The use of SIFT-MS in profiling the faecal volatile metabolome in horses with colic: a pilot study

SIFT-MS is used for the first time in profiling the volatile organic profile in faecal headspace in two groups of horses admitted to an equine hospital, one group with acute intestinal disease (colic) affecting the large colon, plus a control group of similarly managed horses admitted for non-gastrointestinal/metabolic reasons (e.g. acute orthopaedic injury). Compounds in faecal headspace which show statistically significant concentration differences between the groups are acetone and methanol. In addition, some ions at various m/z values show significantly different ion counts between the groups. Further information may be gleaned by using multivariate statistics in evaluating the differences between the two horse groups. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were evaluated for reducing the dimensionality of the SIFT-MS data, and OPLS-DA was found to be best at discriminating between the groups, particularly with SIFT-MS data acquired using the H3O+ precursor ion. Analysis of these data also show the significance of ammonia as a discriminating ion. These results show that SIFT-MS may potentially be used on the headspace of horse faecal samples for detecting altered microbial fermentation associated with acute intestinal disease of the colon

Is equine colic seasonal? Novel application of a model based approach

BACKGROUND: Colic is an important cause of mortality and morbidity in domesticated horses yet many questions about this condition remain to be answered. One such question is: does season have an effect on the occurrence of colic? Time-series analysis provides a rigorous statistical approach to this question but until now, to our knowledge, it has not been used in this context. Traditional time-series modelling approaches have limited applicability in the case of relatively rare diseases, such as specific types of equine colic. In this paper we present a modelling approach that respects the discrete nature of the count data and, using a regression model with a correlated latent variable and one with a linear trend, we explored the seasonality of specific types of colic occurring at a UK referral hospital between January 1995–December 2004. RESULTS: Six- and twelve-month cyclical patterns were identified for all colics, all medical colics, epiploic foramen entrapment (EFE), equine grass sickness (EGS), surgically treated and large colon displacement/torsion colic groups. A twelve-month cyclical pattern only was seen in the large colon impaction colic group. There was no evidence of any cyclical pattern in the pedunculated lipoma group. These results were consistent irrespective of whether we were using a model including latent correlation or trend. Problems were encountered in attempting to include both trend and latent serial dependence in models simultaneously; this is likely to be a consequence of a lack of power to separate these two effects in the presence of small counts, yet in reality the underlying physical effect is likely to be a combination of both. CONCLUSION: The use of a regression model with either an autocorrelated latent variable or a linear trend has allowed us to establish formally a seasonal component to certain types of colic presented to a UK referral hospital over a 10 year period. These patterns appeared to coincide with either times of managemental change or periods when horses are more likely to be intensively managed. Further studies are required to identify the determinants of the observed seasonality. Importantly, this type of regression model has applications beyond the study of equine colic and it may be useful in the investigation of seasonal patterns in other, relatively rare, conditions in all species

Epidemiology of impaction colic in donkeys in the UK

BACKGROUND: Colic (abdominal pain) is a clinical condition of serious concern affecting the welfare and survival of donkeys at the Donkey Sanctuary in the UK. One of the most commonly reported causes is due to impacted ingesta in the large intestine ("impaction colic"). However little is known about the incidence of, or risk factors for, this condition. Here we describe the epidemiology of colic in donkeys, specifically impaction colic. We focus on temporal aspects of the disease and we identify environmental and management related risk factors for impaction colic in UK donkeys. RESULTS: There were 807 colic episodes in the population of 4596 donkeys between January 1(st )2000 and March 31(st )2005. The majority (54.8%) of episodes were due to a suspected or confirmed diagnosis of impaction of the gastrointestinal tract. The mortality risk for all colics (51.1%) was higher than reported in other equids. The incidence rate of all colics (5.9 episodes per 100 donkeys per year) and of impaction colic (3.2 episodes) was similar to that in horses. A retrospective matched case-control study of all impaction colics from January 2003 (193) indicated that older donkeys, those fed extra rations and those that previously suffered colic were at increased risk of impaction. Lighter body weight, musculo-skeletal problems, farm and dental disease were also significantly associated with a diagnosis of impaction colic. CONCLUSION: To our knowledge this is the first study to estimate the incidence rate of colic in a large population of donkeys in the UK. In contrast to other equids, impaction was the most commonly reported cause of colic. We identified several risk factors for impaction colic. Increasing age, extra rations and previous colic are known risk factors for colic in other equids. Results support the hypothesis that dental disease is associated with impaction colic. Musculo-skeletal problems may be associated with colic for various reasons including change in amount of exercise or time at pasture. Other associated factors (weight and farm) are the subject of further research. Identification of risk factors for impaction colic may highlight high risk donkeys and may allow intervention strategies to be introduced to reduce the incidence of the disease

A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee

INTRODUCTION: AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee. METHODS: In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score. RESULTS: In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively). CONCLUSIONS: The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov with the identifier NCT00110942.Stanley B Cohen, Susanna Proudman, Alan J Kivitz, Francis X Burch, John P Donohue, Deborah Burstein, Yu-Nien Sun, Christopher Banfield, Michael S Vincent, Liyun Ni, and Debra J Zac

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field

The effect of body fat distribution on systemic sclerosis.

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genome-wide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.This work was supported by grant RTI2018101332-B-100 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” funded by the European Union. Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013). 115565. LB-C was funded by Grant IJC2018-038026-I funded by MCIN/AEI/10.13039/501100011033. MA-H is a recipient of a Miguel Servet fellowship (CP21/00132) from Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). EL-I was funded by Grant IJC2019-040080-I funded by MCIN/AEI/10.13039/501100011033. GV-M was funded by Grant PRE2019-087586 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”

GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments