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Background: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. Methods: The plasma proteome was evaluated using an aptamer‐based affinity proteomics platform (SOMAscan®), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. Results: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under‐explored. Conclusion: This investigational study evaluating the plasma proteome in clinically‐phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups. [ABSTRACT FROM AUTHOR]

Objective Recent findings suggest that β-adrenergic blockers have antinociceptive properties. The aim of this study was to compare levels of large-joint pain between those taking adrenergic blockers and those taking other antihypertensive medications. Methods Data from the Genetics of Osteoarthritis and Lifestyle (GOAL) study, a secondary-care cohort of osteoarthritis (OA) patients, were used. Joint pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores in 873 individuals with symptomatic hip and/or knee OA and hypertension, who were taking ≥1 prescription antihypertensive medications. The association between adrenergic blocker prescription and at least moderate joint pain (WOMAC score <75) and use of prescription analgesics was examined using binary logistic regression. Analyses were adjusted for age, sex, body mass index, knee or hip OA, history of joint replacement (at other joints), anxiety, and depression. Results The use of β-adrenergic blockers was associated with lower WOMAC pain scores and with a lower prevalence of joint pain after adjustment for demographic variables and comorbidity (adjusted odds ratio [ORadj] for pain 0.68 [95% confidence interval (95% CI) 0.51, 0.92]; P < 0.011). No associations with pain were observed with use of alpha-blockers (ORadj for pain 0.94 [95% CI 0.55, 1.58]) or with any other class of antihypertensive medications. Prescription of beta-blockers was also associated negatively with opioid use (ORadj for opioids 0.73 [95% CI 0.54, 0.98]; P < 0.037) and with the use of prescription analgesics in general (ORadj for analgesics 0.74 [95% CI 0.56, 0.94]; P < 0.032). Conclusion The use of beta-blockers is associated with less joint pain and a lower use of opioids and other analgesics in individuals with symptomatic large-joint OA. This observation needs to be confirmed by other studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To determine the distribution of clinically palpable hand interphalangeal (IP) nodes at each finger and thumb joint in a population with nodes, the influence of left or right hand dominance and sex on the development of nodes, and the association between nodes and underlying radiographic features of osteoarthritis (OA). Methods We performed a cross-sectional analysis of participants in the Genetics of Osteoarthritis and Lifestyle (GOAL) study who had ≥1 Heberden's nodes or Bouchard's nodes on clinical examination. Frequencies (%) of nodes were described for each IP joint in the hand. Associations between nodes and underlying radiographic OA were shown with odds ratios (ORs) and 95% confidence intervals. A logistic regression model was used to adjust for the following confounding factors: age, sex, body mass index, left or right hand dominance, hand trauma, occupation with heavy manual activity, and participation in sports. Results Of the 3,170 GOAL participants, 1,939 had ≥1 nodes (mean age 68 years, 54% women). The distal IP joints of the index finger were the most frequently affected, followed by the thumb IP joint. Nodes were more common in dominant hands and women. There was a significant association between nodes and underlying radiographic OA (OR range 2.26-21.23). This association was stronger for joint space narrowing than for osteophytes. A dose-response relationship was found between clinical severity of Heberden's nodes and underlying radiographic change. Conclusion Our study supports the positive association between nodes and radiographic OA, especially narrowing, and the influence of sex and left or right hand dominance on development of nodes. In this age group, presence of nodes may be taken as an indication of underlying small joint OA. [ABSTRACT FROM AUTHOR]

Objectives: To determine cross-sectionally the influence of risk factors on chronic pain following total joint replacement (TJR) of the knee (TKR) or the hip (THR). Methods: Eight hundred sixty post-TKR and 928 post-THR patients were studied. Western Ontario and McMaster Osteoarthritis Index pain scores taken on average 3.2 years postsurgery were correlated to preoperative radiographic severity measured by Kellgren-Lawrence grade (K/L) grade for the knee, Croft grade, and minimum joint space width (minJSW) for the hip and presence of comorbidities. Results: Known risk factors were able to explain less than 20% of the variance in pain scores post-TJR. The presence of chronic widespread pain determined a higher risk of high pain in both TKR cases (odds ratio (OR) = 3.15 95%CI 1.86-5.30) and THR cases (OR = 5.02 95%CI 2.76-9.14). Other risk factors common to both TKR and THR pain postsurgery were the presence of depression, higher body mass index, younger age, and female gender. Interestingly, low radiographic grade at the index joint presurgery (defined as tibiofemoral K/L <3 for the knee and minJSW >2 mm for the hip) resulted in a significantly increased risk of high pain post-TJR (OR = 1.56; 95%CI 1.04-2.36). Conclusions: The risk factors contributing to chronic pain post-TJR remain mostly unknown. Individuals with lower preoperative radiographic OA severity undergoing TJR are more likely to experience high pain post-TJR. [Copyright &y& Elsevier]

Objective To determine if self-reported current and early adult life knee malalignment is associated with knee chondrocalcinosis (CC). Methods A case-control study embedded in the Genetics of Osteoarthritis and Lifestyle (GOAL) study was performed. A validated self-reported line-drawing instrument was mailed to 3,022 participants of GOAL, inquiring about knee malalignment (straight, valgus, varus) in their third decade (20s) and currently. Self-reported weight in 20s and present weight and height measured at the initial visit were used to calculate body mass index (BMI) in 20s and currently. Occupational risk was present if participants self-reported mechanically demanding activities in their longest held job. Cases were participants with radiographic CC at any tibiofemoral (TF) joints. Osteoarthritis was defined as a Kellgren/Lawrence score of ≥3 at TF joints or patellofemoral joints. Odds ratio (OR), adjusted OR, and 95% confidence interval (95% CI) were calculated for associations with knee CC. Results A total of 2,167 participants responded to the questionnaire, of which 7.5% respondents had knee CC. Knee CC was associated with self-reported varus (adjusted OR 1.77 [95% CI 1.05, 2.98]) and any knee malalignment in 20s (adjusted OR 1.64 [95% CI 1.02, 2.64]). This association was not restricted to the mechanically loaded TF compartment. There was no association between current knee malalignment and knee CC. Age (adjusted OR 1.73 [95% CI 1.36, 2.19]) and knee OA (adjusted OR 2.88 [95% CI 1.89, 4.38]) were associated with knee CC. There was no association between BMI in 20s (adjusted OR 1.14 [95% CI 0.92, 1.42]), occupational risk (adjusted OR 1.32 [95% CI 0.94, 1.85]), and knee CC. Conclusion Early life knee malalignment, predominantly varus, is an independent risk factor for knee CC. This association is not restricted to the mechanically loaded compartment, implying a generalized predisposition throughout the knee. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR) = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the metaanalysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals. [ABSTRACT FROM AUTHOR]

Objective: To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel Na(V)1.7.Methods: Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes.Results: No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of β = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses.Conclusion: We find evidence that the R1150W amino acid change in the Na(V)1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain. [ABSTRACT FROM AUTHOR]

Objective To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel NaV1.7. Methods Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes. Results No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of β = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses. Conclusion We find evidence that the R1150W amino acid change in the NaV1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is emerging as the method of choice for measuring cartilage loss in osteoarthritis (OA), but current methods of analysis are imperfect for therapeutic clinical trials. In this paper, we present and evaluate, in two multicenter multivendor studies, a new method for anatomically corresponded regional analysis of cartilage (ACRAC) that allows analysis of knee cartilage morphology in anatomically corresponding focal regions defined on the bone surface. In our first study, 3-D knee MR Images were obtained from 19 asymptomatic female volunteers, followed by segmentations of the bone and cartilage. Minimum description length (MDL) statistical shape models (SSMs) were constructed from the segmented bone surfaces, providing mean bone shapes and a dense set of anatomically corresponding positions on each individual bone, the accuracy of which were measured using repeat images from a subset of the volunteers. Cartilage thicknesses were measured at these locations along 3-D normals to the bone surfaces, yielding corresponded cartilage thickness maps. Functional subregions of the joint were defined on the mean bone shapes, and propagated, using the correspondences, to each individual. ACRAC improved reproducibility, particularly in the central, load bearing subregions of the joint, compared with measures of volume obtained directly from the segmented cartilage surfaces. In our second study, MR Images were obtained from 31 female patient-volunteers with knee OA at baseline and six months. We obtained manual segmentations of the cartilage, and automatic segmentations of the bone using active appearance models (AAMs) built from the bone SSMs of the first study. ACRAC enabled the detection of significant thickness loss in the central, load-bearing regions of the whole femur (-5.57% p = 0.01, annualized) and the medial condyle (-13.08%, p = 0.024 Bonferroni corrected, annualized). We conclude that statistical shape modelling of bone surfaces defines correspondences invariant to individual joint size or shape, providing focal measures of cartilage with improved reproducibility compared to whole compartment measures. It permits the identification of anatomically equivalent regions, and provides the ability to identify the main load-bearing regions of the joint, based on the imputed premorbid state. The method permitted detection of tiny morphological change in cartilage thickness over six months in a small study, and may be useful for OA disease analysis and treatment monitoring. [ABSTRACT FROM AUTHOR]

Objective: Recent findings suggest that β-adrenergic blockers have antinociceptive properties. The aim of this study was to compare levels of large-joint pain between those taking adrenergic blockers and those taking other antihypertensive medications.Methods: Data from the Genetics of Osteoarthritis and Lifestyle (GOAL) study, a secondary-care cohort of osteoarthritis (OA) patients, were used. Joint pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores in 873 individuals with symptomatic hip and/or knee OA and hypertension, who were taking ≥1 prescription antihypertensive medications. The association between adrenergic blocker prescription and at least moderate joint pain (WOMAC score <75) and use of prescription analgesics was examined using binary logistic regression. Analyses were adjusted for age, sex, body mass index, knee or hip OA, history of joint replacement (at other joints), anxiety, and depression.Results: The use of β-adrenergic blockers was associated with lower WOMAC pain scores and with a lower prevalence of joint pain after adjustment for demographic variables and comorbidity (adjusted odds ratio [ORadj ] for pain 0.68 [95% confidence interval (95% CI) 0.51, 0.92]; P < 0.011). No associations with pain were observed with use of alpha-blockers (ORadj for pain 0.94 [95% CI 0.55, 1.58]) or with any other class of antihypertensive medications. Prescription of beta-blockers was also associated negatively with opioid use (ORadj for opioids 0.73 [95% CI 0.54, 0.98]; P < 0.037) and with the use of prescription analgesics in general (ORadj for analgesics 0.74 [95% CI 0.56, 0.94]; P < 0.032).Conclusion: The use of beta-blockers is associated with less joint pain and a lower use of opioids and other analgesics in individuals with symptomatic large-joint OA. This observation needs to be confirmed by other studies. [ABSTRACT FROM AUTHOR]

Background: Biomechanical factors may play a role in osteoarthritis (OA) development and progression. Previous biomechanical studies have indicated that types of footwear may modulate forces across the knee joint, and high heeled womens' shoes in particular are hypothesised to be detrimental to lower limb joint health. This analysis of data from a case control study investigated persistent users of different adult footwear for risks of knee and hip OA. Our underlying hypotheses were that high heeled, narrow heeled, and hard soled shoe types were putative risk factors for lower limb OA.Methods: Data on footwear were initially obtained from participants during the Genetics of Osteoarthritis and Lifestyle (GOAL) hospital-based, case control study using standardised interview-delivered questionnaires. An additional questionnaire was later sent to GOAL study participants to verify findings and to further investigate specific shoe use per decade of life. Persistent users of footwear types (high or narrow heel; sole thickness or hardness) were identified from early adulthood. Participants were grouped into single sex knee OA, hip OA or control groups. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were calculated.Results: Univariate analysis of persistent users of women's high heeled and narrow heeled shoes during early adulthood showed negative associations with knee OA and hip OA. After logistic regression, persistent narrow heel users were associated with less risk of OA (knee OA aOR 0.59, 95% CI 0.35 - 1.00 and hip aOR: 0.50, 95% CI 0.30 - 0.85), and other analyses were not statistically significant. Further analysis suggested that women with hip OA may have stopped wearing high and narrow heeled footwear to attenuate hip pain in early adulthood. Consistent associations between shoe soles and OA were not found.Conclusions: In general, persistent users of high and narrow heeled shoes during early adulthood had a negative association with knee or hip OA. This does not necessarily imply a causal relationship, as changing footwear during early adulthood to modulate index joint pain may provide a possible explanation. Despite the findings of previous biomechanical studies of high heels, we did not find a positive association between women's shoes and lower limb osteoarthritis. [ABSTRACT FROM AUTHOR]

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes. [ABSTRACT FROM AUTHOR]

Abstract: Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug. [Copyright &y& Elsevier]

Tumor necrosis factor (TNF) α-converting enzyme (TACE/ADAM-17) has diverse roles in the proteolytic processing of cell surface molecules and, due to its ability to process TNFα is a validated therapeutic target for anti-inflammatory therapies. Unlike a number of other ADAM proteins, which interact with integrin receptors via their disintegrin domains, there is currently no evidence for an ADAM-17-integrin association. By analyzing the adhesion of a series of cell lines with recombinant fragments of the extracellular domain of ADAM-17, we now demonstrate a functional interaction between ADAM-17 and α5β3 integrin in a trans orientation. Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/ cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the α5β1 ligand binding pocket. Intriguingly, ADAM-17 and α5β1 were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. When confluent HeLa cell monolayers were wounded, ADAM-17 and α5β1 redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. We postulate that the interaction of ADAM-17 with α5β1 may target or modulate its metalloproteolytic activity. [ABSTRACT FROM AUTHOR]