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https://www.readbyqxmd.com/read/28643370/developing-a-natural-history-progression-model-for-duchenne-muscular-dystrophy-using-the-six-minute-walk-test
#1
Lora Hamuro, Phyllis Chan, Giridhar Tirucherai, Malaz AbuTarif
The six minute walk test (6MWT) is used as a clinical endpoint to evaluate drug efficacy in Duchenne Muscular Dystrophy (DMD) trials. A model was developed using digitized 6MWT data that estimated two slopes and two intercepts to characterize 6MWT improvement during development and 6MWT decline. Mean baseline 6MWT was 362 (± 87) meters. The model predicted an improvement at a rate of 20 meter/year (9.4-30, 95% confidence interval (CI)) up until 10 years old (6.78-13.1, 95% CI), and then decline at a rate of 85 meter/year (72-98, 95% CI)...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28643003/recent-developments-in-solution-nuclear-magnetic-resonance-nmr-based-molecular-biology
#2
REVIEW
Joshua J Ziarek, Diego Baptista, Gerhard Wagner
Visualizing post-translational modifications, conformations, and interaction surfaces of protein structures at atomic resolution underpins the development of novel therapeutics to combat disease. As computational resources expand, in silico calculations coupled with experimentally derived structures and functional assays have led to an explosion in structure-based drug design (SBDD) with several compounds in clinical trials. It is increasingly clear that "hidden" transition-state structures along activation trajectories can be harnessed to develop novel classes of allosteric inhibitors...
June 23, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28641925/safety-pharmacokinetics-and-sialic-acid-production-after-oral-administration-of-n-acetylmannosamine-mannac-to-subjects-with-gne-myopathy
#3
Xin Xu, Amy Q Wang, Lea L Latham, Frank Celeste, Carla Ciccone, May Christine Malicdan, Barry Goldspiel, Pramod Terse, James Cradock, Nora Yang, Selwyn Yorke, John C McKew, William A Gahl, Marjan Huizing, Nuria Carrillo
GNE myopathy is a rare, autosomal recessive, inborn error of sialic acid metabolism, caused by mutations in GNE, the gene encoding UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no medical therapy available for this debilitating disease. Hyposialylation of muscle glycoproteins likely contributes to the pathophysiology of this disease. N-acetyl-D-mannosamine (ManNAc), an uncharged monosaccharide and the first committed precursor in the sialic acid biosynthetic pathway, is a therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy...
April 26, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28641461/the-impact-of-data-errors-on-the-outcome-of-randomized-clinical-trials
#4
Marc Buyse, Pierre Squifflet, Elisabeth Coart, Emmanuel Quinaux, Cornelis Ja Punt, Everardo D Saad
Background/aims Considerable human and financial resources are typically spent to ensure that data collected for clinical trials are free from errors. We investigated the impact of random and systematic errors on the outcome of randomized clinical trials. Methods We used individual patient data relating to response endpoints of interest in two published randomized clinical trials, one in ophthalmology and one in oncology. These randomized clinical trials enrolled 1186 patients with age-related macular degeneration and 736 patients with metastatic colorectal cancer...
June 1, 2017: Clinical Trials: Journal of the Society for Clinical Trials
https://www.readbyqxmd.com/read/28636403/applying-precision-medicine-to-trial-design-using-physiology-extracorporeal-co2-removal-for-ards
#5
Ewan C Goligher, Marcelo B P Amato, Arthur S Slutsky
In clinical trials of therapies for ARDS, the average treatment effect in the study population may be attenuated because individual patient responses vary widely. This inflates sample size requirements and increases the cost and difficulty of conducting successful clinical trials. One solution is to enrich the study population with patients most likely to benefit based on predicted patient response to treatment (predictive enrichment). In this perspective, we apply the precision medicine paradigm to the emerging use of extracorporeal CO2 removal (ECCO2R) for ultra-protective ventilation in ARDS...
June 21, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28634131/cost-effectiveness-of-pre-versus-post-liver-transplant-hepatitis-c-treatment-with-direct-acting-antivirals
#6
Sumeyye Samur, Brian Kues, Turgay Ayer, Mark S Roberts, Fasiha Kanwal, Chin Hur, Drew Michael S Donnell, Raymond T Chung, Jagpreet Chhatwal
BACKGROUND & AIMS: Oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment offer new hope to both pre- and post-liver transplant (LT) patients. However, whether to treat HCV patients pre- versus post-LT is not clear, as treatment can improve liver function but could reduce the chance of receiving a LT while on the waiting list. Our objective was to evaluate the cost-effectiveness of pre-LT versus post-LT HCV treatment with oral DAAs in decompensated cirrhotic patients on the LT waiting list...
June 17, 2017: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28633609/modelling-and-sample-size-reestimation-for-longitudinal-count-data-with-incomplete-follow-up
#7
Thomas Asendorf, Robin Henderson, Heinz Schmidli, Tim Friede
We consider modelling and inference as well as sample size estimation and reestimation for clinical trials with longitudinal count data as outcomes. Our approach is general but is rooted in design and analysis of multiple sclerosis trials where lesion counts obtained by magnetic resonance imaging are important endpoints. We adopt a binomial thinning model that allows for correlated counts with marginal Poisson or negative binomial distributions. Methods for sample size planning and blinded sample size reestimation for randomised controlled clinical trials with such outcomes are developed...
January 1, 2017: Statistical Methods in Medical Research
https://www.readbyqxmd.com/read/28631331/missing-data-in-clinical-trials-control-based-mean-imputation-and-sensitivity-analysis
#8
Devan V Mehrotra, Fang Liu, Thomas Permutt
In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between-treatment difference in population means of a clinical endpoint that is free from the confounding effects of "rescue" medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post-rescue data...
June 20, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28630525/a-bayesian-adaptive-design-for-clinical-trials-in-rare-diseases
#9
S Faye Williamson, Peter Jacko, Sofía S Villar, Thomas Jaki
Development of treatments for rare diseases is challenging due to the limited number of patients available for participation. Learning about treatment effectiveness with a view to treat patients in the larger outside population, as in the traditional fixed randomised design, may not be a plausible goal. An alternative goal is to treat the patients within the trial as effectively as possible. Using the framework of finite-horizon Markov decision processes and dynamic programming (DP), a novel randomised response-adaptive design is proposed which maximises the total number of patient successes in the trial and penalises if a minimum number of patients are not recruited to each treatment arm...
September 2017: Computational Statistics & Data Analysis
https://www.readbyqxmd.com/read/28630393/sample-size-re-estimation-without-un-blinding-for-time-to-event-outcomes-in-oncology-clinical-trials
#10
Huang Lihong, Bai Jianling, Yu Hao, Chen Feng
Sample size re-estimation is essential in oncology studies. However, the use of blinded sample size reassessment for survival data has been rarely reported. Based on the density function of the exponential distribution, an expectation-maximization (EM) algorithm of the hazard ratio was derived, and several simulation studies were used to verify its applications. The method had obvious variation in the hazard ratio estimates and overestimation for the relatively small hazard ratios. Our studies showed that the stability of the EM estimation results directly correlated with the sample size, the convergence of the EM algorithm was impacted by the initial values, and a balanced design produced the best estimates...
June 20, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28630378/randomised-controlled-trial-of-the-efficacy-of-a-blue-enriched-light-intervention-to-improve-alertness-and-performance-in-night-shift-workers
#11
Tracey L Sletten, Suzanne Ftouni, Christian L Nicholas, Michelle Magee, Ronald R Grunstein, Sally Ferguson, David J Kennaway, Darren O'Brien, Steven W Lockley, Shantha M W Rajaratnam
OBJECTIVES: Night workers often experience high levels of sleepiness due to misalignment of the sleep-wake cycle from the circadian pacemaker, in addition to acute and chronic sleep loss. Exposure to light, in particular short wavelength light, can improve alertness and neurobehavioural performance. This randomised controlled trial examined the efficacy of blue-enriched polychromatic light to improve alertness and neurobehavioural performance in night workers. DESIGN: Participants were 71 night shift workers (42 males; 32...
June 19, 2017: Occupational and Environmental Medicine
https://www.readbyqxmd.com/read/28629344/antiresorptive-effect-of-a-cathepsin-k-inhibitor-ono-5334-and-its-relationship-to-bmd-increase-in-a-phase-ii-trial-for-postmenopausal-osteoporosis
#12
Makoto Tanaka, Yoshitaka Hashimoto, Chihiro Hasegawa, Steve Deacon, Richard Eastell
BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship...
June 19, 2017: BMC Musculoskeletal Disorders
https://www.readbyqxmd.com/read/28629264/a-comparative-study-of-subgroup-identification-methods-for-differential-treatment-effect-performance-metrics-and-recommendations
#13
Demissie Alemayehu, Yang Chen, Marianthi Markatou
Subgroup identification with differential treatment effects serves as an important step towards precision medicine, as it provides evidence regarding how individuals with specific characteristics respond to a given treatment. This knowledge not only supports the tailoring of treatment strategies but also prompts the development of new treatments. This manuscript provides a brief overview of the issues associated with the methodologies aimed at identifying subgroups with differential treatment effects, and studies in depth the operational characteristics of five data-driven methods that have appeared recently in the literature...
January 1, 2017: Statistical Methods in Medical Research
https://www.readbyqxmd.com/read/28628931/-the-probabilistic-efficiency-frontier-a-value-assessment-of-treatment-options-in-hepatitis-c
#14
Axel C Mühlbacher, Andrew Sadler
Background The German Institute for Quality and Efficiency in Health Care (IQWiG) recommends the concept of the efficiency frontier to assess health care interventions. The efficiency frontier supports regulatory decisions on reimbursement prices for the appropriate allocation of health care resources. Until today this cost-benefit assessment framework has only been applied on the basis of individual patient-relevant endpoints. This contradicts the reality of a multi-dimensional patient benefit. Objective The objective of this study was to illustrate the operationalization of multi-dimensional benefit considering the uncertainty in clinical effects and preference data in order to calculate the efficiency of different treatment options for hepatitis C (HCV)...
June 19, 2017: Das Gesundheitswesen
https://www.readbyqxmd.com/read/28627356/aquatic-therapy-for-children-with-duchenne-muscular-dystrophy-a-pilot-feasibility-randomised-controlled-trial-and-mixed-methods-process-evaluation
#15
Daniel Hind, James Parkin, Victoria Whitworth, Saleema Rex, Tracey Young, Lisa Hampson, Jennie Sheehan, Chin Maguire, Hannah Cantrill, Elaine Scott, Heather Epps, Marion Main, Michelle Geary, Heather McMurchie, Lindsey Pallant, Daniel Woods, Jennifer Freeman, Ellen Lee, Michelle Eagle, Tracey Willis, Francesco Muntoni, Peter Baxter
BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES: To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work...
May 2017: Health Technology Assessment: HTA
https://www.readbyqxmd.com/read/28624331/long-term-detection-of-atrial-fibrillation-with-insertable-cardiac-monitors-in-a-real-world-cryptogenic-stroke-population
#16
Paul D Ziegler, John D Rogers, Scott W Ferreira, Allan J Nichols, Mark Richards, Jodi L Koehler, Shantanu Sarkar
BACKGROUND: The long-term incidence of atrial fibrillation (AF) in cryptogenic stroke (CS) patients has been explored in carefully controlled clinical trials but real-world data are limited. We investigated the two-year incidence of AF in real-world clinical practice among a large cohort of patients with an insertable cardiac monitor (ICM) placed for AF detection following CS. METHODS: Patients in the de-identified Medtronic Discovery™ Link database who received an ICM (Reveal LINQ™) for the purpose of AF detection following CS were included and monitored for up to 2years...
June 10, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28621000/how-serious-is-bias-in-effect-estimation-in-randomised-trials-with-survival-data-given-risk-heterogeneity-and-informative-censoring
#17
Roseanne McNamee
It is often assumed that randomisation will prevent bias in estimation of treatment effects from clinical trials, but this is not true of the semiparametric Proportional Hazards model for survival data when there is underlying risk heterogeneity. Here, a new formula is proposed for estimation of this bias, improving on a previous formula through ease of use and clarity regarding the role of the mid-study cumulative hazard rate, shown to be an important factor for the bias magnitude. Informative censoring (IC) is recognised as a source of bias...
June 15, 2017: Statistics in Medicine
https://www.readbyqxmd.com/read/28620761/medicinal-chemistry-of-%C3%AF-1-receptor-ligands-pharmacophore-models-synthesis-structure-affinity-relationships-and-pharmacological-applications
#18
Frauke Weber, Bernhard Wünsch
In the first part of this chapter, we summarize the various pharmacophore models for σ1 receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the σ1 receptor. The second part focuses on the synthesis and biological properties of different σ1 receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC50 values of cell growth and survival inhibition studies are given for all derivatives...
June 16, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28619503/clinical-pharmacokinetics-of-levornidazole-in-elderly-subjects-and-dosing-regimen-evaluation-using-pharmacokinetic-pharmacodynamic-analysis
#19
Beining Guo, Gaoli He, Xiaojie Wu, Jicheng Yu, Guoying Cao, Yi Li, Yaxin Fan, Yuancheng Chen, Yaoguo Shi, Yingyuan Zhang, Jing Zhang
PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years)...
June 12, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28616417/the-comparison-the-effect-of-training-by-means-of-simulation-and-oral-method-on-midwives-skill-in-management-of-shoulder-dystocia
#20
Masoumeh Kordi, Fatemeh Erfanian, Farzaneh Rashidi Fakari, Fatemeh Dastfan, Keivan Shariati Nejad
INTRODUCTION: Shoulder dystocia is one of the obstetric emergencies that are accompanied to serious risks for mother and fetus. It necessitates making the method of training of shoulder dystocia management more efficient, i.e., better management and giving services with higher quality. Thus, this study was carried out to compare the impact of training by simulation and oral technique on the skill of the employed midwives in obstetric clinics at Mashhad city (Iran) in shoulder dystocia management during 2012...
2017: Journal of Education and Health Promotion
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