glycated Hb (HbA1c) and mortality are still unclear. Objective To explore the extent to which ranges of HbA1c levels are associated with the risk of mortality among participants with and without diabetes. Design, Setting, and Patients This was a nationwide, community-based prospective cohort study. Included were 15,869 participants (median age 64 years) of the Health and Retirement Study, with available HbA1c data and without a history of cancer. Cox proportional hazards regression models were used to estimate hazard ratios with 95% CIs for mortality. Results A total of 2133 participants died during a median follow-up of 5.8 years. In participants with diabetes, those with an HbA1c level of 6.5% were at the lowest risk of all-cause mortality. When HbA1c level was 7.4%, the increased all-cause mortality risk became statistically significant as compared with an HbA1c level of 6.5%. As for participants without diabetes, those with an HbA1c level of 5.4% were at the lowest risk of all-cause mortality. When the HbA1c level was Conclusions A U-shaped and reverse J-shaped association for all-cause mortality was found among participants with and without diabetes. The corresponding optimal ranges for overall survival are predicted to be 5.6% and 7.4% and 5.0% and 6.5%, respectively.

The patterns of the association between high-density lipoprotein cholesterol (HDL-C) concentrations and mortality among the elderly are still unclear.To examine the association of HDL-C concentrations with mortality and to identify the optimal HDL-C concentration range that predicts the lowest risk of all-cause mortality among the elderly.This was a nationwide, community-based, prospective cohort study.This study included 7766 elderly individuals (aged ≥65 years; mean age: 74.4 years) from the Health and Retirement Study. Cox proportional hazards models and Cox models with penalized smoothing splines were used to estimate hazard ratios (HRs) with 95% CI for all-cause and cause-specific mortality.During a median follow-up of 5.9 years, 1921 deaths occurred. After a full adjustment for covariates, a nonlinear (P0.001 for nonlinearity) association was found between HDL-C and all-cause mortality [minimum mortality risk at 71 mg/dL (1.84 mM)]; the risk for all-cause mortality was significantly higher in the groups with HDL-C concentration61 mg/dL (1.58 mM; HR: 1.18; 95% CI: 1.05 to 1.33) and with HDL-C concentration87 mg/dL (2.25 mM; HR: 1.56; 95% CI: 1.17 to 2.07) than in the group with HDL-C concentrations ranging from 61 to 87 mg/dL (1.58 to 2.25 mM). Nonlinear associations of HDL-C concentrations with both cardiovascular and noncardiovascular mortality were also observed (both P0.001 for nonlinearity).Among the elderly, nonlinear associations were found between HDL-C and all-cause and cardiovascular mortality. The single optimal HDL-C concentration and range were 71 mg/dL and 61 to 87 mg/dL, respectively.

Introduction The aim of this work is to assess the safety and efficacy of repeat administration of triamcinolone acetonide extended-release (TA–ER) in patients with symptomatic knee osteoarthritis (OA), including those with advanced radiographic severity. Methods In this phase 3b, single-arm, open-label study, patients aged ≥ 40 years received the first intra-articular TA-ER injection on day 1. Patients received the second injection timed to the response to the first injection (at either week 12, 16, 20, or 24). Patients who received two injections were evaluated every 4 weeks for 52 weeks. Safety was evaluated via treatment-emergent adverse events and any change at 52 weeks in index-knee radiographs (chondrolysis, osteonecrosis, insufficiency fractures, subchondral bone changes). Exploratory efficacy endpoints included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), -B (stiffness), -C (function), and Knee Injury and Osteoarthritis Outcome Score-Quality of Life (KOOS-QoL) after each injection. Initiative in Methods, Measurements and Pain Assessment in Clinical Trials (IMMPACT) criteria were used to determine moderate and substantial treatment response. Results A total of 208 patients were enrolled and received the first injection of TA-ER; 179 (86.1%) received the second injection (median time to second injection: 16.6 weeks). Both injections were well tolerated, with no unexpected adverse events or significant radiographic changes at week 52. The magnitude and duration of clinical benefit after the first and second injections were similar, and most patients reported a substantial (≥ 50%) analgesic response after both doses. Conclusions Repeat administration of TA–ER using a flexible dosing schedule timed to patient response was well tolerated, with no radiographic evidence of cartilage impact. Both injections resulted in similar improvements in OA symptoms across a broad spectrum of disease severity reflective of that seen in clinical practice. Trial Registration Information ClinicalTrials.gov identifier: NCT03046446. Funding Flexion Therapeutics, Inc. Plain Language Summary Plain language summary available for this article. Electronic supplementary material The online version of this article (10.1007/s40744-019-0140-z) contains supplementary material, which is available to authorized users.

Objectives Currently, most treatment guidelines suggest lowering hypertriglyceridemia of any severity, even in elderly individuals. However associations of serum triglycerides (TGs) with adverse health and mortality risk decrease with age, it remains unclear among the oldest old (aged 80 years and older). The study was to investigate the relationship of serum TG concentrations with cognitive function, activities of daily living (ADLs), frailty, and mortality among the oldest old in a prospective cohort study. Design Longitudinal prospective cohort study. Setting Community-based setting in longevity areas in China. Participants A total of 930 (mean age = 94.0 years) Chinese oldest old. Measurements The TG concentrations were measured at baseline survey in 2009. Cognitive function, ADLs, frailty, and mortality were determined over 5 years of follow-up. Cox proportional hazards models and competing risk models were performed to explore the association, adjusting for potential confounders. Results Each 1-mmol/L increase in TGs was associated with a nearly 20% lower risk of cognitive decline, ADL decline, and frailty aggravation during the 5 years of follow-up. Consistently, higher TGs (each 1 mmol/L) was associated with lower 5-year all-cause mortality after fully adjustment (hazard ratio [HR] = 0.79; 95% confidence interval [CI] = 0.69-0.89). Nonelevated TG concentrations (less than 2.26 mmol/L) were associated with higher mortality risk (HR = 1.72; 95% CI = 1.22-2.44), relative to TGs of 2.26 mmol/L or more. We observed similar results regarding TG concentrations and mortality in 1-year lag analysis and when excluding participants with identified chronic disease. Conclusion In the oldest old, a higher concentration of TGs was associated with a lower risk of cognitive decline, ADL decline, frailty aggravation, and mortality. This paradox suggests the clinical importance of revisiting the concept of "the lower the better" for the oldest old. J Am Geriatr Soc 67:741-748, 2019.

Background Sarcopenic obesity, associated with greater risk of cardiovascular disease (CVD) and mortality in rheumatoid arthritis (RA), may be related to dysregulated muscle remodeling. To determine whether exercise training could improve remodeling, we measured changes in inter-relationships of plasma galectin-3, skeletal muscle cytokines, and muscle myostatin in patients with RA and prediabetes before and after a high-intensity interval training (HIIT) program. Methods Previously sedentary persons with either RA (n = 12) or prediabetes (n = 9) completed a 10-week supervised HIIT program. At baseline and after training, participants underwent body composition (Bod Pod®) and cardiopulmonary exercise testing, plasma collection, and vastus lateralis biopsies. Plasma galectin-3, muscle cytokines, muscle interleukin-1 beta (mIL-1β), mIL-6, mIL-8, muscle tumor necrosis factor-alpha (mTNF-α), mIL-10, and muscle myostatin were measured via enzyme-linked immunosorbent assays. An independent cohort of patients with RA (n = 47) and age-, gender-, and body mass index (BMI)-matched non-RA controls (n = 23) were used for additional analyses of galectin-3 inter-relationships. Results Exercise training did not reduce mean concentration of galectin-3, muscle cytokines, or muscle myostatin in persons with either RA or prediabetes. However, training-induced alterations varied among individuals and were associated with cardiorespiratory fitness and body composition changes. Improved cardiorespiratory fitness (increased absolute peak maximal oxygen consumption, or VO2) correlated with reductions in galectin-3 (r = −0.57, P = 0.05 in RA; r = −0.48, P = 0.23 in prediabetes). Training-induced improvements in body composition were related to reductions in muscle IL-6 and TNF-α (r < −0.60 and P

Summary Objective To evaluate systemic inflammatory biomarkers in symptomatic knee osteoarthritis (OA) and their association with radiographic and biochemical OA progression. Methods Lipopolysaccharide (LPS) binding protein (LBP), soluble Toll-like receptor 4 (sTLR4) and interleukin 6 (IL-6) were measured in plasma of 431 knee OA patients from the doxycycline (DOXY) trial at baseline and 18 months. Plasma lipopolysaccharide and lipopolysaccharide binding protein (LBP) were also measured at 12 months. As a biochemical indicator of disease activity and OA progression, urinary (u) C-telopeptide of Type II collagen (uCTX-II) was measured in samples collected at baseline and 18 months. Change over 16 months in radiographic tibiofemoral joint space width (JSW in mm) and joint space narrowing (JSN≥0.5 mm) were used to indicate radiographic OA progression. Change over 18 months for uCTX-II was used as a secondary outcome. Both univariate and multivariable regression analyses were performed to test the association between Z-score transformed biomarkers and outcomes. Results Baseline LBP and time-integrated concentration (TIC) of LBP over 12 and 18 months were associated with worsening joint space width (JSW) (parameter estimates: −0.1 to −0.07) and JSN (OR: 1.32 to 1.42) adjusting for treatment group, age, body mass index (BMI) and corresponding baseline radiographic measures. Baseline sTLR4 and TIC over 18 months were associated with change in uCTX-II over 18 months (adjusted parameter estimates: 0.0017 to 0.0020). Results were not modified by treatment with doxycycline. Conclusion Plasma LBP and sTLR4 were associated with knee OA progression over 16–18 months. These results lend further support for a role of systemic low-grade inflammation in the pathogenesis of knee OA progression.

Summary Objective The purpose of this overview of osteoarthritis (OA) biomarkers is to provide the non-specialist with a toolbox, based on experience acquired by biomarker researchers over many years, to understand biomarkers in general and their use in the OA field. Methods We provide an update on this subject since the OARSI Primer on osteoarthritis (OA) nearly a decade ago. Results Since the last update, the importance of molecular biomarkers has been increasingly recognized in the field, but no OA-related biomarkers have been adopted for routine use in clinical practice. The current lack of chondroprotective treatments for OA impairs the assessment, validation and qualification of the potential role of biomarkers as tools for monitoring disease status and patient responses to treatment of OA. Yet there is no lack of an evolving compendium of OA-related biomarkers, ever more fit-for-purpose, that could currently facilitate drug development for OA. We provide an abbreviated update and overview of specific soluble OA-related biomarkers for this new OARSI Primer on OA with OA-relevant examples encompassing the concepts of biomarker nomenclature, qualification, interpretation, measurement, reporting requirements, application to research, drug discovery and clinical care, and future needs for biomarker advancement. Conclusion Appropriate biomarkers should play a role at all stages of OA diagnosis, prognosis, drug development, and treatment. The future of OA biomarker research and development holds great promise as its foundation is increasingly robust.

BackgroundLipoprotein Insulin Resistance Index (LP-IR) and Diabetes Risk Index are novel spectroscopic multimarkers of insulin resistance and type 2 diabetes risk. As the Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) randomized trials have previously demonstrated the ability of exercise training to improve traditional markers of insulin action, the aim of this study was to examine the effects of exercise amount, intensity, and mode on LP-IR and the Diabetes Risk Index.MethodsA total of 503 adults with dyslipidemia [STRRIDE I (n = 194), STRRIDE AT/RT (n = 139)] or prediabetes [STRRIDE-PD (n = 170)] were randomized to control or one of 10 exercise interventions, ranging from doses of 8–23 kcal/kg/week; intensities of 50–75% V̇O2peak; and durations of 6–8 months. Two groups included resistance training and one included dietary intervention (7% weight loss goal). Fasting plasma samples were obtained at baseline and 16–24 h after the final exercise bout. LP-IR, the Diabetes Risk Index, and concentrations of the branched chain amino acids valine and leucine were determined using nuclear magnetic resonance spectroscopy. LP-IR and the Diabetes Risk Index scores range from 0–100 and 1–100, respectively (greater scores indicate greater risk). Paired t-tests determined significance within groups (p < 0.05).ResultsAfter training, six exercise groups significantly improved LP-IR (ranging from −4.4 ± 8.2 to −12.4 ± 14.1), and four exercise groups significantly improved the Diabetes Risk Index (ranging from −2.8 ± 8.2 to −8.3 ± 10.4). The most beneficial interventions for both LP-IR and the Diabetes Risk Index were low amount/moderate intensity aerobic, aerobic plus resistance, and aerobic plus diet.SummaryMultiple exercise interventions improved LP-IR and the Diabetes Risk Index. In those with dyslipidemia, adding resistance to aerobic training elicited a synergistic effect on insulin resistance and type 2 diabetes risk. In individuals with prediabetes, combining a dietary intervention and weight loss with aerobic training resulted in the most robust type 2 diabetes risk improvement.

Background Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT. Methods Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3–4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls. Results Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1–2 match. Grade 3–4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival. Conclusions Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.

Objective Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone. Methods PBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). Results We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p p Conclusion The use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

Background: Research on the relationship between long-term exposure to particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) and poor cognitive function is lacking in developing countries, especially in highly polluted areas. Objectives: We evaluated associations of long-term exposure to PM2.5 with poor cognitive function in a diverse, national sample of older adults in China. Methods: This analysis included data on 13,324 older adults (5,879 who were 65–79 years of age, 3,052 who were 80–89 years of age, 2,634 who were 90–99 years of age, and 1,759 who were ≥100 years of age) with normal cognitive function at baseline from March 2002 to September 2014, with 64,648 person-years of follow-up. We used a geographic information system analysis to estimate the annual average satellite-derived PM2.5 concentration for the geocoded location of the participants’ baseline residences. Poor cognitive function was defined as a score of less than 18 on the Chinese version of the Mini-Mental State Examination (MMSE). Competing risk models were performed to explore the association of PM2.5 with poor cognitive function. Results: Each 10-μg/m3 increase in PM2.5 was associated with a 5.1% increased risk of poor cognitive function [adjusted hazard ratio (HR): 1.051; 95% confidence interval (CI): 1.023, 1.079]. Compared to the lowest quartile of PM2.5 (

BackgroundClinically similar older adults demonstrate variable responses to health stressors, heterogeneity attributable to differences in physical resilience. However, molecular mechanisms underlying physical resilience are unknown. We previously derived a measure of physical resilience after hip fracture—the expected recovery differential (ERD)—that captures the difference between actual recovery and predicted recovery. Starting with biomarkers associated with physical performance, morbidity, mortality, and hip fracture, we evaluated associations with the ERD to identify biomarkers of physical resilience after hip fracture.MethodsIn the Baltimore Hip Studies (N = 304) sera, we quantified biomarkers of inflammation (TNFR-I, TNFR-II, sVCAM-1, and IL-6), metabolic and mitochondrial function (non-esterified fatty acids, lactate, ketones, acylcarnitines, free amino acids, and IGF-1), and epigenetic dysregulation (circulating microRNAs). We used principal component analysis, canonical correlation, and least absolute shrinkage and selection operator regression (LASSO) to identify biomarker associations with better-than-expected recovery (greater ERD) after hip fracture.ResultsParticipants with greater ERD were more likely to be women and less disabled at baseline. The complete biomarker set explained 37% of the variance in ERD (p < .001) by canonical correlation. LASSO regression identified a biomarker subset that accounted for 27% of the total variance in the ERD and included a metabolic factor (aspartate/asparagine, C22, C5:1, lactate, glutamate/mine), TNFR-I, miR-376a-3p, and miR-16-5p.ConclusionsWe identified a set of biomarkers that explained 27% of the variance in ERD—a measure of physical resilience after hip fracture. These ERD-associated biomarkers may be useful in predicting physical resilience in older adults facing hip fracture and other acute health stressors.

Neutrophil dysfunction is a common feature of aging, and is associated with the pathogenesis of many age-related diseases, including type 2 diabetes mellitus (T2DM). Although exercise training improves metabolic health, decreases risk of T2DM, and is associated with improving neutrophil functions, involvement in regular physical activity declines with age. The aim of this study was to determine if neutrophil functions could be improved in association with changes in fitness and metabolic parameters in older adults at risk for T2DM using 10-weeks of low volume high-intensity interval exercise training (HIIT). Ten older (71 ± 5 years) sedentary adults with prediabetes (HbA1c: 6.1 ± 0.3%) completed 10 weeks of a supervised HIIT program. Three 30 min sessions/week consisted of ten 60 s intervals of low intensity [50–60% heart rate reserve (HRR)] separated with similar durations of high intensity intervals (80–90% HRR). Before and after training, glucose and insulin sensitivity, neutrophil chemotaxis, bacterial phagocytosis, reactive oxygen species (ROS) production, and mitochondrial functions were assessed. Exercise-mediated changes in cardiorespiratory fitness (VO2peak) and neutrophil functions were compared to six young (23 ± 1 years) healthy adults. Following training, significant reductions in fasting glucose and insulin were accompanied by improved glucose control and insulin sensitivity (all p < 0.05). Before exercise training, VO2peak in the old participants was significantly less than that of the young controls (p < 0.001), but increased by 16 ± 11% following training (p = 0.002) resulting in a 6% improvement of the deficit. Neutrophil chemotaxis, phagocytosis and stimulated ROS production were significantly less than that of the young controls, while basal ROS were higher before training (all p < 0.05). Following training, chemotaxis, phagocytosis and stimulated ROS increased while basal ROS decreased, similar to levels observed in the young controls (all p < 0.05) and reducing the deficit of the young controls between 2 and 154%. In five of the adults with prediabetes, neutrophil mitochondrial functions were significantly poorer than the six young controls before training. Following training, mitochondrial functions improved toward those observed in young controls (all p < 0.05), reducing the deficit of the young controls between 14.3 and 451%. Ten weeks of HIIT in older adults at risk for T2DM reduced disease risk accompanied by improved primary and bioenergetic neutrophil functions. Our results are consistent with a reduced risk of infections mediated by relationships in exercise induced systemic and cellular metabolic features.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02441205, registered on May 12th, 2015.

Summary Objective Human and in vivo animal research implicates inflammation following articular fracture as contributing to post-traumatic arthritis. However, relevant immune cell subsets present following injury are currently undefined. Immunophenotyping human and murine synovial fluid may help to identify immune cell populations that play key roles in the response to articular fracture. Methods Immunophenotyping by polychromatic flow cytometry was performed on human and mouse synovial fluid following articular fracture. Specimens were collected in patients with closed ankle fracture at the time of surgical fixation and from C57BL/6 mice with closed articular knee fracture. Immune cells were collected from injured and uninjured joints in mice via a novel cell isolation method. Whole blood samples were also collected. Immunohistochemistry (IHC) was performed on mouse synovial tissue to assess for macrophages and T cells. Results Following intra-articular fracture, the prominent human synovial fluid immune cell subset was CD3+ T cells, containing both CD4+ and CD8+ T cells. In mice, infiltration of CD45+ immune cells in synovial fluid of the fractured limb was dominated by CD19+ B cells and CD3+ T cells at 7 days after intra-articular fracture. We also detected adaptive immune cells, including macrophages, NK cells, dendritic cells and monocytes. Macrophage and T cell findings were supported by IHC of murine synovial tissue. Conclusions Determining specific cell populations that mediate the immune response is essential to elucidating the chain of events initiated after injury and may be an important step in identifying potential immune signatures predictive of PTA susceptibility or potential therapeutic targets.

Background Dietary fatty acid (FA) content has been shown to influence the development of post-traumatic osteoarthritis (PTOA) in obesity. We used the fat-1 transgenic mouse to examine the hypothesis that endogenous reduction of ω-6 to ω-3 FA ratio, under the same dietary conditions, would mitigate metabolic inflammation and the pathogenesis of PTOA in obese male and female mice. Methods Male and female fat-1 and wild-type littermates were fed either a control diet or an ω-6 FA-rich high-fat diet and underwent destabilization of the medial meniscus (DMM) surgery to induce PTOA. OA severity, synovitis, and osteophyte formation were determined histologically, while biomarker and lipidomic analyses were performed to evaluate levels of adipokines, insulin, pro-/anti-inflammatory cytokines, and FAs in serum and joint synovial fluid. Multivariable models were performed to elucidate the associations of dietary, metabolic, and mechanical factors with PTOA. Results We found that elevated serum levels of ω-3 FAs in fat-1 mice as compared to wild-type controls fed the same diet resulted in reduced OA and synovitis in a sex- and diet-dependent manner, despite comparable body weights. The fat-1 mice showed trends toward decreased serum pro-inflammatory cytokines and increased anti-inflammatory cytokines. Multivariable analysis for variables predicting OA severity in mice resulted in correlations with serum FA levels, but not with body weight. Conclusions This study provides further evidence that circulating FA composition and systemic metabolic inflammation, rather than body weight, may be the major risk factor for obesity-associated OA. We also demonstrate the potential genetic use of ω-3 FA desaturase in mitigating PTOA in obese patients following injury.

Summary: Objective: To examine the feasibility of a 6-week high intensity interval training (HIIT) program in patients with symptomatic knee osteoarthritis (OA). A secondary aim was to evaluate the change in whole-body metabolism. Design: In a single-arm intervention, 16 adults (mean age 59.9 yrs; BMI: 29.0 ± 4.3 kg/m2; 77% female) with radiographically diagnosed knee OA (Kellgren-Lawrence [KLG]: 2–4) and moderate to severe pain score (≥6) from the Western Ontario and McMasters Universities Index (WOMAC) enrolled in a 6-week, twice weekly, supervised HIIT cycle ergometry intervention. The primary outcome was feasibility; secondary outcomes included change in peak oxygen consumption (VO2peak), WOMAC, and circulating biomarkers of metabolism. Results: Feasibility was moderate; of the 21 participants screened by phone, 16 were enrolled; 13 completed pre- and post-testing. The average adherence rate (sessions completed/available) was >96%. VO2peak was significantly improved (mean ± SD: 2.6 ± 3.0 mL/min/kg; 95% CI [0.70–4.56]). Significant improvements in WOMAC (mean ± SD: −8.7 ± 12.5; CI: [18.9 to −2.80]), pain [-5.15 to −1.01], and function [-12.9 to −0.98] resulted. There was a significant reduction in concentrations of amino acids: methionine, phenylalanine, and tyrosine (p

Currently the Chinese government has adopted World Health Organization interim target-1 values as the national ambient air quality standards values. However, the population-based evidence was insufficient, especially for the oldest old (aged 80+). We evaluated the association of fine particulate matters (PM(2.5)) exposure and incidence of disability in activities of daily living (ADL) in 15 453 oldest old in 886 counties/cities in China from 2002 to 2014 using Cox model with penalized splines and competing risk models to evaluate the linear or non-linear association. After adjusting for potential confounders, a J-shaped association existed between PM(2.5) exposure with a threshold concentration of 33 μg/m(3), and incident disability in ADL. Above this threshold, the risk magnitude significantly increased with increase of PM(2.5) concentrations; compared to 33 μg/m(3), the hazard ratio ranged from 1.03 (1.00-1.06) at 40 μg/m(3) to 2.25 (1.54-3.29) at 110 μg/m(3). The risk magnitude was not significantly changed below this threshold. Each 10 μg/m(3) increase in PM(2.5) exposure corresponded to a 7.7% increase in the risk of disability in ADL (hazard ratio 1.077, 95% CI 1.051-1.104). Men, smokers, and participants with cognitive impairment might be more vulnerable to PM(2.5) exposure. The study provided limited population-based evidence for the oldest old and detected a threshold of 33 μg/m(3), and supported that reduction to current World Health Organization interim target-1value (35 μg/m(3)) and Chinese national ambient air quality standards (35 μg/m(3)) or lower may be associated with lower risk of disability in ADL.

Fasting blood glucose level is the primary indicator for the diagnosis of diabetes. We aim to conduct a longitudinal study on the association between long-term fine particulate matter (PM(2.5)) exposure and fasting blood glucose concentrations. We recruited and followed up 1449 participants older than 65 years of age in 2009, 2012, 2014, and 2017 in eight counties in China. Fasting blood glucose was repeatedly measured 3697 times in total among these participants. Data on annual ground-level PM(2.5) concentrations with a 0.01° spatial resolution from 2005 to 2016 were used to assess exposures. An increase of 10μg/m(3) in 3-year average exposure to PM(2.5) was associated with an increase of 0.146 mmol/L (95% confidence interval [CI]: 0.045, 0.248) in fasting blood glucose in all participants. The association was more pronounced among the subgroup with diabetes compared to the subgroup without diabetes (P

Summary Objective Our study analyzes the association between chemokine-ligand-2 (CCL2) serum concentrations at baseline and knee radiographic osteoarthritis (OA) (knee-rOA), knee-rOA progression, individual radiographic features and knee symptomatic OA at 5-year follow-up. Design OA outcomes were analyzed in a community-based cohort including a baseline enrollment and a 5-year follow-up. Baseline CCL2 serum concentrations were assessed by multiplex assay and associated with presence or progression of individual radiographic features at 5-year follow-up. Separate multiple logistic regression models were used to examine adjusted associations between baseline CCL2 and each of the knee OA variables at follow-up. CCL2 at baseline was modeled as an explanatory variable, whereas each of the knee OA variables at follow-up served as the response variables. Models were adjusted for age, BMI, race, and sex. Trend tests were conducted to assess any linear effect on outcomes across CCL2 tertiles. Results Participants (n = 168) had a median age of 57-years and median BMI of 29 kg/m2. About 63% of all participants were women, and 58% Caucasian (42% African American). In adjusted logistic models, continuous log-CCL2 was significantly associated with knee-rOA. For each unit increase in log CCL2, the odds of having knee-rOA at follow-up was increased by 72%. CCL2 tertiles showed significant linear associations with presence and progression of knee-rOA and medial joint space narrowing (JSN), but not with presence or progression of osteophytes, bone sclerosis, knee symptoms, or symptomatic knee-rOA. Conclusions Serum CCL2 may help to elucidate some mechanisms of joint destruction and identify individuals with higher odds of structural knee changes.

BACKGROUND The aim of this study was to identify the predictors of need for allogenic blood transfusion (ALBT) in primary lower limb total joint arthroplasty (TJA). STUDY DESIGN AND METHODS This study utilized a large dataset of 15,187 patients undergoing primary unilateral TJA. Risk factors and demographic information were extracted from the electronic health record. A predictive model was developed by both a random forest (RF) algorithm and logistic regression (LR). The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the accuracy of the two methods. RESULTS The rate of ALBT was 18.9% in total. Patient-related factors associated with higher risk of an ALBT included female sex, American Society of Anesthesiologists (ASA) II, ASA III, and ASA IV. Surgery-related risk factors for ALBT were operative time, drain use, and amount of intraoperative blood loss. Higher preoperative hemoglobin and tranexamic acid use were associated with decreased risk for ALBT. The RF model had a better predictive accuracy (area under the curve [AUC] 0.84) than the LR model (AUC, 0.77; p