Tenascin-C fragments are endogenous inducers of cartilage matrix degradation

Cartilage destruction is a hallmark of osteoarthritis (OA) and is characterized by increased protease activity resulting in the degradation of critical extracellular matrix (ECM) proteins essential for maintaining cartilage integrity. Tenascin-C (TN-C) is an ECM glycoprotein, and its expression is upregulated in OA cartilage. We aimed to investigate the presence of TN-C fragments in arthritic cartilage and establish whether they promote cartilage degradation. Expression of TN-C and its fragments was evaluated in cartilage from subjects undergoing joint replacement surgery for OA and RA compared with normal subjects by western blotting. The localization of TN-C in arthritic cartilage was also established by immunohistochemistry. Recombinant TN-C fragments were then tested to evaluate which regions of TN-C are responsible for cartilage-degrading activity in an ex vivo cartilage explant assay measuring glycosaminoglycan (GAG) release, aggrecanase and matrix metalloproteinase (MMP) activity. We found that specific TN-C fragments are highly upregulated in arthritic cartilage. Recombinant TN-C fragments containing the same regions as those identified from OA cartilage mediate cartilage degradation by the induction of aggrecanase activity. TN-C fragments mapping to the EGF-L and FN type III domains 3-8 of TN-C had the highest levels of aggrecan-degrading ability that was not observed either with full-length TN-C or with other domains of TN-C. TN-C fragments represent a novel mechanism for cartilage degradation in arthritis and may present new therapeutic targets for the inhibition of cartilage degradation

Is complement factor H a shared risk factor for age-related macular degeneration and cardiovascular disease?

Background and Aims: Inflammation is implicated in common disorders of ageing including atherosclerosis and age-related macular degeneration (AMD), although the link between inflammation and cardiovascular disease (CVD) is the more studied. The recent finding that susceptibility to AMD is increased substantially by common single nucleotide polymorphisms (SNPs) in the gene that encodes complement factor H (CFH; a circulating inhibitor of complement activation) provides evidence that inflammation in general, and complement in particular, maybe causally involved in AMD. Since AMD and atherosclerosis share similar pathological features and risk factors, including a link with inflammation, an important question arises: is complement factor H (fH) a shared risk factor for both AMD and CHD? One SNP in particular, which has the most replicated association in AMD, rs1061170, which encodes a putative functional tyrosine to histidine change (Y402H), and has been studied in both AMD and coronary heart disease (CHD). I hypothesised that genetic variants in CFH, in particular rs1061170 is associated with risk of both AMD and CHD and that this association may be mediated through changes in circulating fH concentration. I addressed this hypothesis by: (i) precisely defining the effect of the association of the rs1061170 SNP encoding Y402H in CFH on AMD risk; (ii) precisely defining the association of rs1061170 on risk of CHD events; and (iii) developing and validating a high throughput assay of circulating fH, to enable further evaluation of the nature of the association between CFH genotype and fH concentration, and fH concentration and disease; (iv) measuring fH in a population based sample to determine its non-genetic correlates and genetic determinants (v) measuring fH in case control studies of AMD and genotyping of SNPs in the CFH and related genes to determine the concordance of the genetic associations of fH and AMD. Methods: To address aims (i) and (ii), I conducted a systematic review of published studies investigating the effect of variants in CFH on AMD and CHD risk respectively, supplementing data with results from newly genotyped studies in both AMD and CHD. To address aim (iii) I developed and validated a high-throughput assay measuring circulating fH, which I used to undertake studies in aim (iv) in which I measured fH in a population based sample with an existing range of blood and lifestyle measures as well as anthropometric, cardiovascular, glycaemic, lipid, liver, renal, and inflammation markers. In addition to this genome wide information was also available on ~500,000 SNPs across the genome with additional imputation of un-typed SNPs, giving coverage of ~ 2 million markers across the genome. In order to achieve aim (v) I measured fH in case control studies of AMD, with additional genotyping of SNPs in the CFH and CFH related gene in order to attain a more high resolution signal of association in this genomic region for both fH concentration and AMD risk. Results: Data synthesis from published literature and newly genotyped studies, confirmed the strong association of the rs1061170 SNP with risk of AMD (per-allele odds ratio (OR) of 2.30, 99% CI 1.93, 2.73; p<0.001), in individuals of European descent, although the association was less clear in individuals of Chinese or Japanese descent. However, there was no association of rs1061170 with CHD (per-allele OR 1.01 95% CI 0.98, 1.04), or established risk factors for CHD. Adaptation of an existing commercial, low through-put assay allowed the development and validation of a high throughput assay to measure circulating fH concentrations. With an operating range of 7-1000 mg/L, this assay was reliable, repeatable and robust, enabling assay of fH in stored samples. In a large population study, novel associations of fH with lipids, apo-lipoproteins and indices of adiposity were identified and genetic determinants localised to the CFH/CFHR gene cluster on Chromosome 1. In case-control analysis, there was no association of fH concentration with AMD risk. Conclusions: Genetic variation in CFH, and in particular the effect of the most replicated rs1061170 SNP is robustly associated with AMD with little attenuation in the effect size as data has accrued. However the effect of the same SNP is not associated with CHD. Circulating fH is associated with a range of cardio-metabolic biomarkers and regulated by common genetic variants in the vicinity of the encoding gene on chromosome 1. However fH itself is not associated with risk of AMD, suggesting the genetic association of CFH with AMD is mediated through altered fH function or perhaps through an fH-related protein encoded by an adjacent gene

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions

A Systematic Review Investigating the Presence of Inflammatory Synovitis in Hip and Knee Joint Replacement Surgery.

Synovial tissue can display an inflammatory response in the presence of OA. There is increasing interest to better understand the role of inflammation in OA, particularly with regard to those who require joint replacement. A systematic review of inflammatory synovitis in OA of literature databases was undertaken from their inception until October 14, 2014. Independent critical appraisal of each study was undertaken using the CASP appraisal tool. From a total of sixty-six identified citations, twenty-three studies were deemed eligible for review. The studies presented moderate to strong methodological quality. Strong correlation was identified between histological and imaging synovitis severity. Correlation was weaker between clinical symptoms and imaging and/or histological synovitis severity. There was little consensus, with regard to expressed cytokines and chemokines at the different stages of OA disease progression. Few studies investigated the influence of inflammatory synovitis on the outcome of major joint replacement. Research into inflammatory synovitis in OA is an emerging field. Longitudinal studies applying proven imaging modalities, histological analysis, and longer follow-up are required in order to further define our understanding of the role of synovitis in the pathogenesis of OA and its effects on outcomes following major joint replacement

Beyond Dexamethasone, Emerging Immuno-Thrombotic Therapies for COVID-19

Host immunity is required to clear SARS‐CoV‐2, and inability to clear the virus because of host or pathogen factors renders those infected at risk of poor outcomes. Estimates of those who are able to clear the virus with asymptomatic or paucisymptomatic COVID‐19 remain unclear, and dependent on widespread testing. However, evidence is emerging that in severe cases, pathological mechanisms of hyperinflammation and coagulopathy ensue, the former supported by results from the RECOVERY trial demonstrating a reduction in mortality with dexamethasone in advanced COVID‐19. It remains unclear whether these pathogenic pathways are secondary to a failure to clear the virus because of maladaptive immune responses or if these are sequential COVID‐19 defining illnesses. Understanding the pathophysiological mechanisms underpinning these cascades is essential to formulating rationale therapeutic approaches beyond the use of dexamethasone. Here, we review the pathophysiology thought to underlie COVID‐19 with clinical correlates and the current therapeutic approaches being investigated

Free-of-charge medicine schemes in the NHS: A local and regional drug and therapeutic committee's experience

INTRODUCTION: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. METHODS: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. RESULTS: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth. CONCLUSION: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence

Why we are losing the war against COVID-19 on the data front and how to reverse the situation

With over five million covid-19 positive cases declared, more than 30,000 deaths and more than two million patients recovered, we would expect that the highly digitalised health systems of the high-income countries would have collected, processed and analysed large quantities of clinical data from COVID-19 patients. Those analysis should have served to answer important clinical questions such as: what are the risk factors for becoming infected? What are good clinical variables to predict prognosis? What kind of patients are more likely to survive mechanical ventilation? Are there clinical sub-phenotypes of the disease? All these, and many more, are crucial questions to improve our clinical strategies against the epidemic and save as many lives as possible until we find a vaccine and effective treatments. One might assume that in the era of Big Data and Machine Learning there would be an army of scientist crunching petabytes of clinical data to solve these questions. However, nothing further from the truth. Our health systems have proven completely unprepared to generate in a timely manner a flow of clinical data that could feed these analyses. De-spite gigabytes of data being generated every day, the vast immensity is locked in secure hospitals data servers and is not being made available for analysis. Routinely collected clinical data is, by and large, regarded as a tool to inform about individual patients, and not as a key resource to answer clinical questions thorough statistical analysis. The ini-tiatives to extract COVID-19 clinical data are often promoted by private groups of indi-viduals and not by the health systems. They are uncoordinated and inefficient. The con-sequence is that we have more clinical data than in any other epidemic in history, but we are failing to analyse it quickly enough to make a difference. In this paper we expose this situation and we suggest concrete ideas that the health systems could implement to dynamically analyse their routine clinical data becoming effectively “learning health systems” and reversing the current situation

Future directions for the management of pain in osteoarthritis.

Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future

Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 5.6 million individuals

Background: We aimed to evaluate atrial fibrillation occurrence, reasons for healthcare visits, mortality, causes of death and examined patterns by relative deprivation in the UK. Methods: To study the atrial fibrillation (AF) incidence, mortality and case-fatality, we implemented a prospective cohort study with the linked electronic health records of 5.6 million population in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. A matched case-control study was used to investigate causes of hospitalisation and death comparing individuals with and without incident AF. Results: During a median follow-up of 10.3 years, 199,433(3.6%) patients developed incident AF. Increased risk of hospitalisation for heart failure, cardiovascular conditions and infection was present among patients who later developed AF. Following an AF diagnosis, patients were frequently admitted to the hospital for heart failure, lower respiratory tract infection, chronic obstructive pulmonary disease and ischemic heart disease. One in 5 AF patients died during the first year after diagnosis, and the mortality increased to 42.7% at the fifth year. The excess deaths in AF cases compared to controls may result from cardiovascular diseases, infection and metabolic disorders. Individuals from areas with higher deprivation in socioeconomic and living status had both higher AF incidence and fatality. Interpretation: We observed an elevated risk of hospitalisation for cardiovascular or respiratory diseases among incident AF patients, and the considerable disparity in AF burden by socioeconomic deprivation informs priorities for prevention and provision of patient care