Leveraging deep survival models to predict quality of care risk in diverse hospital readmissions.

Hospital readmissions rate is reportedly high and has caused huge financial burden on health care systems in many countries. It is viewed as an important indicator of health care providers' quality of care. We examine the use of machine learning-based survival analysis to assess quality of care risk in hospital readmissions.

Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study.

Background: A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognised by gluten-specific CD4 T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease.

A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease.

Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial ("RESET CeD") of Nexvax2, a peptide-based immunotherapy for CD.

Patient factors influencing acute gluten reactions and cytokine release in treated coeliac disease.

Background: Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and diverse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production.

Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity.

Background: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD.

Objective: We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS).

Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease.

Background: In patients with coeliac disease, FODMAPs in gluten-containing foods, and participant anticipation of a harmful ('nocebo') effect, may contribute to acute symptoms after gluten challenge.

Aim: To establish acute gluten-specific symptoms linked to immune activation in coeliac disease METHODS: We included 36 coeliac disease patients on a gluten-free diet receiving placebo in the RESET CeD trial. Double-blind, bolus vital wheat gluten (~6-g gluten protein) and sham challenges low in FODMAPs were consumed 2 weeks apart.

Elevated serum interleukin-2 after gluten correlates with symptoms and is a potential diagnostic biomarker for coeliac disease.

Background: Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease.

Aim: To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients.

Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease.

Celiac disease (CeD), caused by immune reactions to cereal gluten, is treated with gluten -elimination diets. Within hours of gluten exposure, either perorally or extraorally by intradermal injection, treated patients experience gastrointestinal symptoms. To test whether gluten exposure leads to systemic cytokine production time -related to symptoms, series of multiplex cytokine measurements were obtained in CeD patients after gluten challenge.

Randomised clinical trial: a placebo-controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease.

Background: Nexvax2 contains three gluten-derived peptides, intended to tolerize coeliac disease patients to gluten. Sequences cover six epitopes that trigger immune activation in human leucocyte antigen-DQ2.5-positive patients, most notably after an initial dose.

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes.

Phagocyte microbiocidal mechanisms and inflammatory cytokine production are temporally coordinated, although their respective interdependencies remain incompletely understood. Here, we identify a nitric-oxide-mediated antioxidant response as a negative feedback regulator of inflammatory cytokine production in phagocytes. In this context, Keap1 functions as a cellular redox sensor that responds to elevated reactive nitrogen intermediates by eliciting an adaptive transcriptional program controlled by Nrf2 and comprised of antioxidant genes, including Prdx5.

Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.

Background: A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells.

Does long term colchicine prevent degradation of collagen fiber network in osteoarthritis?

Aim: Several studies have shown that colchicine exhibits an improvement in the symptoms of knee osteoarthritis (OA) but its effect on disease progression is unknown. To clarify the mechanism of action this study was done to see if colchicine prevents degradation of collagen fiber network in OA by studying serum cartilage oligomeric matrix protein (COMP) levels, a marker of cartilage turnover, over a period of 1 year.

Methods: Seventy-five patients received colchicine plus paracetamol and 75 received placebo alone for the same time period.

Correction: Heterogeneity in Comparisons of Discontinuation of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis-A Meta-Analysis.

[This corrects the article DOI: 10.1371/journal.pone.

Heterogeneity in Comparisons of Discontinuation of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis - A Meta-Analysis.

Objective: We did a systematic review of studies comparing discontinuation of tumor necrosis factor alpha (TNF) antagonists in rheumatoid arthritis (RA) patients, pooled hazard ratios and assessed clinical and methodological heterogeneity.

Methods: We searched MEDLINE and EMBASE until June 2015 for pairwise hazard ratios for discontinuing infliximab, etanercept, and adalimumab from cohorts of RA patients. Hazard ratios were pooled using inverse variance weighting and random effects estimates of the combined hazard ratio were obtained.

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD).

Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2FOXP3).

RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial Autophagy.

Xenophagy is a form of selective autophagy that involves the targeting and elimination of intracellular pathogens through several recognition, recruitment, and ubiquitination events. E3 ubiquitin ligases control substrate selectivity in the ubiquitination cascade; however, systematic approaches to map the role of E3 ligases in antibacterial autophagy have been lacking. We screened more than 600 putative human E3 ligases, identifying E3 ligases that are required for adaptor protein recruitment and LC3-bacteria colocalization, critical steps in antibacterial autophagy.

Characterization of candidate genes in inflammatory bowel disease-associated risk loci.

GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD.

Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks.

The DNA damage response (DDR) is regulated by a protein kinase signaling cascade that orchestrates DNA repair and other processes. Identifying the substrate effectors of these kinases is critical for understanding the underlying physiology and mechanism of the response. We have used quantitative mass spectrometry to profile DDR-dependent phosphorylation in budding yeast and genetically explored the dependency of these phosphorylation events on the DDR kinases MEC1, RAD53, CHK1, and DUN1.

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk.

Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis.

Mechanisms of Pediatric Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is characterized by chronic intestinal inflammation due to a complex interaction of genetic determinants, disruption of mucosal barriers, aberrant inflammatory signals, loss of tolerance, and environmental triggers. Importantly, the incidence of pediatric IBD is rising, particularly in children younger than 10 years. In this review, we discuss the clinical presentation of these patients and highlight environmental exposures that may affect disease risk, particularly among people with a background genetic risk.

New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling.

Aggregation of the high-affinity receptor for IgE (FcεRI) in mast cells initiates activation events that lead to degranulation and release of inflammatory mediators. To better understand the signaling pathways and genes involved in mast cell activation, we developed a high-throughput mast cell degranulation assay suitable for RNA interference experiments using lentivirus-based short hairpin RNA (shRNA) delivery. We tested 432 shRNAs specific for 144 selected genes for effects on FcεRI-mediated mast cell degranulation and identified 15 potential regulators.

Drug Misuse in Adolescents Presenting to the Emergency Department.

Objectives: Drug misuse is a disturbing, common practice among youth. One in 4 American adolescents reports consuming prescription medications without a clinical indication. We sought to explore current trends of drug misuse in adolescents.

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics.

Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway.