Long-term efficacy and safety of brodalumab in the treatment of psoriasis : 120-week results from the randomized, double-blind, placebo- and active comparator-controlled phase 3 AMAGINE-2 trial

Randomized controlled trials have shown the efficacy and safety of brodalumab in patients with moderate to severe plaque psoriasis. To evaluate the efficacy and safety of brodalumab through 120 weeks of treatment in the AMAGINE-2 trial. Patients received ustekinumab through week 52 followed by brodalumab 210 mg every 2 weeks, continuous brodalumab 210 mg every 2 weeks, or any dose of brodalumab. Efficacy data were reported through 120 weeks by using observed data, last observation carried forward, and nonresponder imputation analyses. Of patients who received brodalumab 210 mg every 2 weeks, 84.4%, 75.6%, and 61.1% achieved 75%, 90%, and 100% improvement from baseline in Psoriasis Area and Severity Index at 120 weeks (observed data analysis), respectively. Patients who received brodalumab 210 mg every 2 weeks after receiving ustekinumab through 52 weeks achieved a similar skin clearance response as patients who received continuous brodalumab 210 mg every 2 weeks. Safety through 120 weeks was comparable to that of the blinded study periods. A large number of discontinuations toward the end of the study (31% in the final 6 months) were due to early termination and led to differences between observed data and nonresponder imputation results. Brodalumab is well tolerated and showed robust efficacy for more than 2 years

Synthesis and Characterization of Single-Phase Metal Dodecaboride Solid Solutions: Zr1–xYxB12 and Zr1–xUxB12

Single-phase metal dodecaboride solid solutions, Zr0.5Y0.5B12 and Zr0.5U0.5B12, were prepared by arc melting from pure elements. The phase purity and composition were established by powder X-ray diffraction (PXRD), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and 10B and 11B solid-state nuclear magnetic resonance (NMR) spectroscopy. The effects of carbon addition to Zr1–xYxB12 were studied and it was found that carbon causes fast cooling and as a result rapid nucleation of grains, as well as “templating” and patterning effects of the surface morphology. The hardness of the Zr0.5Y0.5B12 phase is 47.6 ± 1.7 GPa at 0.49 N load, which is ∼17% higher than that of its parent compounds, ZrB12 and YB12, with hardness values of 41.6 ± 2.6 and 37.5 ± 4.3 GPa, respectively. The hardness of Zr0.5U0.5B12 is ∼54% higher than that of its UB12 parent. The dodecaborides were confirmed to be metallic by band structure calculations, diffuse reflectance UV–vis, and solid-state NMR spectroscopies. The nature of the dodecaboride colors—violet for ZrB12 and blue for YB12—can be attributed to charge-transfer. XPS indicates that the metals are in the following oxidation states: Y3+, Zr4+, and U5+/6+. The superconducting transition temperatures (Tc) of the dodecaborides were determined to be 4.5 and 6.0 K for YB12 and ZrB12, respectively, as shown by resistivity and superconducting quantum interference device (SQUID) measurements. The Tc of the Zr0.5Y0.5B12 solid solution was suppressed to 2.5 K

Development of the Gambling Disorder Identification Test: Results from an international Delphi and consensus process

Objectives Diverse instruments are used to measure problem gambling and Gambling Disorder intervention outcomes. The 2004 Banff consensus agreement proposed necessary features for reporting gambling treatment efficacy. To address the challenge of including these features in a single instrument, a process was initiated to develop the Gambling Disorder Identification Test (GDIT), as an instrument analogous to the Alcohol Use Disorders Identification Test and the Drug Use Disorders Identification Test. Methods Gambling experts from 10 countries participated in an international two‐round Delphi (n = 61; n = 30), rating 30 items proposed for inclusion in the GDIT. Gambling researchers and clinicians from several countries participated in three consensus meetings (n = 10; n = 4; n = 3). User feedback was obtained from individuals with experience of problem gambling (n = 12) and from treatment‐seekers with Gambling Disorder (n = 8). Results Ten items fulfilled Delphi consensus criteria for inclusion in the GDIT (M ≥ 7 on a scale of 1–9 in the second round). Item‐related issues were addressed, and four more items were added to conform to the Banff agreement recommendations, yielding a final draft version of the GDIT with 14 items in three domains: gambling behavior, gambling symptoms and negative consequences. Conclusions This study established preliminary construct and face validity for the GDIT

A Participatory Health Promotion Mobile App Addressing Alcohol Use Problems (The Daybreak Program): Protocol for a Randomized Controlled Trial

BACKGROUND: At-risk patterns of alcohol use are prevalent in many countries with significant costs to individuals, families, and society. Screening and brief interventions, including with Web delivery, are effective but with limited translation into practice to date. Previous observational studies of the Hello Sunday Morning approach have found that their unique Web-based participatory health communication method has resulted in a reduction of at-risk alcohol use between baseline and 3 months. The Hello Sunday Morning blog program asks participants to publicly set a personal goal to stop drinking or reduce their consumption for a set period of time, and to record their reflections and progress on blogs and social networks. Daybreak is Hello Sunday Morning's evidence-based behavior change program, which is designed to support people looking to change their relationship with alcohol. OBJECTIVE: This study aims to systematically evaluate different versions of Hello Sunday Morning's Daybreak program (with and without coaching support) in reducing at-risk alcohol use. METHODS: We will use a between groups randomized control design. New participants enrolling in the Daybreak program will be eligible to be randomized to receive either (1) the Daybreak program, including peer support plus behavioral experiments (these encourage and guide participants in developing new skills in the areas of mindfulness, connectedness, resilience, situational strategies, and health), or (2) the Daybreak program, including the same peer support plus behavioral experiments, but with online coaching support. We will recruit 467 people per group to detect an effect size of f=0.10. To be eligible, participants must be resident in Australia, aged =18 years, score =8 on the alcohol use disorders identification test (AUDIT), and not report prior treatment for cardiovascular disease. RESULTS: The primary outcome measure will be reduction in the AUDIT-Consumption (AUDIT-C) scores. Secondary outcomes include mental health (Kessler's K-10), days out of role (Kessler), alcohol consumed (measured with a 7-day drinking diary in standard 10 g drinks), and alcohol-related harms (CORE alcohol and drug survey). We will collect data at baseline and 1, 3, and 6 months and analyze them with random effects models, given the correlated data structure. CONCLUSIONS: A randomized trial is required to provide robust evidence of the impact of the online coaching component of the Daybreak program, including over an extended period

Web-based alcohol intervention:study of systematic attrition of heavy drinkers

Background: Web-based alcohol interventions are a promising way to reduce alcohol consumption because of their anonymity and the possibility of reaching a high numbers of individuals including heavy drinkers. However, Web-based interventions are often characterized by high rates of attrition. To date, very few studies have investigated whether individuals with higher alcohol consumption show higher attrition rates in Web-based alcohol interventions as compared with individuals with lower alcohol consumption. Objectives: The aim of this study was to examine the attrition rate and predictors of attrition in a Web-based intervention study on alcohol consumption. Methods: The analysis of the predictors of attrition rate was performed on data collected in a Web-based randomized control trial. Data collection took place at the University of Konstanz, Germany. A total of 898 people, which consisted of 46.8% males (420/898) and 53.2% females (478/898) with a mean age of 23.57 years (SD 5.19), initially volunteered to participate in a Web-based intervention study to reduce alcohol consumption. Out of the sample, 86.9% (781/898) were students. Participants were classified as non-completers (439/898, 48.9%) if they did not complete the Web-based intervention. Potential predictors of attrition were self-reported: alcohol consumption in the last seven days, per week, from Monday to Thursday, on weekends, excessive drinking behavior measured with the Alcohol Use Disorder Identification Test (AUDIT), and drinking motives measured by the Drinking Motive Questionnaire (DMQ-R SF). Results: Significant differences between completers and non-completers emerged regarding alcohol consumption in the last seven days (B=-.02, P=.05, 95% CI [0.97-1.00]), on weekends (B=-.05, P=.003, 95% CI [0.92-0.98]), the AUDIT (B=-.06, P=.007, 95% CI [0.90-0.98], and the status as a student (B=.72, P=.001, 95% CI [1.35-3.11]). Most importantly, non-completers had a significantly higher alcohol consumption compared with completers. Conclusions: Hazardous alcohol consumption appears to be a key factor of the dropout rate in a Web-based alcohol intervention study. Thus, it is important to develop strategies to keep participants who are at high risk in Web-based interventions

Allele-specific differences in ryanodine receptor 1 mRNA expression levels may contribute to phenotypic variability in malignant hyperthermia

<p>Abstract</p> <p>Background</p> <p>Malignant hyperthermia (MH) is a dominantly inherited skeletal muscle disorder that can cause a fatal hypermetabolic reaction to general anaesthetics. The primary locus of MH (MHS1 locus) in humans is linked to chromosome 19q13.1, the position of the gene encoding the ryanodine receptor skeletal muscle calcium release channel (RyR1).</p> <p>Methods</p> <p>In this study, an inexpensive allele-specific PCR (AS-PCR) assay was designed that allowed the relative quantification of the two RyR1 transcripts in heterozygous samples found to be susceptible to MH (MHS). Allele-specific differences in RyR1 expression levels can provide insight into the observed variable penetrance and variations in MH phenotypes between individuals. The presence/absence of the H4833Y mutation in <it>RYR</it>1 transcripts was employed as a marker that allowed discrimination between the two alleles.</p> <p>Results</p> <p>In four skeletal muscle samples and two lymphoblastoid cell lines (LCLs) from different MHS patients, the wild type allele was found to be expressed at higher levels than the mutant RyR1 allele. For both LCLs, the ratios between the wild type and mutant <it>RYR</it>1 alleles did not change after different incubation times with actinomycin D. This suggests that there are no allele-specific differences in RyR1 mRNA stability, at least in these cells.</p> <p>Conclusion</p> <p>The data presented here revealed for the first time allele-specific differences in <it>RYR</it>1 mRNA expression levels in heterozygous MHS samples, and can at least in part contribute to the observed variable penetrance and variations in MH clinical phenotypes.</p

Snow Control - An RCT protocol for a web-based self-help therapy to reduce cocaine consumption in problematic cocaine users

Background: Cocaine use has increased in most European countries, including Switzerland, and many states worldwide. The international literature has described treatment models that target the general population. In addition to supplying informative measures at the level of primary and secondary prevention, the literature also offers web-based self-help tools for problematic substance users, which is in line with tertiary prevention. Such programs, however, have been primarily tested on individuals with problematic alcohol and cannabis consumption, but not on cocaine-dependent individuals. Methods/Design: This paper presents the protocol of a randomised clinical trial to test the effectiveness of a web-based self-help therapy to reduce cocaine use in problematic cocaine users. The primary outcome is severity of cocaine dependence. Secondary outcome measures include cocaine craving, consumption of cocaine and other substances of abuse in the past month, and changes in depression characteristics. The therapy group will receive a 6-week self-help therapy to reduce cocaine consumption based on methods of Cognitive Behavioural Therapy, principles of Motivational Interviewing and self-control practices. The control group will be presented weekly psycho-educative information with a quiz. The predictive validity of participant characteristics on treatment retention and outcome will be explored. Discussion: To the best of our knowledge, this will be the first randomised clinical trial to test the effectiveness of online self-help therapy to reduce or abstain from cocaine use. It will also investigate predictors of outcome and retention. This trial is registered at Current Controlled Trials and is traceable as NTR-ISRCTN93702927