Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap

<p>Objectives: Rheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA.</p> <p>Methods: Thirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case–Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings.</p> <p>Results: Thirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort.</p> <p>Conclusions: A novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis.</p&gt

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The in vitro efficacy of haemostatic products in the presence of chemical warfare agents-Sulphur mustard (HD) and VX

Haemorrhage remains to be a leading cause of death for trauma victims (Bellamy, 1984). Wound contamination poses an additional complication in the initial management of haemorrhaging wounds, with no specific medical treatment at present. Therefore, a requirement exists to develop haemostatic products that, when applied to wounds, can simultaneously arrest haemorrhage and negate any toxic effects of contaminants. The aim of this study was to assess the effect of chemical warfare agents (CWA; sulphur mustard; HD and VX) on the clotting efficiency of seven, commercial-off-the-shelf haemostats using an in vitro system (thrombelastography; TEG). Serial samples of citrated, whole blood were acquired daily from six large white pigs. After a 30 min stabilisation period, aliquots were analysed by TEG either in the absence of a treatment (control) or following the addition of a haemostat (0.45% w/v) and/or CWA (0.5 μl ml−1). For brevity, only “R time” results (indicative of time to initial fibrin clot formation) are presented (Fig. 1). Statistics were performed using a parametric ANOVA with Tukey post-test (predetermined α level of 0.05).Peer reviewe

Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 2 : Evaluation of in vitro topical decontamination efficacy using undamaged skin

The risk of penetrating, traumatic injury occurring in a chemically contaminated environment cannot be discounted. Should a traumatic injury be contaminated with a chemical warfare (CW) agent, it is likely that standard haemostatic treatment options would be complicated by the need to decontaminate the wound milieu. Thus, there is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. One haemostatic product (WoundStat™) was shown to be as effective as the standard military decontaminants Fuller's earth and M291 for the decontamination of all three CW agents. The most effective haemostatic agents were powder-based and use fluid absorption as a mechanism of action to sequester CW agent (akin to the decontaminant Fuller's earth). The envisaged use of haemostatic decontaminants would be to decontaminate from within wounds and from damaged skin. Therefore, WoundStat™ should be subject to further evaluation using an in vitro model of damaged skin. Copyright © 2014 Crown copyright. Journal of Applied Toxicology © 2014 John Wiley & Sons, Ltd.Peer reviewe

LSL treatment increases spleen size and red pulp area in Apc^min+/- mice.

<p>a; Photographs of dissected spleen from a wt mouse and Apc^min+/- fed with vehicle or LSL. b; Apc^min+/- mice had a significantly greater spleen weight compared to wt mice (**** p<0.00001). LSL administration resulted in a significant increase in splenic weights compared to the vehicle control mice (* p<0.01). Splenic histology from wt mice (6c top), Apc^min+/- mice fed vehicle control only (6c middle) and Apc^{min+/- fed} LSL (6c bottom). WP = White pulp, RP = Red pulp, BV = Blood vessel. Apc^min+/- mice demonstrated altered splenic pathology with increased red pulp regions (hematopoietic rich tissue). LSL fed mice showed a further change in histopathology (<i>c</i>.<i>f</i> 6c middle vs bottom) with spleens demonstrating a significant increase in red pulp (* p<0.05). Graphs represented of mean ± SEM. Animals per group n = 10. Statistical significance was determined by students T-test.</p

LSL induced both necrosis and apoptosis <i>in vitro</i>.

<p>Photomicrographs of acridine orange and ethidium bromide stained cultures following treatments with 0 (a-e), 20 (f-j) or 70μg/ml (k-o) LSL and quantification of live, apoptotic or necrotic cells (p-t). The vast number of CCD-841-CoN (a) and cancer cells treated with vehicle control are morphologically viable with a small number showing condensed nuclei (apoptotic). 20μg/ml LSL resulted in necrosis (red/orange clusters) in all cell lines, although CCD-841-CoN (k.p ****p<0.0001) and Caco2 cells (j.o ** p<0.001) were more susceptible. At 70μg/ml, very few adherent CCD-841-CoN cells were observed (k), remaining adhered cells were either necrotic or apoptotic (p). HT29 (l), HT115 (m), HCT116 (n) and Caco2 (o) cells exposed to 70μg/ml LSL all had 50% of cells with morphological features of cells death (q-t) and statistically significant increases in either the numbers of necrotic (*** p<0.0001) or apoptotic cells (**p<0.001) as compared with vehicle only controls.</p

Purification of LSL produced by S. bombicola.

<p>HPLC-ELSD and LC-MS analysis of the LSL precipitate from the bioreactor. (a) The MW 688 g/mol corresponds to diacetyl C18:1 LSL. (b) HPLC-ELSD analysis following purification of the LSL precipitate. The MW 706 g/mol = diacetyl C18:1 ASL, which is the result of minor hydrolysis of the MW 688 compound.</p

LSL treatment increases tumour number and size in Apc^min+/- mice.

<p>PCR and restriction enzyme analysis of genomic DNA from wt or Apc^{min+/- littermates} (a); wt band: 111bp, heterozygous Apc^min+/- mouse—111 & 123bp. Mice were fed either LSL or vehicle-only every other day for 70 days. Examination of low power images of intestinal segments from wt mice treated with vehicle or 50mg/kg LSL revealed no discernible differences in gross morphology (top). However, in Apc^min+/- (bottom), those treated with vehicle-only (left) showed evidence of occult bleeding (arrow) as well as numerous polyps (c arrow heads) with a modal diameter of 2mm (d). In Apc^min+/- mice treated with LSL, there was evidence of recent hemorrhage (arrows) as well as significant increases in both polyp number (c;*p <0.01) and size (d;**p < 0.001) compared to vehicle-only controls. Values represent mean ± SEM (n = 10/group). Statistical significance was determined by one-way ANOVA (c) or a student T-tests (d). (e) Histological sections from wt (top) or Apc^min+/- (bottom) stained with Haematoxylin and Eosin. Distinct villi in wt treated with vehicle (left) or 50mg/kg LSL are seen. In Apc^min+/- littermate mice villous structure is grossly perturbed within polyps in both vehicle-treated mice (bottom left) as well as those treated with 50mg/kg (bottom right).</p