Guideline adherence and patient satisfaction in the treatment of inflammatory bowel disorders – an evaluation study

Background: Crohn's disease (CD) and ulcerative colitis (UC) are the most frequent inflammatory bowel disorders (IBD). IBD cause a significant burden to society due to extensive health care utilization from the first clinical symptoms until diagnosis and thereafter due to direct and indirect costs. Besides the socio-economic impact of CD and UC, gastrointestinal and extraintestinal symptoms affect quality of life, but there is remarkably little data about the quality of treatment as assessed by patient satisfaction, quality of life and adherence to guidelines. Thus the aim of this study was to identify variables that influence quality of treatment and quality of life as well as patient satisfaction. Methods: The Essener Zirkel Study was a cross sectional study of 86 IBD-patients with a confirmed diagnosis of CD or UC. They were recruited at primary, secondary and tertiary care settings. Quality of treatment, quality of life and patient satisfaction were evaluated. Consulting behaviour and number of examinations, duration of disease and variables regarding adherence to guidelines were evaluated, too. Results: 59 (69%) patients had CD and 27 had UC (31%). 19% spent more than four years until the suspected diagnosis of IBD was confirmed and visited more than five physicians. All patients showed a significantly reduced quality of life compared to the 1998 German normative population. In spite of being under medical treatment, nearly half of the patients suffered from strong quality of life restricting symptoms. Over all, 35% described their treatment as moderate or bad. Patients who consulted psychotherapists and non-medical practitioners suffered significantly less from depression. Conclusion: Besides structural deficiencies due to the health care policy, we revealed the adherence to guidelines to be a problem area. Our findings support the assumption, that providing better health care and especially maintaining constant patient-physician communication improves patient satisfaction.Claudia Pieper, Sebastian Haag, Stefan Gesenhues, Gerald Holtmann, Guido Gerken and Karl-Heinz Jöcke

Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: diagnostic and mechanistic relevance

Background & Aims: Serum microRNAs (miRNAs) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages.Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 NAFLD cases representing the complete NAFLD spectrum and 10 population controls). MiRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional NAFLD cases and 15 population controls by quantitative reverse transcriptase-polymerase chain reaction.Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages but miR-193a-5p consistently the showed increased levels in all comparisons. Relative to NAFL/NASH with mild fibrosis (stage 0/1), three miRNAs (miR-193a-5p, miR-378d and miR378d) were increased in cases with NASH and clinically significant fibrosis (stage 2-4), seven (miR193a-5p, miR-378d, miR-378e, miR-320b, c, d & e) increased in cases with NAFLD Activity Score (NAS) 5-8 compared with lower NAS, and three (miR-193a-5p, miR-378d, miR-378e) increased but one (miR-19b-3p) decreased in steatosis, activity, and fibrosis "activity" (SAF-A) score 2-4 compared with lower SAF-A. The significant findings for miR-193a-5p were replicated in the additional NAFLD cohort. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n=80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD

De-identification of health records using Anonym: Effectiveness and robustness across datasets

Objective Evaluate the effectiveness and robustness of Anonym, a tool for de-identifying free-text health records based on conditional random fields classifiers informed by linguistic and lexical features, as well as features extracted by pattern matching techniques. De-identification of personal health information in electronic health records is essential for the sharing and secondary usage of clinical data. De-identification tools that adapt to different sources of clinical data are attractive as they would require minimal intervention to guarantee high effectiveness. Methods and Materials The effectiveness and robustness of Anonym are evaluated across multiple datasets, including the widely adopted Integrating Biology and the Bedside (i2b2) dataset, used for evaluation in a de-identification challenge. The datasets used here vary in type of health records, source of data, and their quality, with one of the datasets containing optical character recognition errors. Results Anonym identifies and removes up to 96.6% of personal health identifiers (recall) with a precision of up to 98.2% on the i2b2 dataset, outperforming the best system proposed in the i2b2 challenge. The effectiveness of Anonym across datasets is found to depend on the amount of information available for training. Conclusion Findings show that Anonym compares to the best approach from the 2006 i2b2 shared task. It is easy to retrain Anonym with new datasets; if retrained, the system is robust to variations of training size, data type and quality in presence of sufficient training data

Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial

BACKGROUND: The clinical effects of roflumilast, a selective phosphodiesterase-4 inhibitor, are well established, but little is known about the anti-inflammatory mechanisms underlying the drug's efficacy. The aim of the ROflumilast Biopsy European Research Trial (ROBERT) was to assess the anti-inflammatory effects of roflumilast on bronchial mucosal inflammation in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis. METHODS: ROBERT was a randomised, double-blind, placebo-controlled trial done at 18 sites in five countries. Eligible patients were aged 40-80 years, had COPD, and had had a chronic productive cough for 3 months in each of the two previous years. Patients also had to have a post-bronchodilator predicted FEV1 30-80% and a post-bronchodilator FEV1/forced vital capacity ratio of 70% or less. Patients entered a 6-week run-in period before being randomly assigned (1:1) via a computerised central randomisation system to roflumilast 500 \u3bcg once daily or placebo for 16 weeks, in addition to bronchodilator therapy (inhaled corticosteroids were not permitted). Randomisation was stratified by concomitant use of long-acting \u3b2 agonist. Both participants and investigators were masked to group assignment. Roflumilast and placebo were supplied as identical yellow, triangular tablets. Airway inflammation was assessed by quantification of inflammatory cells in bronchial biopsy samples and induced sputum samples. The primary endpoint was the change in the number of CD8 inflammatory cells in bronchial biopsy submucosa from randomisation to week 16 in the intention-to-treat population. Changes in cell counts of additional inflammatory markers, including eosinophils, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, number NCT01509677, and is closed to new participants, with follow-up completed. FINDINGS: Between Jan 4, 2012, and Feb 11, 2016, 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. At week 16, the change in the number of CD8 cells in the bronchial submucosa did not differ significantly between the roflumilast and placebo groups (treatment ratio 1\ub703 [95% CI 0\ub782-1\ub730]; p=0\ub779). However, compared with placebo, roflumilast was associated with a significant reduction in eosinophils in bronchial biopsy samples at week 16 (treatment ratio 0\ub753 [95% CI 0\ub734-0\ub782]; p=0\ub70046). Significant reductions in both absolute (p=0\ub70042) and differential (p=0\ub70086) eosinophil cell counts in induced sputum were also noted with roflumilast compared with placebo, but peripheral blood eosinophil counts were not significantly affected. We noted no other significant effects of roflumilast on bronchial mucosal inflammatory cells. The most common (ie, occurring in >5% patients) moderate adverse events were worsening of COPD (three [4%] patients in the roflumilast group vs seven [9%] in the placebo group), cough (six [8%] vs four [5%]), diarrhoea (four [5%] vs three [4%]), and nasopharyngitis (three [4%] vs five [6%]). Severe adverse events included worsening of COPD, which occurred in four (5%) patients in the roflumilast group and two (3%) in the placebo group. No deaths occurred during the study. Serious adverse events occurred in eight (10%) patients in the roflumilast group and five (6%) in the placebo group. INTERPRETATION: 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo. However, we noted significant reductions in eosinophil cell counts in bronchial biopsy samples and induced sputum, generating the hypothesis that the effect of roflumilast in COPD could be mediated by an effect on lung eosinophils

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

Background & Aims: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods: A time-course study in low-density lipoprotein-receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results: High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions: An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames

Tumour Necrosis Factor α Antagonists in the Treatment of Rheumatoid Arthritis: An Immunological Perspective.

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune conditions, affecting approximately 1 % of the adult population. It is associated with decreased quality of life and considerable morbidity and mortality. Various inflammatory cells, including macrophages, neutrophils, mast cells, natural killer cells, B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression. Several cytokines, including interleukin (IL)-1α and/or IL-1β, and tumour necrosis factor (TNF)-α, are involved at each stage of RA pathogenesis; namely, by augmenting autoimmunity, sustaining long-term inflammatory synovitis and promoting joint damage. Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro-inflammatory mediators. As early as the late 1980s, TNF had been identified as a potential target in RA. Five anti-TNF drugs, infliximab, adalimumab, certolizumab pegol, etanercept and golimumab, are now approved for the treatment of RA in various countries. All are bivalent monoclonal antibodies, with the exception of the monovalent certolizumab and etanercept, which is an engineered dimeric receptor. Although all react with and neutralise soluble TNF in vitro, structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects. Pegylated certolizumab permits once-monthly dosing. Other mechanisms of action proposed to be important for the efficacy of anti-TNF agents are as follows: induction of apoptosis of both monocytes and T cells; neutralization of membrane TNF; antibody-dependent cell-mediated and complement-dependent cytotoxicity; and reverse signaling via membrane TNF