Patient-reported impact of symptoms in adrenoleukodystrophy (PRISM-ALD).

Background: Adrenoleukodystrophy (ALD) is a multifaceted, X-linked, neurodegenerative disorder that comprises several clinical phenotypes. ALD affects patients through a variety of physical, emotional, social, and other disease-specific factors that collectively contribute to disease burden. To facilitate clinical care and research, it is important to identify which symptoms are most common and relevant to individuals with any subtype of ALD.

Endocannabinoid Modulation Using Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A Phase 1 Randomized, Placebo-Controlled Study.

Introduction: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by chronic motor and vocal tics. While consistently effective treatment is lacking, evidence indicates that the modulation of endocannabinoid system is potentially beneficial. Lu AG06466 (previously ABX-1431) is a highly selective inhibitor of monoacylglycerol lipase, the primary enzyme responsible for the degradation of the endocannabinoid ligand 2-arachidonoylglycerol.

Monoacylglycerol Lipase Inhibition in Tourette Syndrome: A 12-Week, Randomized, Controlled Study.

Background: Modulation of the endocannabinoid system via monoacylglycerol lipase inhibition with Lu AG06466 (formerly known as ABX-1431) has previously been shown to reduce tics in patients with Tourette syndrome.

Objective: The aim of this study was to evaluate the efficacy and safety of Lu AG06466 in reducing tics, premonitory urges, and comorbidities in patients with Tourette syndrome.

Methods: This was a 12-week, multicenter, randomized, placebo-controlled, double-blind clinical trial of Lu AG06466 given at two dose levels in 49 adults with Tourette syndrome.

Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes.

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.

Magnetic resonance imaging of the hand and wrist in a randomized, double-blind, multicenter, placebo-controlled trial of infliximab for rheumatoid arthritis: Comparison of dynamic contrast enhanced assessments with semi-quantitative scoring.

The objective of this study was to compare the scope and the discriminative power of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) to those of semi-quantitative MRI scoring for evaluating treatments for rheumatoid arthritis (RA) in multicenter randomized clinical trials (RCTs). Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. The most symptomatic wrist and metacarpophalangeal joints (MCPs) were imaged using MRI.

Insulin secretory effect of sitagliptin: assessment with a hyperglycemic clamp combined with a meal challenge.

Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened.

Metabolic improvements following Roux-en-Y surgery assessed by solid meal test in subjects with short duration type 2 diabetes.

Background: Glucose homeostasis improves within days following Roux-en-Y gastric bypass (RYGB) surgery. The dynamic metabolic response to caloric intake following RYGB has been assessed using liquid mixed meal tolerance tests (MMTT). Few studies have evaluated the glycemic and hormonal response to a solid mixed meal in subjects with diabetes prior to, and within the first month following RYGB.

Linearity of β-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series.

The graded glucose infusion (GGI) examines insulin secretory response patterns to continuously escalating glycemia. The current study series sought to more fully appraise its performance characteristics. Key questions addressed were comparison of the GGI to the hyperglycemic clamp (HGC), comparison of insulin secretory response patterns across three volunteer populations known to differ in β-cell function (healthy nonobese, obese nondiabetic, and type 2 diabetic), and characterization of effects of known insulin secretagogues in the context of a GGI.

Immune response and reactogenicity of intradermal administration versus subcutaneous administration of varicella-zoster virus vaccine: an exploratory, randomised, partly blinded trial.

Background: The licensed live, attenuated varicella-zoster virus vaccine prevents herpes zoster in adults older than 50 years. We aimed to determine whether intradermal administration of zoster vaccine could enhance vaccine immunogenicity compared with conventional needle subcutaneous administration.

Methods: In this randomised, dose-ranging study, adults aged 50 years or older who had a history of varicella or who had resided in a country with endemic varicella-zoster virus infection for 30 years or more were eligible.

Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.

Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine.

Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population.

Background: Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

Objectives: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability.

Methods: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design.

Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients.

Unlabelled: Approximately 30% of rheumatoid arthritis patients achieve inadequate response to anti-TNF biologics. Attempts to identify molecular biomarkers predicting response have met with mixed success. This may be attributable, in part, to the variable and subjective disease assessment endpoints with large placebo effects typically used to classify patient response.

Efavirenz modulation of sleep spindles and sleep spectral profile.

Non-nucleoside reverse transcriptase inhibitors are important antiretroviral agents for the treatment of human immunodeficiency virus. Some non-nucleoside reverse transcriptase inhibitors, in particular efavirenz, have prominent effects on sleep, cognition and psychiatric variables that limit their tolerability. To avoid confounds due to drug-drug and drug-disease interactions, we assessed the effects of efavirenz in healthy volunteers on sleep, cognition and psychological endpoints during the first week of treatment.

High-dimensional analysis of the aging immune system: verification of age-associated differences in immune signaling responses in healthy donors.

Background: Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors.

Methods: In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)].

Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.

Objectives: The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission tomography/computed tomographic imaging (FDG-PET/CT).

Background: Intensification of statin therapy reduces major cardiovascular events.

Methods: Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial.

Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized, two-center placebo-controlled study.

Introduction: We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA).

Methods: A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15 mg or 7.5 mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively.

Segmental bioimpedance for measuring amlodipine-induced pedal edema: a placebo-controlled study.

Background: The development of antihypertensives requires efficient and accurate tools for identifying pedal edema. Methodologies used to gauge the potential of an agent to induce pedal edema in short-term (<4-week) clinical trials have not been reported in the literature.

Objective: The purpose of this study was to identify a robust and practical method for measuring drug-induced pedal edema for use in the clinical development of antihypertensives.

A comparison of the natriuretic and kaliuretic effects of cicletanine and hydrochlorothiazide in prehypertensive and hypertensive humans.

Objectives: The aim of this study was to compare the single-dose effects of thiazide-type diuretics cicletanine and hydrochlorothiazide (HCTZ), on natriuresis and kaliuresis in prehypertensive and treatment-naïve, stage 1 hypertensive patients and to explore the impact of GRK4 gene polymorphisms on thiazide-induced urinary electrolyte excretion.

Methods: The study was a randomized, double-blind, placebo-controlled, three-period, four-treatment, balanced incomplete block, cross-over study in male patients assigned to treatment sequences consisting of placebo, cicletanine 50 mg, cicletanine 150 mg, and HCTZ 25 mg, doses used to treat hypertension. Cumulative urine samples were collected predosing and over 24 h after dosing in each period to compare urine electrolyte excretion profiles of potassium (UKV), sodium (UNaV), magnesium, calcium, phosphate, chloride, and pH among groups.

Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals.

Objective: Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisone's acute, dose-dependent effects on inflammation as well as biomarkers of glucose regulation and bone homeostasis.

Design: In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25 or 60 mg daily for 7 days.

A randomized clinical trial comparing point-of-care platelet function assays and bleeding time in healthy subjects treated with aspirin or clopidogrel.

Traditional assays of the coagulation status of patients, bleeding time assessment (BT) and light transmission aggregometry (LTA), are useful in clinical drug development. However, these assays are both labor intensive and expensive. BT results can be operator dependent and by its nature can inhibit subject enrollment in a clinical trial.

Evaluation of an experimental urodynamic platform to identify treatment effects: a randomized, placebo-controlled, crossover study in patients with overactive bladder.

Aims: To evaluate a urodynamic platform designed to identify treatment effects in small numbers of patients after a short duration of treatment using a medication with known efficacy in overactive bladder (OAB).

Methods: Twenty women with OAB were randomized in a crossover study with 7-day treatment periods with either tolterodine 4 mg long-acting (LA) or placebo and 7-day washout. Patients underwent urodynamic study (UDS) at baseline, 4-hr post-dose on Day 1 (PD1) and 4 hr post-dose on Day 7 (PD7) in each treatment period.

Test-retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C.

Purpose: To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis-C-infected subjects.

Materials And Methods: A biopsy-correlated repeatability study using four-slice MRE was conducted in five healthy and four HCV-infected subjects. Subjects were scanned twice on day 1 and after 7-14 days.

Evaluation of early biomarkers of muscle anabolic response to testosterone.

BACKGROUND: Early biomarkers of skeletal muscle anabolism will facilitate the development of therapies for sarcopenia and frailty. METHODS AND RESULTS: We examined plasma type III collagen N-terminal propeptide (P3NP), skeletal muscle protein fractional synthesis rate, and gene and protein expression profiles to identify testosterone-induced changes in muscle anabolism. Two placebo-controlled studies enrolled community-dwelling men (study 1, 60-75 years; study 2, 18-40 years) with low to normal testosterone levels.

The effects of simvastatin treatment on plasma lipid-related biomarkers in men with dyslipidaemia.

Background: Lipidomic biomarkers will facilitate the development of novel anti-atherosclerotic therapies.

Objective: To evaluate the responses of circulating biomarkers to simvastatin treatment.

Methods: A randomized, cross-over study in men with mixed dyslipidaemia was used to compare effects of simvastatin 40 mg/day with placebo.