Assessment and Implication of Prognostic Imbalance in Randomized Controlled Trials with a Binary Outcome – A Simulation Study

Chance imbalance in baseline prognosis of a randomized controlled trial can lead to over or underestimation of treatment effects, particularly in trials with small sample sizes. Our study aimed to (1) evaluate the probability of imbalance in a binary prognostic factor (PF) between two treatment arms, (2) investigate the impact of prognostic imbalance on the estimation of a treatment effect, and (3) examine the effect of sample size (n) in relation to the first two objectives.We simulated data from parallel-group trials evaluating a binary outcome by varying the risk of the outcome, effect of the treatment, power and prevalence of the PF, and n. Logistic regression models with and without adjustment for the PF were compared in terms of bias, standard error, coverage of confidence interval and statistical power.For a PF with a prevalence of 0.5, the probability of a difference in the frequency of the PF≥5% reaches 0.42 with 125/arm. Ignoring a strong PF (relative risk = 5) leads to underestimating the strength of a moderate treatment effect, and the underestimate is independent of n when n is >50/arm. Adjusting for such PF increases statistical power. If the PF is weak (RR = 2), adjustment makes little difference in statistical inference. Conditional on a 5% imbalance of a powerful PF, adjustment reduces the likelihood of large bias. If an absolute measure of imbalance ≥5% is deemed important, including 1000 patients/arm provides sufficient protection against such an imbalance. Two thousand patients/arm may provide an adequate control against large random deviations in treatment effect estimation in the presence of a powerful PF.The probability of prognostic imbalance in small trials can be substantial. Covariate adjustment improves estimation accuracy and statistical power, and hence should be performed when strong PFs are observed

NF-kappaB mediates the survival of human bronchial epithelial cells exposed to cigarette smoke extract

Background: We have previously reported that low concentrations of cigarette smoke extract induce DNA damage without leading to apoptosis or necrosis in human bronchial epithelial cells (HBECs), and that IL-6/STAT3 signaling contributes to the cell survival. Since NF-kappa B is also involved in regulating apoptosis and cell survival, the current study was designed to investigate the role of NF-kappa B in mediating cell survival in response to cigarette smoke exposure in HBECs. Methods: Both the pharmacologic inhibitor of NF-kappa B, curcumin, and RNA interference targeting p65 were used to block NF-kappa B signaling in HBECs. Apoptosis and cell survival were then assessed by various methods including COMET assay, LIVE/DEAD Cytotoxicity/Viability assay and colony formation assay. Results: Cigarette smoke extract (CSE) caused DNA damage and cell cycle arrest in S phase without leading to apoptosis in HBECs as evidenced by TUNEL assay, COMET assay and DNA content assay. CSE stimulated NF-kappa B -DNA binding activity and up-regulated Bcl-XL protein in HBECs. Inhibition of NF-kappa B by the pharmacologic inhibitor curcumin (20 mu M) or suppression of p65 by siRNA resulted in a significant increase in cell death in response to cigarette smoke exposure. Furthermore, cells lacking p65 were incapable of forming cellular colonies when these cells were exposed to CSE, while they behaved normally in the regular culture medium. Conclusion: The current study demonstrates that CSE activates NF-kappa B and up-regulates Bcl-XL through NF-kappa B activation in HBECs, and that CSE induces cell death in cells lacking p65. These results suggest that activation of NF-kappa B regulates cell survival following DNA damage by cigarette smoke in human bronchial epithelial cells.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000260432600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Respiratory SystemSCI(E)28ARTICLEnull

Detection of hCG Responsive Expression of the Steroidogenic Acute Regulatory Protein in Mouse Leydig Cells

The steroidogenic acute regulatory (StAR) protein, a novel mitochondrial protein, is involved in the regulation of steroid hormone biosynthesis through its mediation of the intramitochondrial transport of the steroid substrate, cholesterol, to the cytochrome P450 cholesterol side chain cleavage (P450scc) enzyme. The expression of StAR protein is regulated by cAMP-dependent signaling in steroidogenic cells. During the course of our studies in mouse Leydig cells, we employ several methods for studying the regulation of StAR protein expression by human chorionic gonadotropin (hCG). A sensitive quantitative reverse transcription and polymerase chain reaction (RT-PCR) was utilized for determining StAR mRNA expression. Stimulation of mLTC-1 mouse Leydig tumor cells with hCG resulted in the coordinate regulation of StAR mRNA expression and progesterone accumulation in a time-response manner. The validity and accuracy of quantitative RT-PCR results in mLTC-1 cells were verified by a competitive PCR approach and were further confirmed in primary cultures of isolated mouse Leydig cells. Immunoblotting studies demonstrated an increase in the levels of the StAR protein in a concentration dependent manner following hCG stimulation in mLTC-1 cells. Northern hybridization analysis revealed three StAR transcripts, all of which were of sufficient size to encode functional StAR protein, and which were coordinately expressed in response to hCG. Collectively, the experimental approaches utilized in the present investigation allow for the demonstration and characterization of hCG mediated regulation of StAR mRNA and StAR protein expression in mouse Leydig cells

Association between ultrasound-detected synovitis and knee pain: a population-based case-control study with both cross-sectional and follow-up data

Background: Recently an important role for synovial pathology in the initiation and progression of knee osteoarthritis (OA) has been emphasised. This study aimed to examine whether ultrasonographydetected synovial changes (USSCs) associate with knee pain (KP) in a community population. Methods: A case-control study was conducted to compare people with early KP (n=298), established KP (n=100) or no KP (n=94) at baseline. Multinomial logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) between groups adjusted for radiographic osteoarthritis (ROA) severity and other confounding factors. After one year 255 participants with early and established KP completed the followup questionnaire for changes in KP. Logistic regression with adjustment was used to determine predictors of KP worsening. Results: At baseline, effusion was associated with early (OR 2.64, 95%CI 1.57 to 4.45) and established KP (OR 5.07, 95%CI 2.74 to 9.38). Synovial hypertrophy was also associated with early (OR 5.43, 95%CI 2.12 to 13.92) and established KP (OR 13.27, 95%CI 4.97 to 35.43). The association with effusion diminished when adjusted for ROA. Power Doppler signal was uncommon (early KP 3%, established KP 2%, controls 0%). Baseline effusion predicted worsening of knee pain at one year (OR 1.95, 95% CI 1.05 to 3.64). However, after adjusting for ROA, the prediction was insignificant (aORs 0.95, 95%CI 0.44 to 2.02). Conclusion: US effusion and synovial hypertrophy are associated with KP, but only effusion predicts KP worsening. However, the association/prediction are not independent from ROA. Power Doppler signal is uncommon in people with KP. Further study is needed to understand whether synovitis is directly involved in different types of KP

Situational awareness within objective structured clinical examination stations in undergraduate medical training - a literature search

Background: Medical students may not be able to identify the essential elements of situational awareness (SA) necessary for clinical reasoning. Recent studies suggest that students have little insight into cognitive processing and SA in clinical scenarios. Objective Structured Clinical Examinations (OSCEs) could be used to assess certain elements of situational awareness. The purpose of this paper is to review the literature with a view to identifying whether levels of SA based on Endsley's model can be assessed utilising OSCEs during undergraduate medical training. Methods: A systematic search was performed pertaining to SA and OSCEs, to identify studies published between January 1975 (first paper describing an OSCE) and February 2017, in peer reviewed international journals published in English. PUBMED, EMBASE, PsycINFO Ovid and SCOPUS were searched for papers that described the assessment of SA using OSCEs among undergraduate medical students. Key search terms included "objective structured clinical examination", "objective structured clinical assessment" or "OSCE" and "non-technical skills", "sense-making", "clinical reasoning", "perception", "comprehension", "projection", "situation awareness", "situational awareness" and "situation assessment". Boolean operators (AND, OR) were used as conjunctions to narrow the search strategy, resulting in the limitation of papers relevant to the research interest. Areas of interest were elements of SA that can be assessed by these examinations. Results: The initial search of the literature retrieved 1127 publications. Upon removal of duplicates and papers relating to nursing, paramedical disciplines, pharmacy and veterinary education by title, abstract or full text, 11 articles were eligible for inclusion as related to the assessment of elements of SA in undergraduate medical students. Discussion: Review of the literature suggests that whole-task OSCEs enable the evaluation of SA associated with clinical reasoning skills. If they address the levels of SA, these OSCEs can provide supportive feedback and strengthen educational measures associated with higher diagnostic accuracy and reasoning abilities. Conclusion: Based on the findings, the early exposure of medical students to SA is recommended, utilising OSCEs to evaluate and facilitate SA in dynamic environment

Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

Previously, we demonstrated that allopregnanolone (APα) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease

A Research Agenda for Helminth Diseases of Humans: Social Ecology, Environmental Determinants, and Health Systems

In this paper, the Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), with the mandate to review helminthiases research and identify research priorities and gaps, focuses on the environmental, social, behavioural, and political determinants of human helminth infections and outlines a research and development agenda for the socioeconomic and health systems research required for the development of sustainable control programmes. Using Stockols' social-ecological approach, we describe the role of various social (poverty, policy, stigma, culture, and migration) and environmental determinants (the home environment, water resources development, and climate change) in the perpetuation of helminthic diseases, as well as their impact as contextual factors on health promotion interventions through both the regular and community-based health systems. We examine these interactions in regard to community participation, intersectoral collaboration, gender, and possibilities for upscaling helminthic disease control and elimination programmes within the context of integrated and interdisciplinary approaches. The research agenda summarises major gaps that need to be addressed