Gender and age differences in the associations between cortical thickness and hand osteoarthritis severity: data from the Osteoarthritis Initiative.

OBJECTIVE: To evaluate gender differences in the association between metacarpal cortical thickness (Tcort)-a surrogate for bone density-and severity of radiographic hand osteoarthritis (HOA) in a longitudinal observational study. METHOD: Hand radiographs of 3575 participants (2039 F/1536 M) from the Osteoarthritis Initiative were assessed at baseline and 48 months. A reader used a semi-automated software tool to calculate Tcort, a measurement of the cortical thickness, for metacarpals 2-4. Average Tcort at baseline and change in Tcort from baseline to 48 months was determined and stratified by gender and age for 7 5-year age groups. Spearman's rank correlation coefficients were calculated for the association of baseline Tcort and 2 measures of baseline HOA severity: the sum of Kellgren-Lawrence (KL) grade and total number of joints with radiographic HOA. Longitudinally, logistic regression was used to assess the relationship of Tcort loss to new finger joint radiographic HOA, increase in KL grades, and incident hand pain. RESULTS: Male Tcort was higher than females. Significant correlations between Tcort and radiographic severity were noted for women but not men, with stronger associations among women >60 years (rho = -0.25; 95% confidence interval (CI) = -0.31 to -0.19). Statistically significant associations were seen between Tcort change and radiographic osteoarthritis change among women but not men, with substantial gender differences for Tcort change, particularly ages 50 to 70 years (p < 0.01; e.g., Tcort change ages 55 to <60: males = -0.182 (0.118), females = -0.219 (0.124)). CONCLUSION: We found significant HOA-related gender differences in Tcort, suggesting the involvement of female bone loss during and after menopause.

Gender differences in patterns of cartilage loss: Data from the Osteoarthritis Initiative.

OBJECTIVE: Understanding gender-specific differences in patterns of cartilage loss can improve our knowledge of the pathogenesis of knee osteoarthritis (KOA) development and progression and may inform clinical trials of treatments for KOA. The goal of our observational study was to examine gender differences in patterns of cartilage loss in the central weight-bearing regions of the femur. METHODS: We measured cartilage volume change in the indexed knee of 700 subjects with Kellgren-Lawrence 1, 2, or 3 from the Osteoarthritis Initiative for four follow-up periods (baseline [BL] to 24 mo, BL to 48 mo, BL to 72 mo, and BL to 96 mo) using the local area cartilage segmentation (LACS) method. Briefly, the LACS method uses robust coordinate systems fixed to anatomical landmarks to measure patterns of change in cartilage volume in sub-regions using responsiveness heat maps. RESULTS: We observed a statistically significant gender difference in cartilage change in the medial femur (MF), lateral femur (LF), and medial tibia. The heat maps showed loss was primarily in the posterior central weight-bearing portion of the LF and more general in the LT and MF. Similar patterns were observed for each of the four follow-up periods. CONCLUSIONS: The LACS method was capable of illustrating gender-specific differences in patterns of cartilage loss that may offer insight into the variation of gender differences in the natural history of KOA and may be useful in evaluating the benefit of interventions for KOA.

Associations of inflammatory and metabolic biomarkers with incident erosive hand osteoarthritis in the osteoarthritis initiative cohort.

OBJECTIVE: Erosive hand osteoarthritis (eHOA) is a subtype of hand osteoarthritis (OA) that develops in finger joints with pre-existing OA and is differentiated by clinical characteristics (hand pain/disability, inflammation, and erosions) that suggest inflammatory or metabolic processes. METHOD: This was a longitudinal nested case-cohort design among Osteoarthritis Initiative participants who had hand radiographs at baseline and 48-months, and biospecimens collected at baseline. We classified incident radiographic eHOA in individuals with ≥1 joint with Kellgren-Lawrence ≥2 and a central erosion present at 48-months but not at baseline. We used a random representative sample (n = 1282) for comparison. We measured serum biomarkers of inflammation, insulin resistance and dysglycemia, and adipokines using immunoassays and enzymatic colorimetric procedures, blinded to case status. RESULTS: Eighty-six participants developed incident radiographic eHOA. In the multivariate analyses adjusted for age, gender, race, smoking, and body mass index, and after adjustment for multiple analyses, incident radiographic eHOA was associated with elevated levels of interleukin-7 (risk ratio (RR) per SD = 1.30 [95% confidence interval (CI) 1.09, 1.55] p trend 0.01). CONCLUSION: This exploratory study suggests an association of elevated interleukin-7, an inflammatory cytokine, with incident eHOA, while other cytokines or biomarkers of metabolic inflammation were not associated. Interleukin-7 may mediate inflammation and tissue damage in susceptible osteoarthritic finger joints and participate in erosive progression.

Investigation Into the Effects of Intra-Articular Steroid on Post-Traumatic Osteoarthritis in Distal Radius Fractures: A Randomized Controlled Pilot Study.

PURPOSE: The aim of this prospective, randomized, controlled, double-blinded pilot study was to determine the rates of post-traumatic osteoarthritis and assess joint space width in the presence or absence of a single intra-articular injection of corticosteroid after an acute, intra-articular distal radius fracture (DRF). METHODS: Forty patients received a single, intra-articular, radiocarpal joint injection of 4 mg of dexamethasone (DEX) (n = 19) or normal saline placebo (n = 21) within 2 weeks of a surgically or nonsurgically treated intra-articular DRF. The primary outcome measure was minimum radiocarpal joint space width (mJSW) on noncontrast computed tomography scans at 2 years postinjection. Secondary outcomes were obtained at 3 months, 6 months, 1 year, and 2 years postinjection and included Disabilities of the Arm, Shoulder, and Hand; Michigan Hand Questionnaire; Patient-Rated Wrist Evaluation; wrist range of motion; and grip strength. RESULTS: At 2-year follow-up, there was no difference in mean mJSW between the DEX group (2.2 mm; standard deviation, 0.6; range, 1.4-3.2) and the placebo group (2.3 mm; standard deviation, 0.7; range, 0.9-3.9). Further, there were no differences in any secondary outcome measures at any postinjection follow-up interval. CONCLUSIONS: Radiocarpal joint injection of corticosteroid within 2 weeks of an intra-articular DRF does not appear to affect the development of post-traumatic osteoarthritis within 2 years follow-up in a small pilot cohort. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Radiographic joint space width in individuals with hand osteoarthritis: Are their "healthy" joints really healthy?

OBJECTIVES: We aimed to investigate the systemic nature of hand osteoarthritis (OA). We hypothesized that people who suffer from hand OA would display narrower radiographic joint space width (JSW) - not only in joints with apparent radiographic OA but also in their unaffected "healthy" joints. METHOD: We examined 3394 participants from the Osteoarthritis Initiative with available dominant hand radiographs at baseline. Cases were defined as having interphalangeal OA (IPOA) based on a Kellgren and Lawrence (KL) score of ≥2 in two or more finger joints, whereas controls did not have IPOA. We used custom software to make JSW measurements of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints in fingers 2-5 per hand. In joint-level analyses, we included only KL score=0, allowing us to compare all joints without IPOA in cases and controls. We used generalized estimating equation models to compare JSW between both groups, adjusted for age, gender, metacarpal length, and joint type. RESULTS: Finger joints without radiographic OA had significantly narrower JSW in the IPOA group compared to finger joints in the control group (p < 0.001). The differences were significant across all joint types and for both total JSW measurements as well as for central and lateral sub-regions within each joint group (p < 0.001). CONCLUSION: Unaffected finger joints in people with IPOA had narrower joint space than joints of healthy controls. This implies a systemic nature of hand OA, in which people may have a predisposition for general cartilage deterioration.

Pancreatic cancer epigenetics: adaptive metabolism reprograms starving primary tumors for widespread metastatic outgrowth.

Pancreatic cancer is a paradigm for adaptation to extreme stress. That is because genetic drivers are selected during tissue injury with epigenetic imprints encoding wound healing responses. Ironically, epigenetic memories of trauma that facilitate neoplasia can also recreate past stresses to restrain malignant progression through symbiotic tumor:stroma crosstalk. This is best exemplified by positive feedback between neoplastic chromatin outputs and fibroinflammatory stromal cues that encase malignant glands within a nutrient-deprived desmoplastic stroma. Because epigenetic imprints are chemically encoded by nutrient-derived metabolites bonded to chromatin, primary tumor metabolism adapts to preserve malignant epigenetic fidelity during starvation. Despite these adaptations, stromal stresses inevitably awaken primordial drives to seek more hospitable climates. The invasive migrations that ensue facilitate entry into the metastatic cascade. Metastatic routes present nutrient-replete reservoirs that accelerate malignant progression through adaptive metaboloepigenetics. This is best exemplified by positive feedback between biosynthetic enzymes and nutrient transporters that saturate malignant chromatin with pro-metastatic metabolite byproducts. Here we present a contemporary view of pancreatic cancer epigenetics: selection of neoplastic chromatin under fibroinflammatory pressures, preservation of malignant chromatin during starvation stresses, and saturation of metastatic chromatin by nutritional excesses that fuel lethal metastasis.

Automatic Measuring of Finger Joint Space Width on Hand Radiograph using Deep Learning and Conventional Computer Vision Methods.

Hand osteoarthritis (OA) severity can be assessed visually through radiographs using semi-quantitative grading systems. However, these grading systems are subjective and cannot distinguish minor differences. Joint space width (JSW) compensates for these disadvantages, as it quantifies the severity of OA by accurately measuring the distances between joint bones. Current methods used to assess JSW require users' interaction to identify the joints and delineate initial joint boundary, which is time-consuming. To automate this process and offer a more efficient and robust measurement for JSW, we proposed two novel methods to measure JSW: 1) The segmentation-based (SEG) method, which uses traditional computer vision techniques to calculate JSW; 2) The regression-based (REG) method, which is a deep learning approach employing a modified VGG-19 network to predict JSW. On a dataset with 3,591 hand radiographs, 10,845 DIP joints were cut as regions of interest and served as input to the SEG and REG methods. The bone masks of the ROI images generated by a U-Net model were sent as input in addition to the ROIs. The ground truth of JSW was labeled by a trained research assistant using a semi-automatic tool. Compared with the ground truth, the REG method achieved a correlation coefficient of 0.88 and mean square error (MSE) of 0.02 mm on the testing set; the SEG method achieved a correlation coefficient of 0.42 and MSE of 0.15 mm. Results show the REG method has promising performance in automatic JSW measurement and in general, Deep Learning approaches can facilitate the automatic quantification of distance features in medical images.

Reliability and Validity of Single Axial Slice vs. Multiple Slice Quantitative Measurement of the Volume of Effusion-Synovitis on 3T Knee MRI in Knees with Osteoarthritis.

Effusion-synovitis (ES) is recognized as a component of osteoarthritis, creating a need for rapid methods to assess ES on MRI. We describe the development and reliability of an efficient single-slice semi-automated quantitative approach to measure ES. We used two samples from the Osteoarthritis Initiative (OAI): 50 randomly selected OAI participants with radiographic osteoarthritis (i.e., Kellgren-Lawrence (KL) grade 2 or 3) and a subset from the Foundation for the National Institutes of Health Osteoarthritis Biomarker study. An experienced musculoskeletal radiologist trained four non-expert readers to use custom semi-automated software to measure ES on a single axial slice and then read scans blinded to prior assessments. The estimated intraclass correlation coefficient (ICC) for intra-reader reliability of the single-slice ES method in the KL 2-3 sample was 0.96 (95% CI: 0.93, 0.97), and for inter-reader reliability, the ICC was 0.90 (95% CI: 0.87, 0.95). The intra-reader mean absolute difference (MAD) was 35 mm3 (95% CI: 28, 44), and the inter-reader MAD was 61 mm3 (95% CI: 48, 76). Our single-slice quantitative knee ES measurement offers a reliable, valid, and efficient surrogate for multi-slice quantitative and semi-quantitative assessment.

Quantitative bone marrow lesion, meniscus, and synovitis measurement: current status.

Imaging plays a pivotal role in osteoarthritis research, particularly in epidemiological and clinical trials of knee osteoarthritis (KOA), with the ultimate goal being the development of an effective drug treatment for future prevention or cessation of disease. Imaging assessment methods can be semi-quantitative, quantitative, or a combination, with quantitative methods usually relying on software to assist. The software generally attempts image segmentation (outlining of relevant structures). New techniques using artificial intelligence (AI) or deep learning (DL) are currently a frequent topic of research. This review article provides an overview of the literature to date, focusing primarily on the current status of quantitative software-based assessment techniques of KOA using magnetic resonance (MR) imaging. We will concentrate on the imaging evaluation of three specific structural imaging biomarkers: bone marrow lesions (BMLs), meniscus, and synovitis consisting of effusion synovitis (ES) and Hoffa's synovitis (HS). A brief clinical and imaging background review of osteoarthritis evaluation, particularly relating to these three structural markers, is provided as well as a general summary of the software methods. A summary of the literature with respect to each KOA assessment method will be presented overall as well as with respect to each specific biomarker individually. Novel techniques, as well as future goals and directions using quantitative imaging assessment, will be discussed.

Fast quantitative bone marrow lesion measurement on knee MRI for the assessment of osteoarthritis.

Objective: Knee osteoarthritis (KOA) is a prevalent disease with a high economic and social cost. Magnetic resonance imaging (MRI) can be used to visualize many KOA-related structures including bone marrow lesions (BMLs), which are associated with OA pain. Several semi-automated software methods have been developed to segment BMLs, using manual, labor-intensive methods, which can be costly for large clinical trials and other studies of KOA. The goal of our study was to develop and validate a more efficient method to quantify BML volume on knee MRI scans. Materials and methods: We have applied a deep learning approach using a patch-based convolutional neural network (CNN) which was trained using 673 MRI data sets and the segmented BML masks obtained from a trained reader. Given the location of a BML provided by the reader, the network performed a fully automated segmentation of the BML, removing the need for tedious manual delineation. Accuracy was quantified using the Pearson's correlation coefficient, by a comparison to a second expert reader, and using the Dice Similarity Score (DSC). Results: The Pearson's R2 value was 0.94 and we found similar agreement when comparing two readers (R2 â€‹= â€‹0.85) and each reader versus the DL model (R2 â€‹= â€‹0.95 and R2 â€‹= â€‹0.81). The average DSC was 0.70. Conclusions: We developed and validated a deep learning-based method to segment BMLs on knee MRI data sets. This has the potential to be a valuable tool for future large studies of KOA.

En1 and Lmx1b do not recapitulate embryonic dorsal-ventral limb patterning functions during mouse digit tip regeneration.

The mouse digit tip regenerates following amputation. How the regenerate is patterned is unknown, but a long-standing hypothesis proposes developmental patterning mechanisms are re-used during regeneration. The digit tip bone exhibits dorsal-ventral (DV) polarity, so we focus on En1 and Lmx1b, two factors necessary for DV patterning during limb development. We investigate whether they are re-expressed during regeneration in a developmental-like pattern and whether they direct DV morphology of the regenerate. We find that both En1 and Lmx1b are expressed in the regenerating digit tip epithelium and mesenchyme, respectively, but without DV polarity. Conditional genetics and quantitative analysis of digit tip bone morphology determine that genetic deletion of En1 or Lmx1b in adult digit tip regeneration modestly reduces bone regeneration but does not affect DV patterning. Collectively, our data suggest that, while En1 and Lmx1b are re-expressed during mouse digit tip regeneration, they do not define the DV axis during regeneration.

Racket or Bat Sports: No Association With Thumb-Base Osteoarthritis.

CONTEXT: Repetitive joint use is a risk factor for osteoarthritis, which is a leading cause of disability. Sports requiring a racket or bat to perform repetitive high-velocity impacts may increase the risk of thumb-base osteoarthritis. However, this hypothesis remains untested. OBJECTIVE: To determine if a history of participation in racket or bat sports was associated with the prevalence of thumb-base osteoarthritis. DESIGN: Descriptive epidemiologic study. SETTING: Four US clinical sites associated with the Osteoarthritis Initiative. PATIENTS OR OTHER PARTICIPANTS: We recruited 2309 men and women from the community. Eligible participants had dominant-hand radiographic readings, hand symptom assessments, and historical physical activity survey data. MAIN OUTCOME MEASURE(S): A history of exposure to racket or bat sports (badminton, baseball or softball, racketball or squash, table tennis [or ping pong], tennis [doubles], or tennis [singles]) was based on self-reported recall data covering 3 age ranges (12-18, 19-34, and 35-49 years). Prevalent radiographic thumb-base osteoarthritis was defined as Kellgren-Lawrence grade >2 in the first carpometacarpal joint or scaphotrapezoidal joint at the Osteoarthritis Initiative baseline visit. Symptomatic thumb-base osteoarthritis was defined as radiographic osteoarthritis and hand or finger symptoms. RESULTS: Radiographic or symptomatic thumb-base osteoarthritis was present in 355 (34%) and 56 (5%), respectively, of men (total = 1049) and 535 (42%) and 170 (13%), respectively, of women (total = 1260). After adjusting for age, race, and education level, we found no significant associations between a history of any racket or bat sport participation and thumb-base osteoarthritis (radiographic or symptomatic; odds ratios ranged from 0.82 to 1.34). CONCLUSIONS: In a community-based cohort, a self-reported history of participation in racket or bat sports was not associated with increased odds of having radiographic or symptomatic thumb-base osteoarthritis in the dominant hand.

Cartilage Topography Assessment With Local-Area Cartilage Segmentation for Knee Magnetic Resonance Imaging.

OBJECTIVE: Local-area cartilage segmentation (LACS) software was developed to segment medial femur (MF) cartilage on magnetic resonance imaging (MRI). Our objectives were 1) to extend LACS to the lateral femur (LF), medial tibia (MT), and lateral tibia (LT), 2) to compare LACS to an established manual segmentation method, and 3) to visualize cartilage responsiveness over each cartilage plate. METHODS: Osteoarthritis Initiative participants with symptomatic knee osteoarthritis (OA) were selected, including knees selected at random (n = 40) and knees identified with loss of cartilage based on manual segmentation (Chondrometrics GmbH), an enriched sample of 126 knees. LACS was used to segment cartilage in the MF, LF, MT, and LT on sagittal 3D double-echo steady-state MRI scans at baseline and at 2-year follow-up. We compared LACS and Chondrometrics average thickness measures by estimating the correlation in each cartilage plate and estimating the standardized response mean (SRM) for 2-year cartilage change. We illustrated cartilage loss topographically with SRM heatmaps. RESULTS: The estimated correlation between LACS and Chondrometrics measures was r = 0.91 (95% confidence interval [95% CI] 0.86, 0.94) for LF, r = 0.93 (95% CI 0.89, 0.95) for MF, r = 0.97 (95% CI 0.96, 0.98) for LT, and r = 0.87 (95% CI 0.81, 0.91) for MT. Estimated SRMs for LACS and Chondrometrics measures were similar in the random sample, and SRM heatmaps identified subregions of LACS-measured cartilage loss. CONCLUSION: LACS cartilage thickness measurement in the MF and LF and tibia correlated well with established manual segmentation-based measurement, with similar responsiveness to change, among knees with symptomatic knee OA. LACS measurement of cartilage plate topography enables spatiotemporal analysis of cartilage loss in future knee OA studies.

Associations Between Baseline and Longitudinal Semiautomated Quantitative Joint Space Width at the Hip and Incident Hip Osteoarthritis: Data From a Community-Based Cohort.

OBJECTIVE: To evaluate quantitative joint space width (JSW) at 10-, 30-, and 50-degree locations in relation to incident radiographic and symptomatic hip osteoarthritis (HOA) in a community-based cohort. METHODS: Data were from Johnston County OA Project participants with supine hip radiographs at each of 4 time points; all had Kellgren/Lawrence (K/L) grades and quantitative JSW. We assessed covariates (age, race, height, weight, body mass index [BMI]) associated with quantitative JSW and hip-level associations between quantitative JSW and HOA over time using sex-stratified and multivariable-adjusted linear mixed models. A cluster analysis with logistic regression estimated associations between quantitative JSW trajectory groups and incident radiographic HOA and symptomatic HOA. RESULTS: At baseline, 397 participants (784 hips, 41% men, 24% Black, mean age 57 years) had a mean BMI of 29 kg/m2 . Over a mean of 18 years, 20% and 12% developed incident K/L grade-defined radiographic HOA or symptomatic HOA, respectively. Quantitative JSW was more sensitive to changes over time at 50 degrees. Values were stable among men but declined over time in women. Heavier women lost more quantitative JSW; changes in quantitative JSW were not significantly associated with race, education, or injury in women or men. In women only, loss of quantitative JSW over time was associated with 2-3 times higher odds of radiographic HOA and symptomatic HOA; among women and men, narrower baseline quantitative JSW was associated with these outcomes. CONCLUSION: Hip quantitative JSW demonstrates marked differences in respect to sex, with significant loss over time only in women. Loss of quantitative JSW over time in women and narrower baseline quantitative JSW in men and women were associated with incident radiographic HOA and symptomatic HOA.

Erosive Hand Osteoarthritis: Incidence and Predictive Characteristics Among Participants in the Osteoarthritis Initiative.

OBJECTIVE: To evaluate age, sex, race, osteoarthritis (OA) severity, metabolic factors, and bone health as risk factors for erosive hand OA at baseline and its incidence over a 48-month period. METHODS: This was a longitudinal cohort study that included participants from the Osteoarthritis Initiative (OAI) with complete hand radiographs from baseline and 48-month visits who were eligible at baseline for incident erosive hand OA (i.e., had or were at risk for knee OA [criterion for OAI inclusion] and did not currently have erosive hand OA). Individuals were classified as having erosive hand OA if the Kellgren/Lawrence (K/L) grade was ≥2 in at least 1 interphalangeal joint on 2 different fingers and central erosion was present in at least 1 joint. RESULTS: Of the 3,365 individuals without prevalent erosive hand OA at baseline, 86 (2.6%) developed erosive hand OA during the 48-month period. Risk factors included older age (relative risk [RR] per SD 1.63 [95% confidence interval 1.35-1.97]), female sex (RR 2.47 [95% confidence interval 1.52-4.02]), greater OA severity (sum K/L grade 13.9 versus 5.3; P < 0.001), and less cortical width (1.38 mm versus 1.52 mm; P < 0.001). After 48 months, subjects who had developed erosive hand OA were characterized by greater progression of radiographic OA (i.e., joint space narrowing, K/L grade progression [RR 1.35], and loss of cortical thickness [RR 1.23]), adjusted for age, sex, race, body mass index, and baseline OA severity (sum K/L grade). CONCLUSION: These findings demonstrate that erosive hand OA is more common in older women and is strongly associated with severity of articular structural damage and its progression. Individuals who develop erosive hand OA have thinner bones prior to erosive hand OA development and as it progresses, suggesting that erosive hand OA is a disorder of skeletal frailty.

Bone Structure Analysis of the Radius Using Ultrahigh Field (7T) MRI: Relevance of Technical Parameters and Comparison with 3T MRI and Radiography.

Bone fractal signature analysis (FSA-also termed bone texture analysis) is a tool that assesses structural changes that may relate to clinical outcomes and functions. Our aim was to compare bone texture analysis of the distal radius in patients and volunteers using radiography and 3T and 7T magnetic resonance imaging (MRI)-a patient group (n = 25) and a volunteer group (n = 25) were included. Participants in the patient group had a history of chronic wrist pain with suspected or confirmed osteoarthritis and/or ligament instability. All participants had 3T and 7T MRI including T1-weighted turbo spin echo (TSE) sequences. The 7T MRI examination included an additional high-resolution (HR) T1 TSE sequence. Radiographs of the wrist were acquired for the patient group. When comparing patients and volunteers (unadjusted for gender and age), we found a statistically significant difference of horizontal and vertical fractal dimensions (FDs) using 7T T1 TSE-HR images in low-resolution mode (horizontal: p = 0.04, vertical: p = 0.01). When comparing radiography to the different MRI sequences, we found a statistically significant difference for low- and high-resolution horizontal FDs between radiography and 3T T1 TSE and 7T T1 TSE-HR. Vertical FDs were significantly different only between radiographs and 3T T1 TSE in the high-resolution mode; FSA measures obtained from 3T and 7T MRI are highly dependent on the sequence and reconstruction resolution used, and thus are not easily comparable between MRI systems and applied sequences.

Association of quantitative measures of effusion-synovitis and hoffa-synovitis with radiographic and pain progression: Data from the FNIH OA biomarkers consortium.

Objective: To validate a semi-automated software method of quantifying knee osteoarthritis (KOA) related effusion-synovitis (ES) and Hoffa-synovitis (HS) on MRI. Materials and methods: 301 subjects were randomly selected from the FNIH sub cohort, a nested case control study within the Osteoarthritis Initiative (OAI), and distributed into 4 groups based on pain and radiographic progression. Measurements of ES and HS volume were made by 2 readers. Criterion validation was assessed through comparison with the MRI Osteoarthritis Knee Score (MOAKS) and the Spearman correlation coefficient r value. Reader reliability was measured on a subset of 30 subjects and intra-class correlation coefficients (ICCs). Clinical validity was assessed based on case control status using logistic regression and the area under the curve (AUC). Results: ES volume was highly correlated with MOAKS Scores (r â€‹= â€‹0.74), as was the HS measure but to a lesser extent (r â€‹= â€‹0.55). For ES, the intra-reader and intra-reader precision ICCs were 0.83 and 0.95 respectively and 0.98 and 0.96 for HS. For clinical validity, we found similar AUC values when comparing the software method to MOAKS. The average reader time was less than 15 â€‹min per knee for both ES and HS. Conclusion: We have demonstrated the validity of an efficient, accurate, and rapid ES and HS measurement method for KOA using MRI. To our knowledge, this is the first such software to measure both ES and HS. This method will offer an objective and efficient tool for clinical trials and other epidemiologic studies of KOA.

Unique and non-redundant function of csf1r paralogues in regulation and evolution of post-embryonic development of the zebrafish.

Evolution is replete with reuse of genes in different contexts, leading to multifunctional roles of signaling factors during development. Here, we explore osteoclast regulation during skeletal development through analysis of colony-stimulating factor 1 receptor (csf1r) function in the zebrafish. A primary role of Csf1r signaling is to regulate the proliferation, differentiation and function of myelomonocytic cells, including osteoclasts. We demonstrate the retention of two functional paralogues of csf1r in zebrafish. Mutant analysis indicates that the paralogues have shared, non-redundant roles in regulating osteoclast activity during the formation of the adult skeleton. csf1ra, however, has adopted unique roles in pigment cell patterning not seen in the second paralogue. We identify a unique noncoding element within csf1ra of fishes that is sufficient for controlling gene expression in pigment cells during development. As a role for Csf1r signaling in pigmentation is not observed in mammals or birds, it is likely that the overlapping roles of the two paralogues released functional constraints on csf1ra, allowing the signaling capacity of Csf1r to serve a novel function in the evolution of pigment pattern in fishes.

Knee osteoarthritis risk in non-industrial societies undergoing an energy balance transition: evidence from the indigenous Tarahumara of Mexico.

Non-industrial societies with low energy balance levels are expected to be less vulnerable than industrial societies to diseases associated with obesity including knee osteoarthritis. However, as non-industrial societies undergo rapid lifestyle changes that promote positive energy balance, individuals whose metabolisms are adapted to energetic scarcity are encountering greater energy abundance, increasing their propensity to accumulate abdominal adipose tissue and thus potentially their sensitivity to obesity-related diseases. OBJECTIVES: Here, we propose that knee osteoarthritis is one such disease for which susceptibility is amplified by this energy balance transition. METHODS: Support for our hypothesis comes from comparisons of knee radiographs, knee pain and anthropometry among men aged ≥40 years in two populations: Tarahumara subsistence farmers in Mexico undergoing the energy balance transition and urban Americans from Framingham, Massachusetts. RESULTS: We show that despite having markedly lower obesity levels than the Americans, the Tarahumara appear predisposed to accrue greater abdominal adiposity (ie, larger abdomens) for a given body weight, and are more vulnerable to radiographic and symptomatic knee osteoarthritis at lower levels of body mass index. Also, proportionate increases in abdomen size in the two groups are associated with greater increases in radiographic knee osteoarthritis risk among the Tarahumara than the Americans, implying that the abdominal adipose tissue of the Tarahumara is a more potent stimulus for knee degeneration. CONCLUSIONS: Heightened vulnerability to knee osteoarthritis among non-industrial societies experiencing rapid lifestyle changes is a concern that warrants further investigation since such groups represent a large but understudied fraction of the global population.