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In radiotherapy centers, there are various types of treatment machines for treating patients. Different machines have their respective treatment planning systems (TPS) but without interchangeability between the systems. Raystation TPS includes a function of fallback planning, providing an alternative way to solve the machine breakdown situation. The fallback planning system enables to generate plans of different radiotherapy techniques and treatment machines. The aim of this study is to demonstrate the feasibility and effectiveness of the fallback planning system in producing plans of two different L-shape linear accelerators (LINACs) using the volumetric modulated arc radiation therapy (VMAT) in prostate cancer. 30 patients with localized prostate cancers who treated with VMAT were recruited. By using the Raystation fallback planning system, plans of the Varian LINAC were converted to plans of the Elekta LINAC. Dosimetric metrics in terms of the targets, organs at risk (OARs) and the monitor units (MU) were compared between the two VMAT plans. The dose coverage, homogeneity, and conformity of the targets in the converted Elekta plans were commonly inferior to the Varian plans. The rectum and bladder received higher dose in the Elekta VMAT plans, mean dose of the penile bulb, normal tissues and MU were lower, and the doses of femoral heads were comparable between the two VMAT plans. All the converted Elekta VMAT plans were acceptable for treatment. The Raystation fallback planning was capable of producing backup plans under the circumstances of machine breakdown. [ABSTRACT FROM AUTHOR]

Purpose: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA., Methods: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race., Results: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration., Conclusions: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors., Methods: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors., Results: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects., Conclusion: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Osteoarthritis (OA) is highly heterogeneous and has both biomechanical and systemic components that may not have the same etiology. We therefore aimed to identify specific knee OA phenotypes that may be more strongly associated with hand OA to refine the criteria used to define multi-joint OA., Design: We assessed data from the Multicenter Osteoarthritis Study (MOST). We ascertained hand OA from bilateral hand photographs; scores for each joint row were summed to yield an aggregate hand OA score. Knee OA was ascertained from bilateral posteroanterior knee radiographs read for Kellgren-Lawrence grade and individual radiographic features. We tested associations between hand and knee OA with phenotypes including symptomatic OA, hyper- and atrophic knee OA, and one excluding post-traumatic OA. Associations between hand and knee OA were assessed with logistic regression, adjusted for age., Results: We studied 2493 participants with hand and knee OA measures. Median age was 63 years with 57% women. 55% had an aggregate hand OA score ≥2; frequency of knee OA phenotypes ranged from 8% to 34%. The age-adjusted odds ratio (OR) was 1.14 (95% confidence interval (CI) ​= ​1.04-1.26) for knee OA per standard deviation of the hand OA aggregate score. Hand OA associations with symptomatic knee OA and knee OA excluding post-traumatic knee OA were OR ​= ​1.16 (95% CI ​= ​1.03-1.31) and OR ​= ​1.21 (95% CI ​= ​1.08-1.35), respectively. No other knee OA phenotype reached statistical significance., Conclusions: Age-adjusted associations between hand and knee OA were modest and were largely similar across knee OA phenotypes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Purpose: To facilitate studies of knee osteoarthritis (OA) in large databases, case finding algorithms with high levels of diagnostic performance are needed., Methods: From a UK general practitioner (GP) practice derived database, we selected adults ages 40-90 years meeting algorithms that included various combinations of codes for knee OA or knee pain and imaging. The GP for each patient was mailed a questionnaire to assess the cause of knee pain and provide knee x-ray and/or MRI findings. We considered knee pain with x-ray and/or MRI findings consistent with OA the gold standard. We calculated positive predictive values (PPV) and sensitivity for case identification algorithms., Results: Of 100 questionnaires sent, 93 were returned; we excluded 8 subjects who had other rheumatic disorders or total knee replacements. Among those with one code for OA, the PPV was 64% (95% CI = 49%-79%) and it increased to 92% (95% CI = 76%-100%) when two or more OA codes over six months were required. The increase in PPV was accompanied by a drop in sensitivity from 44% (95% CI = 31%-57%) to 19% (95% CI = 9%-30%). Use of one pain code yielded similar results to use of one OA code. Requiring two or more knee pain codes over six months yielded a PPV of 68% (95% CI = 49%-88%) and sensitivity of 26% (95% CI = 15%-38%)., Discussion: A case identification algorithm requiring two or more knee OA codes yielded the highest PPV at the cost of reduced sensitivity. Tradeoffs between PPV and sensitivity will need to be weighed alongside study goals when selecting a case identification algorithm., Competing Interests: Declaration of competing interest The authors have no relevant conflicts of interest to disclose.

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I 2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10 -4 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10 -4 ) and 7q31 (WNT16, p = 2.96 × 10 -5 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10 -4 ), 11q14 (DCDC5, p < 5.35 × 10 -5 ), and 17p13 (SMG6, p < 6.78 × 10 -5 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10 -2 ), MBL2 (p = 4.09 × 10 -2 ), MEPE (p = 3.15 × 10 -2 ), SLC25A13 (p = 3.03 × 10 -2 ), STARD3NL (p = 3.35 × 10 -2 ), and TNFRSF11A (p = 3.18 × 10 -3 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Background: Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology., Methods: We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees., Results: We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa , RUNX2 , COL27A1 , ASTN2 , IL11 and GDF5 loci., Conclusions: We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Osteoarthritis (OA) disease progression may lead to deteriorating psychosocial function, but it is unclear what aspects of disease severity are related to the onset of depression. This study assessed which components of OA disease progression cumulatively contribute to depression onset in persons with radiographic knee OA., Methods: Osteoarthritis Initiative participants (n = 1651) with radiographic disease (Kellgren-Lawrence grade ≥2) in one or both knees and below the screening threshold for probable depression [Center for Epidemiological Studies Depression (CES-D) scale <16] at baseline were included. Disease severity was measured from baseline to the third annual follow-up visit using joint space width, 20-meter gait speed, and the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale, each categorized into quintiles. Depression onset (CES-D ≥ 16) was assessed annually at four follow-up visits. Marginal structural models that account for time-dependent confounding and attrition evaluated the association between each time-varying disease severity measure and depression onset., Results: Each disease severity measure exhibited a non-linear relationship concerning the probability of depression onset, with the higher quintiles generally being associated with a larger risk. The highest quintile (relative to the lowest) of joint space width and gait speed were both significantly associated with depression onset. By contrast, none of the higher pain quintiles compared with the lowest were significantly associated with the onset of depression., Conclusion: Faster disease progression as measured by either worsening structural severity or decreasing physical performance corresponds to an increased risk of depression among individuals with radiographic knee OA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The present study was undertaken to identify depression subtypes in individuals with or at risk for symptomatic knee osteoarthritis (OA) and to evaluate differences in pain and disability trajectories between groups., Methods: Participants (n = 4,486) were enrolled in the Osteoarthritis Initiative. Latent class analysis was applied to the 20-item Center for Epidemiologic Studies Depression Scale measured at baseline to identify groups with similar patterns of depressive symptoms, and subtypes were assigned using posterior probability estimates. The relationships between depression subtypes and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and disability subscales were modeled over 4 years and stratified by baseline knee OA status (symptomatic [n = 1,626] or at risk [n = 2,860])., Results: Four subtypes were identified: asymptomatic (80.6%), catatonic (5.3%), anhedonic (10.6%), and melancholic (3.5%). Catatonic and anhedonic subtypes were differentiated by symptoms corresponding to psychomotor agitation and the inability to experience pleasure, respectively. The melancholic subtype expressed symptoms related to reduced energy and movement, anhedonia, and other somatic symptoms. Detectable mean differences in pain and disability compared to the asymptomatic group were observed for the anhedonic (1.5-2.3 WOMAC units) and melancholic (4.8-6.6 WOMAC units) subtypes, and associations were generally larger in individuals with symptomatic knee OA relative to those at risk., Conclusion: Among individuals with or at risk for symptomatic knee OA, there is evidence of depression subtypes characterized by distinct clusters of depressive symptoms that have differential effects on reports of pain and disability over time. Our findings thus imply that depression interventions could be optimized by targeting the specific symptomology that these subtypes exhibit., (© 2019, American College of Rheumatology.)

Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 ( P  = 1.32 × 10 -12 ), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 ( P  = 1.49 × 10 -8 ). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain., Competing Interests: Competing interestsJ.S., A.A. and members of the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. Other authors declare no competing interests.

A strategy to construct multivariate biomarkers for exposure to algal neurotoxins via correlating changes to the profiles of a series of neurotransmitters and their metabolites in the central nervous system (CNS) of exposed test organism is reported. 3-Month-old marine medaka (Oryzais melastigma) were exposed to waterborne brevetoxin PbTx-1 at two sub-lethal dose levels (0.5 and 2.5 μg-PbTx-1 L -1 ) for a duration of 12 h before quantification of 43 selected neurotransmitters and metabolites in their CNS were measured via dansyl chloride derivatization and LC-MS/MS determination. The profiling data were analyzed by multivariate statistical analyses, including principle component analysis (PCA), projection on latent structure-discriminate analysis (PLS-DA) and orthogonal projection on latent structure-discriminate analysis (OPLS-DA). Neurotransmitters and metabolites related to activation of voltage-gated sodium channels (VGSCs), N-methyl-D-aspartic acid receptors (NMDARs) and cholinergic neurotransmission were found to contribute significantly to class separation in the corresponding OPLS-DA models. Those models obtained from different exposure dosages were correlated by the Shared and Unique Structures Plot (SUS-plot) to identify appropriate variables for the construction of exposure biomarkers in the form of multivariate predictive scores. The established biomarkers for male and female medaka fish were able to predict acute sub-lethal exposure to PbTx-1 with good sensitivity and specificity (male fish: sensitivity 94.7%, specificity 80.0%; female fish: sensitivity 91.4%, specificity 83.3%). Neurotransmitter profiles in the CNS of medaka fish that should have recovered from exposure to PbTx-1 have also been determined to reveal long-term impacts to the CNS of the affected organism even after the exposure has been interrupted., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Depressive symptoms in knee osteoarthritis (OA) are associated with increased pain severity and declines in physical performance. This study examined whether pain severity mediates the association between depressive symptoms and physical performance in persons with radiographic knee OA., Method: Three years of annual data from participants (n = 1,463) with radiographic knee OA in the Osteoarthritis Initiative (OAI) were analyzed. Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D) scale. Pain severity was evaluated with the Western Ontario and McMaster Universities Arthritis Index. Physical performance was assessed via standardized gait speed. Marginal structural models were used to assess the direct (unmediated) effects of depressive symptoms on physical performance and indirect (mediated) effects through pain severity., Results: Direct and indirect effects for a difference in CES-D score of 0-1 were -0.0051 (95% confidence intervals (CI): -0.0053, -0.0049) and -0.0016 (95% CI: -0.0024, -0.0007) standard deviations in gait speed, respectively. Higher depressive symptom severity exhibited diminishing, incremental, direct and indirect effects and for a difference in CES-D score of 15-16 were -0.0045 (95% CI: -0.0047, -0.0042) and -0.0009 (95% CI: -0.0014, -0.0004) standard deviations in gait speed, respectively. Therefore, the magnitude of the mediated, indirect effect, was never larger than 24%., Conclusion: Pain severity mediated approximately one-fifth of the association between depressive symptoms and physical performance in persons with radiographic knee OA, and the diminishing incremental effects may explain why unimodal treatment strategies with a single disease target are often ineffective in depressed OA patients., (Published by Elsevier Ltd.)

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC)., Competing Interests: BMP serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; YSA and LK are founders and co-owners of PolyOmica, a private genomics research organization; these relationships do not pose known conflicts with the content of this work presented. We the authors do not have any other financial interests that could create a potential conflict or the appearance of a potential conflict of interest with regard to this work.

Objective: To estimate the dynamic causal effects of depressive symptoms on osteoarthritis (OA) knee pain., Methods: Marginal structural models were used to examine dynamic associations between depressive symptoms and pain over 48 months among older adults (n = 2,287) with radiographic knee OA (Kellgren/Lawrence grade 2 or 3) in the Osteoarthritis Initiative. Depressive symptoms at each annual visit were assessed (threshold ≥16) using the Center for Epidemiologic Studies Depression Scale. OA knee pain was measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, rescaled to range from 0 to 100., Results: Depressive symptoms at each visit were generally not associated with greater OA knee pain at subsequent time points. Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients ranged from 1.78 (95% confidence interval [95% CI] -0.73, 4.30) to 2.58 (95% CI 0.23, 4.93) within the first and fourth years, and the depressive symptoms by time interaction were not statistically significant (P = 0.94). However, there was a statistically significant dose-response relationship between the persistence of depressive symptoms and OA knee pain severity (P = 0.002). Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients were 0.89 (95% CI -0.17, 1.96) for 1 visit with depressive symptoms, 2.35 (95% CI 0.64, 4.06) for 2 visits with depressive symptoms, and 3.57 (95% CI 0.43, 6.71) for 3 visits with depressive symptoms., Conclusion: The causal effect of depressive symptoms on OA knee pain does not change over time, but pain severity significantly increases with the persistence of depressed mood., (© 2017, American College of Rheumatology.)

Objective: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism., Methods: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage., Results: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10 -10 ) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10 -9 ) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Beta meta =0.83, P meta =1.8*10 -15 ). This variant is high linkage disequilibrium with a coding variant in MGP , a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10 -16 )., Conclusions: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP , which may increase the burden of hand OA by decreased inhibition of cartilage calcification., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: The etiology of knee osteoarthritis (OA), the most common form of arthritis, is complex and may differ by race or ethnicity. In recent years, genetic studies have identified many genetic variants associated with OA, but nearly all the studies were conducted in European whites and Asian Americans. Few studies have focused on the genetics of knee OA in African Americans., Methods: We performed a genome-wide association study of radiographic knee OA in 1217 African Americans from 2 North American cohort studies: 590 subjects from the Johnston County Osteoarthritis Project and 627 subjects from the Osteoarthritis Initiative. Analyses were conducted in each cohort separately and combined in an inverse variance fixed effects metaanalysis, which were then included in pathway analyses. We additionally tested 12 single-nucleotide polymorphisms robustly associated with OA in European white populations for association in African Americans., Results: We identified a genome-wide significant variant in LINC01006 (minor allele frequency 12%; p = 4.11 × 10 -9 ) that is less common in European white populations (minor allele frequency < 3%). Five other independent loci reached suggestive significance (p < 1 × 10 -6 ). In pathway analyses, dorsal/ventral neural tube patterning and iron ion transport pathways were significantly associated with knee OA in African Americans (false discovery rate < 0.05). We found no evidence that previously reported OA susceptibility variants in European whites were associated with knee OA in African Americans., Conclusion: These results highlight differences in the genetic architecture of knee OA between African American and European whites. This finding underscores the need to include more diverse populations in OA genetics studies.

Bisphenol A (BPA) glucuronide and sulfate conjugates are major products of Phase II metabolism of BPA in humans. In the past, their determination in body fluids usually involves tedious enzymatic hydrolysis and multiresidual analysis. The recent availability of authentic standards of these conjugates enables our better understand of the human metabolism of BPA and the distribution of their metabolites in body fluids. In this work, we report the chemical synthesis and purification of BPA mono- and di-glucuronide and BPA mono- and di-sulfate. Their levels, as well as that of BPA, in 140 paired human plasma and urine samples collected randomly from voluntary donors in Hong Kong SAR, China, were determined by solid-phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS). BPA was found in more than 135 human plasma and urine samples. Its Phase II metabolites, ranging from N.D. to 36.7 µg g -1 -creatinine, also were detected in 139 of the 140 urine samples. Good correlation (r = 0.911) between molar concentration of BPA in the plasma and that of "total urinary BPA" (i.e., ln [(BPA + ∑ BPA phase II conjugate) molar concentration ]) was observed. Direct quantification of Phase II metabolites of BPA in human urine can be a useful assessment tool for population exposure to this potent endocrine disrupting chemical.

The simultaneous profiling of 43 functional metabolites in the brain of the small model vertebrate organism, marine medaka (Oryzais melastigma), has been accomplished via dansyl chloride derivatization and LC-MS/MS quantification. This technique was applied to examine effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), one of the most abundant polybrominated diphenyl ether flame retardants in the natural environment, on the central nervous system (CNS) of vertebrates. The model teleosts were fed with bioencapsulated Artemia nauplii for up to 21 days. Multivariate statistical analysis has demonstrated that levels of numerous classical neurotransmitters and their metabolites in the CNS of the fish were perturbed even at the early phase of dietary exposure. Subsequent metabolic pathway analysis further implied potential impairment of the arginine and proline metabolism; glycine, serine and threonine metabolism; D-glutamine and D-glutamate metabolism; alanine, aspartate, and glutamate metabolism; valine, leucine, and isoleucine biosynthesis, and the cysteine and methionine metabolism in the brain of the test organism. Our results demonstrate that targeted profiling of functional metabolites in the CNS may shed light on how the various neurological pathways of vertebrates, including humans, are affected by toxicant/stress exposure.

Objective: A major barrier to genetic studies of osteoarthritis (OA) is the need to obtain large numbers of individuals with standardized radiographic evaluations for OA. To address this gap, we performed a genome-wide association study (GWAS) of radiographically defined tibiofemoral knee OA in 3,898 cases and 3,168 controls from 4 well-characterized North American cohorts, and we performed replication analysis of previously reported OA loci., Methods: We performed meta-analysis using a 2-stage design. Stage 1 (discovery) consisted of a GWAS meta-analysis of radiographic knee OA carried out in the Osteoarthritis Initiative and the Johnston County Osteoarthritis Project. Knee OA was defined as definite osteophytes and possible joint space narrowing or total joint replacement in one or both knees. Stage 2 (validation) was performed in the Multicenter Osteoarthritis Study and the Genetics of Osteoarthritis study. We genotyped lead meta-analysis variants (P ≤ 1 × 10 -4 ) from stage 1 and tested the association between these variants and knee OA. We then combined results from all cohorts in a meta-analysis., Results: Lead variants from stage 1, representing 49 unique loci, were analyzed in stage 2; none met genome-wide significance in the combined analysis of stage 1 and stage 2. We validated 1 locus (rs4867568 near LSP1P3) with nominal significance (P < 0.05), which was also our top finding in the combined meta-analysis (odds ratio [OR] 0.84 [95% confidence interval (95% CI) 0.79-0.91], P = 3.02 × 10 -6 ). We observed nominally significant associations (P < 0.05) with 3 previously reported OA loci: rs143383 in GDF5 (OR 1.12 [95% CI 1.04-1.21], P = 2.13 × 10 -3 ), rs835487 in CHST11 (OR 0.93 [95% CI 0.85-0.99], P = 0.03), and rs8044769 in FTO (OR 1.10 [95% CI 1.03-1.19], P = 6.13 × 10 -3 )., Conclusion: These findings provide suggestive evidence of a novel knee OA locus and confirm previously reported associations in GDF5, CHST11, and FTO., Competing Interests: None of the authors has any relevant conflicts of interest to report., (© 2016, American College of Rheumatology.)

Depressive symptoms are associated with increases in pain and functional limitations in knee osteoarthritis (OA). The aim was to determine whether depressive symptoms are also associated with greater structural knee OA progression. Four years of annual radiographic and clinical assessments from the Osteoarthritis Initiative were analyzed. The Center for Epidemiological Studies Depression Scale was used to identify depressive symptoms (threshold = ≥16) at the baseline visit. Propensity scores were used to match participants with and without baseline depressive symptoms on multiple potential confounders. Assessment of radiographic knee OA was based on changes in individual radiographic features, which included osteophyte (OST) grade and joint space narrowing (JSN) grade. Mixed effect models were used to examine structural progression between depressed and non-depressed participants with definitive radiographic knee OA. Depressive symptoms were significantly associated with a higher risk of OST progression (odds ratio [OR] = 1.74; 95% confidence interval [CI]: 1.01, 3.00) and a non-significant lower risk of JSN progression (OR = 0.40; 95% CI: 0.14, 1.15) 1 year after baseline. Conversely, there was a non-significant lower risk of OST progression (OR = 0.71; 95% CI: 0.28, 1.79) and higher risk of JSN progression (OR = 1.89; 95% CI: 0.71, 5.06) from year 3 to year 4 of follow-up. However, the patterns of OST progression and JSN progression were not significantly different between the depressed and non-depressed (P = 0.25 and 0.15, respectively). The findings provide no evidence that depressive symptoms have a detectable effect on changes in radiographic disease severity in knee OA.

3,3',5,5'-Tetrabromobisphenol-A (TBBPA) is an important brominated flame retardant in epoxy, vinyl esters and polycarbonate resins. Previous studies have already shown the occurrence of its Phase II metabolites, TBBPA-glucuronide and sulfate conjugates, in human urine, after oral administration of TBBPA. The main objective of this work is to examine correlations among level of TBBPA in human blood and those of its Phase II metabolites in human urine. Four water-soluble TBBPA conjugates were synthesized, purified and characterized. An analytical protocol using solid-phase extraction and liquid chromatography-electrospray tandem mass spectrometry (SPE-LC-MS/MS) quantification was developed for the simultaneous analysis of these glucuronide and sulfate conjugates in human urine samples. TBBPA and its Phase II metabolites in paired human plasma and urine samples collected randomly from 140 voluntary donors in Hong Kong SAR, China, were determined. One or more TBBPA conjugates were detected in all of the urine samples, with concentration ranging from 0.19 to 127.24μgg -1 -creatinine. TBBPA was also quantified in >85% of the plasma and urine samples. Strong correlations were observed between TBBPA content in plasma and the total amount of TBBPA-related compounds in urine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co-occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T 4 -T 12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (ρˆ G , -0.46; 95% CI, -0.67 to -0.26), vertebral fracture (ρˆ G , 0.39; 95% CI, 0.18 to 0.61), vBMD (ρˆ G , -0.23; 95% CI, -0.41 to -0.04), and paraspinal muscle density (ρˆ G , -0.22; 95% CI, -0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (ρˆ G , 0.17; 95% CI, -0.05 to 0.38) and facet joint OA (ρˆ G , 0.05; 95% CI, -0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density. © 2016 American Society for Bone and Mineral Research., Competing Interests: All authors state that they have no conflicts of interest., (© 2016 American Society for Bone and Mineral Research.)

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies., Competing Interests: The collection of GOAL samples was funded by Astra Zeneca UK. Dr R. Maciewicz has ownership of stocks or shares in AstraZeneca and has paid employment in AstraZeneca. Dr J. Jordan was funded for genotyping by Algynomics, Inc. and had, but no longer has, stock options in Algynomics. Dr. U. Styrkarsdottir is an employee of deCODE, a biotechnology company that provides genetic testing services. The set-up of the GARP study was partially funded by Pfzer. The GoGo study was funded by GlaxoSmithKline. The rest of the authors have declared that they have no competing interests.

One possible source of urinary bromophenol (BP) glucuronide and sulfate conjugates in mammalian animal models and humans is polybromodiphenyl ethers (PBDEs), a group of additive flame-retardants found ubiquitously in the environment. In order to study the correlation between levels of PBDEs in human blood plasma and those of the corresponding BP-conjugates in human urine, concentrations of 17 BDE congeners, 22 OH-BDE and 13 MeO-BDE metabolites, and 3 BPs in plasma collected from 100 voluntary donors in Hong Kong were measured by gas chromatograph tandem mass spectrometry (GC-MS). Geometric mean concentration of ΣPBDEs, ΣOH-BDEs, ΣMeO-BDEs and ΣBPs in human plasma were 4.45 ng g(-1) lw, 1.88 ng g(-1) lw, 0.42 ng g(-1) lw and 1.59 ng g(-1) lw respectively. Concentrations of glucuronide and sulfate conjugates of 2,4-dibromophenol (2,4-DBP) and 2,4,6-tribromophenol (2,4,6-TBP) in paired samples of urine were determined by liquid chromatography tandem triple quadrupole mass spectrometry (LC-MS/MS). BP-conjugates were found in all of the parallel urine samples, in the range of 0.08-106.49 μg g(-1)-creatinine. Correlations among plasma concentrations of ΣPBDEs/ΣOH-BDEs/ΣMeO-BDEs/ΣBPs and BP-conjugates in urine were evaluated by multivariate regression and Pearson product correlation analyses. These urinary BP-conjugates were positively correlated with ΣPBDEs in blood plasma, but were either not or negatively correlated with other organobromine compounds in blood plasma. Stronger correlations (Pearson's r as great as 0.881) were observed between concentrations of BDE congeners having the same number and pattern of bromine substitution on their phenyl rings in blood plasma and their corresponding BP-conjugates in urine., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) risk is widely recognized to be heritable but few loci have been identified. Observational studies have identified higher systemic bone mineral density (BMD) to be associated with an increased risk of radiographic knee osteoarthritis. With this in mind, we sought to evaluate whether well-established genetic loci for variance in BMD are associated with risk for radiographic OA in the Osteoarthritis Initiative (OAI) and the Johnston County Osteoarthritis (JoCo) Project. Cases had at least one knee with definite radiographic OA, defined as the presence of definite osteophytes with or without joint space narrowing (Kellgren-Lawrence [KL] grade ≥ 2) and controls were absent for definite radiographic OA in both knees (KL grade ≤ 1 bilaterally). There were 2014 and 658 Caucasian cases, respectively, in the OAI and JoCo Studies, and 953 and 823 controls. Single nucleotide polymorphisms (SNPs) were identified for association analysis from the literature. Genotyping was carried out on Illumina 2.5M and 1M arrays in Genetic Components of Knee OA (GeCKO) and JoCo, respectively and imputation was done. Association analyses were carried out separately in each cohort with adjustments for age, body mass index (BMI), and sex, and then parameter estimates were combined across the two cohorts by meta-analysis. We identified four SNPs significantly associated with prevalent radiographic knee OA. The strongest signal (p = 0.0009; OR = 1.22; 95% CI, 1.08-1.37) maps to 12q3, which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5), and 11p14.1 (LIN7C). For all four loci the allele associated with higher BMD was associated with higher odds of OA. A BMD risk allele score was not significantly associated with OA risk. This meta-analysis demonstrates that several genomewide association studies (GWAS)-identified BMD SNPs are nominally associated with prevalent radiographic knee OA and further supports the hypothesis that BMD, or its determinants, may be a risk factor contributing to OA development. © 2014 American Society for Bone and Mineral Research., (© 2014 American Society for Bone and Mineral Research.)

The bioaccumulation and maternal transfer of 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47) were investigated in the marine medaka (Oryzias melastigma) following dietary exposure, in which PBDE 47 was bioencapsulated into brine shrimp (Artemia sp.) and fed daily to male-female pairs of medaka. In the accumulation experiment, each 2-month-old (pre-breeding) medaka were provided with dietary PBDE 47 at 1.3±0.2 μg/day for 21 days. Growth-corrected concentrations of PBDE 47 in the medaka increased over the 21 days of exposure and there were no significant differences between males and females at any of the sampling times. Final concentrations were similar for males and females after 21 days (230±30 and 250±30 μgg(-1) wet weight, respectively), accounting for 84-100% of the PBDE 47 provided in the diet. In the maternal transfer experiment, 3-month-old (breeding) medaka were provided with dietary PBDE 47 at 1.2±0.2 μg/day for 18 days, and reached body concentrations of 76±3 (males) and 61±6 (females)μgg(-1) wet weight. Female growth-corrected PBDE 47 concentrations were significantly lower than males by day 12 (P<0.05), and egg PBDE 47 concentrations were up to 25 ng/egg by day 18. Our results showed that maternal transfer is an important offloading mechanism for female fish. The fact that lipid normalized egg:female PBDE ratios did not significantly deviate from 1 further indicated that the maternal transfer of PBDE 47 is associated with lipid mobilization during egg production., (Copyright © 2011 Elsevier B.V. All rights reserved.)