ARFIMA-GARCH modeling of HRV: Clinical application in acute brain injury

In the last decade, several HRV based novel methodologies for describing and assessing heart rate dynamics have been proposed in the literature with the aim of risk assessment. Such methodologies attempt to describe the non-linear and complex characteristics of HRV, and hereby the focus is in two of these characteristics, namely long memory and heteroscedasticity with variance clustering. The ARFIMA-GARCH modeling considered here allows the quantification of long range correlations and time-varying volatility. ARFIMA-GARCH HRV analysis is integrated with multimodal brain monitoring in several acute cerebral phenomena such as intracranial hypertension, decompressive craniectomy and brain death. The results indicate that ARFIMA-GARCH modeling appears to reflect changes in Heart Rate Variability (HRV) dynamics related both with the Acute Brain Injury (ABI) and the medical treatments effects. (c) 2017, Springer International Publishing AG

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Evaluation and Management of Laryngopharyngeal Reflux Disease: State of the Art Review

Objective: To review the current literature about the epidemiology, clinical presentation, diagnosis, and treatment of laryngopharyngeal reflux (LPR). Data Sources: PubMed, Cochrane Library, and Scopus. Methods: A comprehensive review of the literature on LPR epidemiology, clinical presentation, diagnosis, and treatment was conducted. Using the PRISMA statement, 3 authors selected relevant publications to provide a critical analysis of the literature. Conclusions: The important heterogeneity across studies in LPR diagnosis continues to make it difficult to summarize a single body of thought. Controversies persist concerning epidemiology, clinical presentation, diagnosis, and treatment. No recent epidemiologic study exists regarding prevalence and incidence with the use of objective diagnostic tools. There is no survey that evaluates the prevalence of symptoms and signs on a large number of patients with confirmed LPR. Regarding diagnosis, an increasing number of authors used multichannel intraluminal impedance\u2013pH monitoring, although there is no consensus regarding standardization of the diagnostic criteria. The efficiency of proton pump inhibitor (PPI) therapy remains poorly demonstrated and misevaluated by incomplete clinical tools that do not take into consideration many symptoms and extralaryngeal findings. Despite the recent advances in knowledge about nonacid LPR, treatment protocols based on PPIs do not seem to have evolved. Implications for Practice: The development of multichannel intraluminal impedance\u2013pH monitoring and pepsin and bile salt detection should be considered for the establishment of a multiparameter diagnostic approach. LPR treatment should evolve to a more personalized regimen, including diet, PPIs, alginate, and magaldrate according to individual patient characteristics. Multicenter international studies with a standardized protocol could improve scientific knowledge about LPR

The development of new clinical instruments in laryngopharyngeal reflux disease: The international project of young otolaryngologists of the International Federation of Oto-rhino-laryngological Societies

Introduction: To analyze the epidemiological characteristics of placebo controlled randomized trials (RCTs) that evaluated the effectiveness of medical treatments over placebo in laryngopharyngeal reflux (LPR). Material and methods: PubMed, Cochrane database, and Scopus were assessed for subject headings using the PRISMA recommendations. Placebo RCTs published between 1990 and 2018 describing clinical evolution throughout LPR treatment were extracted and analyzed for evidence-based level, number of patients, inclusion and exclusion criteria, gender, age, symptoms and signs used as therapeutic outcomes, and treatment schemes. Results: The database search identified 15 placebo RCTs with a total of 763 patients. The mean age of patients was 48.59 years and 52.68% of patients were female. Among the 15 placebo RCTs, 9 have demonstrated a partial or total superiority of a medical treatment over placebo. Most of authors based the LPR diagnosis on symptoms and signs without additional examination. Our analysis reveals an important heterogeneity between studies with regard to the diagnosis criteria, treatment schemes and signs and symptoms used as therapeutic outcomes. Many commonly reported signs and symptoms related to LPR were not used as therapeutic outcomes. Half of the authors did not prescribe diet and behavioral changes along the treatment. Conclusion: The controversy in the RCTs about the superiority of medical treatment over placebo in LPR disease is probably due to discrepancies in the diagnosis method, exclusion criteria, therapeutic schemes and the lack of comprehensive tools for the assessment of signs and symptoms. In this context, the LPR Study Group of Young-Otolaryngologists of the International Federations of Oto-Rhino-Laryngological Societies developed two new instruments to precisely assess signs and symptoms throughout the treatment. These two instruments could be used in future trials comparing medical treatment over placebo in LPR disease

Prospective Randomized Open-label Multicenter Phase I/II Dose Escalation Trial of Visilizumab (HuM291) in Severe Steroid-refractory Ulcerative Colitis

Background: Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). Methods: In all, 104 patients were treated. In Stage 1, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 mu g/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 mu g/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. Results: The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 mu g/kg dose groups were 71%, 70%, 50%, and 61%. respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 3.5%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 mu g/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. Conclusions: Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 mu g/kg/day were similar to those observed with higher doses (NCT00267306 at www.clinicaltrials.gov).Cellular mechanisms in basic and clinical gastroenterology and hepatolog

A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease

Objective Semapimod, a small molecule known to inhibit proinflammatory cytokine activity, was studied to determine the optimal dose necessary to achieve a response in patients with moderate to severe Crohn's disease (CD). Methods A randomised, double-blind, placebo-controlled trial (CD04) was carried out followed by an open-label extension study (CD05). The trial was conducted in international multicentre outpatient clinics and included patients with moderate to severe CD (Crohn's Disease Activity Index (CDAI) 250-400). Placebo was administered for 3 days; 60 mg semapimod intravenously for 1 day with placebo for 2 days; or 60 mg semapimod intravenously for 3 days. Participants who completed CD04 could participate in the open-label extension study, CD05, to receive up to five additional semapimod HCl 60 mg daily doses three times every 6-8 weeks. The main outcome measures were CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Endoscopic Inflammation Score (CDEIS) and serum C-reactive protein (CRP) concentration. Results 152 patients were randomised in CD04. Responses for 1 and 3 day regimens were similar to placebo for CDAI (p=0.82), IBDQ (p=0.85), CDEIS (p=0.57) and CRP (p=0.40). The only noteworthy treatment-related safety finding was infusion reaction (phlebitis): 7.3, 34.8 and 62.7% for the placebo and 1 and 3 day semapimod treatment groups, respectively (p= 360 mg was associated with decreased CDAI in a limited number of patients.Cellular mechanisms in basic and clinical gastroenterology and hepatolog