Carter, Rickey E.

Introduction Acute lung injury (ALI) is a devastating condition that places a heavy burden on public health resources. Although the need for effective ALI prevention strategies is increasingly recognised, no effective preventative strategies exist. The Lung Injury Prevention Study with Aspirin (LIPS-A) aims to test whether aspirin (ASA) could prevent and/or mitigate the development of ALI. Methods and analysis LIPS-A is a multicentre, double-blind, randomised clinical trial testing the hypothesis that the early administration of ASA will result in a reduced incidence of ALI in adult patients at high risk. This investigation will enrol 400 study participants from 14 hospitals across the USA. Conditional logistic regression will be used to test the primary hypothesis that early ASA administration will decrease the incidence of ALI. Ethics and dissemination Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approval of both the protocol and informed consent documents were also obtained from the institutional review board of each participating institution prior to enrolling study participants at the respective site. In addition to providing important clinical and mechanistic information, this investigation will inform the scientific merit and feasibility of a phase III trial on ASA as an ALI prevention agent. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to Pub Med Central in accordance with the National Institute of Health Public Access Policy.

OBJECTIVE Physical activity (PA), even at low intensity, promotes health and improves hyperglycemia. However, the effect of low-intensity PA captured with accelerometery on glucose variability in healthy individuals and patients with type 1 diabetes has not been examined. Quantifying the effects of PA on glycemic variability would improve artificial endocrine pancreas (AEP) algorithms. RESEARCH DESIGN AND METHODS We studied 12 healthy control subjects (five males, 37.7 ± 13.7 years of age) and 12 patients with type 1 diabetes (five males, 37.4 ± 14.2 years of age) for 88 h. Participants performed PA approximating a threefold increase over their basal metabolic rate. PA was captured using a PA-monitoring system, and interstitial fluid glucose concentrations were captured with continuous glucose monitors. In random order, one meal per day was followed by inactivity, and the other meals were followed by walking. Glucose and PA data for a total of 216 meals were analyzed from 30 min prior to meal ingestion to 270 min postmeal. RESULTS In healthy subjects, the incremental glucose area under the curve was 4.5 mmol/L/270 min for meals followed by walking, whereas it was 9.6 mmol/L/270 min (P = 0.022) for meals followed by inactivity. The corresponding glucose excursions for those with type 1 diabetes were 7.5 mmol/L/270 min and 18.4 mmol/L/270 min, respectively (P < 0.001). CONCLUSIONS Walking significantly impacts postprandial glucose excursions in healthy populations and in those with type 1 diabetes. AEP algorithms incorporating PA may enhance tight glycemic control end points.

Magnetic resonance elastography (MRE) is a MR imaging method capable of spatially resolving the intrinsic mechanical properties of normal lung parenchyma. We tested the hypothesis that the mechanical properties of edematous lung exhibit local properties similar to those of a fluid-filled lung at transpulmonary pressures (Ptp) up to 25 cm H2O. Pulmonary edema was induced in anesthetized female adult Sprague-Dawley rats by mechanical ventilation to a pressure of 40 cm H2O for ∼30 min. Prior to imaging the wet weight of each ex vivo lung set was measured. MRE, high-resolution T1-weighted spin echo and T2* gradient echo data were acquired at each Ptpfor both normal and injured ex vivo lungs. At Ptps of 6 cm H2O and greater, the shear stiffness of normal lungs was greater than injured lungs ( P ≤ 0.0003). For Ptps up to 12 cm H2O, shear stiffness was equal to 1.00, 1.07, 1.16, and 1.26 kPa for the injured and 1.31, 1.89, 2.41, and 2.93 kPa for normal lungs at 3, 6, 9, and 12 cm H2O, respectively. For injured lungs MRE magnitude signal and shear stiffness within regions of differing degrees of alveolar flooding were calculated as a function of Ptp. Differences in shear stiffness were statistically significant between groups ( P < 0.001) with regions of lower magnitude signal being stiffer than those of higher signal. These data demonstrate that when the alveolar space filling material is fluid, MRE-derived parenchymal shear stiffness of the lung decreases, and the lung becomes inherently softer compared with normal lung.

Multiple testing and its impact on the type I and type II error rates are frequently discussed in the statistical and biomedical literature. The Bonferroni adjustment is one of the most widely used approaches, yet it suffers from poor statistical performance when there are correlated test statistics. For example, it is criticized to be too conservative. Nonetheless, part of the strong appeal of the Bonferroni approach is the straightforward implementation and relatively intuitive explanation. In this manuscript, a novel adaptation to the traditional Bonferroni approach that accounts for correlated data is proposed. A simple correction factor based on intraclass correlation is applied to the standard Bonferroni method to overcome the shortcomings of the standard Bonferroni adjustment yet maintains its advantages. The method is motivated by an early phase clinical trial examining the effect of a study medication on marijuana craving, which is commonly quantified into four correlated constructs. A detailed simulation study demonstrated that the proposed approach is statistically sound and appropriate for a wide range of common settings. Copyright © 2012 John Wiley & Sons, Ltd.

OBJECTIVE To test whether diabetic polyneuropathies (DPNs), retinopathy, or nephropathy is more prevalent in subjects with impaired glycemia (IG) (abnormality of impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired HbA1c [IA1C]) than in healthy subjects (non-IG). RESEARCH DESIGN AND METHODS Matched IG and non-IG volunteers were randomly identified from population-based diagnostic and laboratory registries, restudied, and reclassified as non-IG (n = 150), IG (n = 174), or new diabetes (n = 218). RESULTS Frequency (%) of DPN in non-IG, IG, and new diabetes was 3 (2.0%), 3 (1.7%), and 17 (7.8%) narrowly defined (no other cause for polyneuropathy) and 19 (12.7%), 22 (12.6%), and 38 (17.4%) broadly defined. Mean and frequency distribution of composite scores of nerve conduction and quantitative sensation tests were not significantly different between IG and non-IG but were worse in new diabetes. Frequency of retinopathy and nephropathy was significantly increased only in new diabetes. In secondary analysis, small but significant increases in retinopathy and nephropathy were found in IGT, IFG, and IGT combined groups. CONCLUSIONS In population studies of Olmsted County, Minnesota, inhabitants, prevalence of typical DPN, retinopathy, and nephropathy was significantly increased only in subjects with new diabetes—not in subjects with IG as defined by American Diabetes Association (ADA) criteria of abnormality of IFG, IGT, or IA1C. For atypical DPN, such an increase was not observed even in subjects with new diabetes. In medical practice, explanations other than IG should be sought for patients with atypical DPN (chronic idiopathic axonal polyneuropathy) who have IG.

Objective: This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. Method: The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the Clinical Global Impression (CGI) ratings and substance abuse as quantified by urine drug screens and self-reported use. Results: Significant improvements from baseline were found on both the WRAADS and CGI measurements. No abuse of the study medication was observed. Conclusion: The findings suggested that MTS may improve ADHD symptoms in adults with a history of stimulant misuse; however, there were limitations. The study data showed the need for subsequent randomized studies that further explore findings made in this study.

SummaryClinical trials often include binary end points. In some cases, no successes are observed and the usual large sample estimates of relative risk are undefined. The paper proposes an estimator for relative risk based on the median unbiased estimator. The relative risk estimator proposed is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and an SAS macro is available to perform the necessary calculations. An on-going randomized clinical trial motivated the development of the estimator and is used to illustrate the approach.