D-optimal designs for multiarm trials with dropouts.

Multiarm trials with follow-up on participants are commonly implemented to assess treatment effects on a population over the course of the studies. Dropout is an unavoidable issue especially when the duration of the multiarm study is long. Its impact is often ignored at the design stage, which may lead to less accurate statistical conclusions. We develop an optimal design framework for trials with repeated measurements, which takes potential dropouts into account, and we provide designs for linear mixed models where the presence of dropouts is noninformative and dependent on design variables. Our framework is illustrated through redesigning a clinical trial on Alzheimer's disease, whereby the benefits of our designs compared with standard designs are demonstrated through simulations.Grant codes MR∕N028171∕ and MC_UP_1302∕

PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al

Association between poor oral health and diabetes among Indian adult population: potential for integration with NCDs.

BACKGROUND: Studies in high-income countries have reported associations between oral health and diabetes. There is however a lack of evidence on this association from low and middle-income countries, especially India. The current study aimed to assess the prevalence of common oral diseases and their association with diabetes. METHODS: This cross-sectional study was nested within the second Cardiometabolic Risk Reduction in South Asia Surveillance Study. A subset of study participants residing in Delhi were administered the World Health Organization's Oral Health Assessment Questionnaire and underwent oral examination for caries experience and periodontal health assessment using standard indices. Diabetes status was ascertained by fasting blood glucose, glycosylated hemoglobin values or self-reported medication use. Information was captured on co-variates of interest. The association between oral health and diabetes was investigated using Multivariable Zero-Inflated Poisson (ZIP) regression analysis. RESULTS: Out of 2045 participants, 47% were women and the mean age of study participants was 42.17 (12.8) years. The age-standardised prevalence (95% confidence interval) estimates were 78.9% (75.6-81.7) for dental caries, 35.9% (32.3-39.6) for periodontitis. Nearly 85% participants suffered from at least one oral disease. Compared to diabetes-free counterparts, participants with diabetes had more severe caries experience [Mean Count Ratio (MCR)?=?1.07 (1.03-1.12)] and attachment loss [MCR?=?1.10 (1.04-1.17)]. Also, the adjusted prevalence of periodontitis was significantly higher among participants with diabetes [42.3%(40.0-45.0)] compared to those without diabetes [31.3%(30.3-32.2)]. CONCLUSION: We found that eight out of ten participants in urban Delhi suffered from some form of oral disease and participants with diabetes had worse oral health. This highlights the need for public health strategies to integrate oral health within the existing Non-Communicable Disease control programs

Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

The 5'-cap-structures of higher eukaryote mRNAs are ribose 2'-O-methylated. Likewise, a number of viruses replicating in the cytoplasm of eukayotes have evolved 2'-O-methyltransferases to modify autonomously their mRNAs. However, a defined biological role of mRNA 2'-O-methylation remains elusive. Here we show that viral mRNA 2'-O-methylation is critically involved in subversion of type-I-interferon (IFN-I) induction. We demonstrate that human and murine coronavirus 2'-O-methyltransferase mutants induce increased IFN-I expression, and are highly IFN-I sensitive. Importantly, IFN-I induction by 2'-O-methyltransferase-deficient viruses is dependent on the cytoplasmic RNA sensor melanoma differentiation-associated gene 5 (MDA5). This link between MDA5-mediated sensing of viral RNA and mRNA 2'-O-methylation suggests that RNA modifications, such as 2'-O-methylation, provide a molecular signature for the discrimination of self and non-self mRNA

Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients

Comparison between human fetal and adult skin

Healing of early-gestation fetal wounds results in scarless healing. Since the capacity for regeneration is probably inherent to the fetal skin itself, knowledge of the fetal skin composition may contribute to the understanding of fetal wound healing. The aim of this study was to analyze the expression profiles of different epidermal and dermal components in the human fetal and adult skin. In the human fetal skin (ranging from 13 to 22 weeks’ gestation) and adult skin biopsies, the expression patterns of several epidermal proteins (K10, K14, K16, K17, SKALP, involucrin), basement membrane proteins, Ki-67, blood vessels and extracellular matrix proteins (fibronectin, chondroitin sulfate, elastin) were determined using immunohistochemistry. The expression profiles of K17, involucrin, dermal Ki-67, fibronectin and chondroitin sulfate were higher in the fetal skin than in adult skin. In the fetal skin, elastin was not present in the dermis, but it was found in the adult skin. The expression patterns of basement membrane proteins, blood vessels, K10, K14, K16 and epidermal Ki-67 were similar in human fetal skin and adult skin. In this systematic overview, most of the differences between fetal and adult skin were found at the level of dermal extracellular matrix molecules expression. This study suggests that, especially, dermal components are important in fetal scarless healing

Qualitative assessment of innovations in healthcare provision

<p>Abstract</p> <p>Background</p> <p>The triad of quality, innovation and economic restraint is as important in health care as it is in the business world. There are many proposals for the assessment of quality and of economic restraints in health care but only a few address assessment of innovations. We propose a strategy and new structures to standardize the description of health care innovations and to quantify them.</p> <p>Discussion</p> <p>Strategy and structure are based on the assumption that in the early phase of an innovation only data on the feasibility and possibly on the efficacy or effectiveness of an innovation can be expected. From the patient's perspective, benefit resulting from an innovation can be confirmed only in a later phase of development. Early indicators of patient's benefit will be surrogate parameters which correlate only weakly with the desired endpoints. After the innovation has been in use, there will be more evidence on correlations between surrogate parameters and the desired endpoints to provide evidence of the patient benefit. From an administrative perspective, this evidence can be considered in decisions about public financing. Different criteria are proposed for the assessment of innovations in prevention, diagnosis and therapy. For decisions on public financing a public fund for innovations may be helpful. Depending on the phase of innovation risk sharing models are proposed between manufacturers, private insurers and public funding.</p> <p>Summary</p> <p>Potential for patient benefit is always uncertain during early stages of innovations. This uncertainty decreases with increasing information on the effects of the innovation. Information about an innovation can be quantified, categorized and integrated into rational economic decisions.</p

Determination of monolayer-protected gold nanoparticle ligand–shell morphology using NMR

It is accepted that the ligand shell morphology of nanoparticles coated with a monolayer of molecules can be partly responsible for important properties such as cell membrane penetration and wetting. When binary mixtures of molecules coat a nanoparticle, they can arrange randomly or separate into domains, for example, forming Janus, patchy or striped particles. To date, there is no straightforward method for the determination of such structures. Here we show that a combination of one-dimensional and two-dimensional NMR can be used to determine the ligand shell structure of a series of particles covered with aliphatic and aromatic ligands of varying composition. This approach is a powerful way to determine the ligand shell structure of patchy particles; it has the limitation of needing a whole series of compositions and ligands' combinations with NMR peaks well separated and whose shifts due to the surrounding environment can be large enough

Diverse species-specific phenotypic consequences of loss of function sorting nexin 14 mutations

Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) have also been conducted, demonstrated an important biochemical role during lipid biogenesis. In this study we report the effect of loss of SNX14 in mice, which resulted in embryonic lethality around mid-gestation due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. In contrast to other vertebrates, zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation were both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the consequences of loss of function varies between species. Mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo