Adaptive clinical trials incorporating treatment selection and evaluation: methodology and application in progressive multiple sclerosis

In progressive multiple sclerosis (MS) irreversible disability often takes many years to accumulate as a result prolonged trials are required to assess the benefits of therapies. There is a need to understand the relationship between short-term outcome measures such as MRI endpoints and long-term clinical outcomes in progression to determine the evolution of the disease early on. Thus, the common phase I-II-III paradigm for clinical trial design with separate trials for each phase may not be appropriate

Peripheral Blood Mitochondrial DNA as a Biomarker of Cerebral Mitochondrial Dysfunction Following Traumatic Brain Injury in a Porcine Model

Background Traumatic brain injury (TBI) has been shown to activate the peripheral innate immune system and systemic inflammatory response, possibly through the central release of damage associated molecular patterns (DAMPs). Our main purpose was to gain an initial understanding of the peripheral mitochondrial response following TBI, and how this response could be utilized to determine cerebral mitochondrial bioenergetics. We hypothesized that TBI would increase peripheral whole blood relative mtDNA copy number, and that these alterations would be associated with cerebral mitochondrial bioenergetics triggered by TBI. Methodology Blood samples were obtained before, 6 h after, and 25 h after focal (controlled cortical impact injury: CCI) and diffuse (rapid non-impact rotational injury: RNR) TBI. PCR primers, unique to mtDNA, were identified by aligning segments of nuclear DNA (nDNA) to mtDNA, normalizing values to nuclear 16S rRNA, for a relative mtDNA copy number. Three unique mtDNA regions were selected, and PCR primers were designed within those regions, limited to 25-30 base pairs to further ensure sequence specificity, and measured utilizing qRT-PCR. Results Mean relative mtDNA copy numbers increased significantly at 6 and 25 hrs after following both focal and diffuse traumatic brain injury. Specifically, the mean relative mtDNA copy number from three mitochondrial-specific regions pre-injury was 0.84 ± 0.05. At 6 and 25 h after diffuse non-impact TBI, mean mtDNA copy number was significantly higher: 2.07 ± 0.19 (P \u3c 0.0001) and 2.37 ± 0.42 (P \u3c 0.001), respectively. Following focal impact TBI, relative mtDNA copy number was also significantly higher, 1.35 ± 0.12 (P \u3c 0.0001) at 25 hours. Alterations in mitochondrial respiration in the hippocampus and cortex post-TBI correlated with changes in the relative mtDNA copy number measured in peripheral blood. Conclusions Alterations in peripheral blood relative mtDNA copy numbers may be a novel biosignature of cerebral mitochondrial bioenergetics with exciting translational potential for non-invasive diagnostic and interventional studies

Food chain approach to lowering the saturated fat of milk and dairy products

Lactating cow diets were supplemented with high oleic acid sunflower oil over two production periods spanning two years, to modify the milk fat, partially replacing saturated fatty acids (SFA) with cis-monounsaturated fatty acids (MUFA). The resulting milk was used for ultra-high temperature (UHT) milk, butter and Cheddar cheese production, and fatty acid profiles were compared with those of conventionally-produced products. Fat from products made with modified milk had lower SFA and higher cis- and trans-MUFA concentrations than that of conventional products. This was consistent over production periods, demonstrating that this food chain approach could be adopted on a wider scale

Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis

Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes. Method: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented. Results: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10−7, OR = 1.70, 95%CI = 1.38 − 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10−8, OR = 0.65(0.57 − 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10−9, OR = 1.73 95%CI = (1.44 − 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10−5, OR = 1.39, 95%CI = (1.19 − 1.61)], previously demonstrated in metabolic disease and diabetes in adults. Conclusion: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications

Extinction Corrected Star Formation Rates Empirically Derived from Ultraviolet-Optical Colors

Using a sample of galaxies from the Sloan Digital Sky Survey spectroscopic catalog with measured star-formation rates (SFRs) and ultraviolet (UV) photometry from the GALEX Medium Imaging Survey, we derived empirical linear correlations between the SFR to UV luminosity ratio and the UV-optical colors of blue sequence galaxies. The relations provide a simple prescription to correct UV data for dust attenuation that best reconciles the SFRs derived from UV and emission line data. The method breaks down for the red sequence population as well as for very blue galaxies such as the local ``supercompact'' UV luminous galaxies and the majority of high redshift Lyman Break Galaxies which form a low attenuation sequence of their own.Comment: 20 pages, 11 figures, accepted for publication in the ApJS GALEX special issu

Practical guidance for clinical microbiology laboratories: Viruses causing acute respiratory tract infections

Respiratory viral infections are associated with a wide range of acute syndromes and infectious disease processes in children and adults worldwide. Many viruses are implicated in these infections, and these viruses are spread largely via respiratory means between humans but also occasionally from animals to humans. This article is an American Society for Microbiology (ASM)-sponsored Practical Guidance for Clinical Microbiology (PGCM) document identifying best practices for diagnosis and characterization of viruses that cause acute respiratory infections and replaces the most recent prior version of the ASM-sponsored Cumitech 21 document, Laboratory Diagnosis of Viral Respiratory Disease, published in 1986. The scope of the original document was quite broad, with an emphasis on clinical diagnosis of a wide variety of infectious agents and laboratory focus on antigen detection and viral culture. The new PGCM document is designed to be used by laboratorians in a wide variety of diagnostic and public health microbiology/virology laboratory settings worldwide. The article provides guidance to a rapidly changing field of diagnostics and outlines the epidemiology and clinical impact of acute respiratory viral infections, including preferred methods of specimen collection and current methods for diagnosis and characterization of viral pathogens causing acute respiratory tract infections. Compared to the case in 1986, molecular techniques are now the preferred diagnostic approaches for the detection of acute respiratory viruses, and they allow for automation, high-throughput workflows, and near-patient testing. These changes require quality assurance programs to prevent laboratory contamination as well as strong preanalytical screening approaches to utilize laboratory resources appropriately. Appropriate guidance from laboratorians to stakeholders will allow for appropriate specimen collection, as well as correct test ordering that will quickly identify highly transmissible emerging pathogens

Ultraviolet through Infrared Spectral Energy Distributions from 1000 SDSS Galaxies: Dust Attenuation

The meaningful comparison of models of galaxy evolution to observations is critically dependent on the accurate treatment of dust attenuation. To investigate dust absorption and emission in galaxies we have assembled a sample of ~1000 galaxies with ultraviolet (UV) through infrared (IR) photometry from GALEX, SDSS, and Spitzer and optical spectroscopy from SDSS. The ratio of IR to UV emission (IRX) is used to constrain the dust attenuation in galaxies. We use the 4000A break as a robust and useful, although coarse, indicator of star formation history (SFH). We examine the relationship between IRX and the UV spectral slope (a common attenuation indicator at high-redshift) and find little dependence of the scatter on 4000A break strength. We construct average UV through far-IR spectral energy distributions (SEDs) for different ranges of IRX, 4000A break strength, and stellar mass (M_*) to show the variation of the entire SED with these parameters. When binned simultaneously by IRX, 4000A break strength, and M_* these SEDs allow us to determine a low resolution average attenuation curve for different ranges of M_*. The attenuation curves thus derived are consistent with a lambda^{-0.7} attenuation law, and we find no significant variations with M_*. Finally, we show the relationship between IRX and the global stellar mass surface density and gas-phase-metallicity. Among star forming galaxies we find a strong correlation between IRX and stellar mass surface density, even at constant metallicity, a result that is closely linked to the well-known correlation between IRX and star-formation rate.Comment: 12 pages, 8 figures, 2 tables, appearing in the Dec 2007 GALEX special issue of ApJ Supp (29 papers

Human and biophysical influences on fire occurrence in the United States

National-scale analyses of fire occurrence are needed to prioritize fire policy and management activities across the United States. However, the drivers of national-scale patterns of fire occurrence are not well understood, and how the relative importance of human or biophysical factors varies across the country is unclear. Our research goal was to model the drivers of fire occurrence within ecoregions across the conterminous United States. We used generalized linear models to compare the relative influence of human, vegetation, climate, and topographic variables on fire occurrence in the United States, as measured by MODIS active fire detections collected between 2000 and 2006. We constructed models for all fires and for large fires only and generated predictive maps to quantify fire occurrence probabilities. Areas with high fire occurrence probabilities were widespread in the Southeast, and localized in the Mountain West, particularly in southern California, Arizona, and New Mexico. Probabilities for large-fire occurrence were generally lower, but hot spots existed in the western and southcentral United States The probability of fire occurrence is a critical component of fire risk assessments, in addition to vegetation type, fire behavior, and the values at risk. Many of the hot spots we identified have extensive development in the wildland–urban interface and are near large metropolitan areas. Our results demonstrated that human variables were important predictors of both all fires and large fires and frequently exhibited nonlinear relationships. However, vegetation, climate, and topography were also significant variables in most ecoregions. If recent housing growth trends and fire occurrence patterns continue, these areas will continue to challenge policies and management efforts seeking to balance the risks generated by wildfires with the ecological benefits of fire.Keywords: MODIS active fires, Wildfire risk, Wildland–urban interface, Fire occurrenc

IR and UV Galaxies at z=0.6 -- Evolution of Dust Attenuation and Stellar Mass as Revealed by SWIRE and GALEX

We study dust attenuation and stellar mass of $\rm z\sim 0.6$ star-forming galaxies using new SWIRE observations in IR and GALEX observations in UV. Two samples are selected from the SWIRE and GALEX source catalogs in the SWIRE/GALEX field ELAIS-N1-00 ($\Omega = 0.8$ deg$^2$). The UV selected sample has 600 galaxies with photometric redshift (hereafter photo-z) $0.5 \leq z \leq 0.7$ and NUV$\leq 23.5$ (corresponding to \rm L_{FUV} \geq 10^{9.6} L_\sun). The IR selected sample contains 430 galaxies with $f_{24\mu m} \geq 0.2$ mJy (\rm L_{dust} \geq 10^{10.8} L_\sun) in the same photo-z range. It is found that the mean $\rm L_{dust}/L_{FUV}$ ratios of the z=0.6 UV galaxies are consistent with that of their z=0 counterparts of the same $\rm L_{FUV}$. For IR galaxies, the mean $\rm L_{dust}/L_{FUV}$ ratios of the z=0.6 LIRGs (\rm L_{dust} \sim 10^{11} L_\sun) are about a factor of 2 lower than local LIRGs, whereas z=0.6 ULIRGs (\rm L_{dust} \sim 10^{12} L_\sun) have the same mean $\rm L_{dust}/L_{FUV}$ ratios as their local counterparts. This is consistent with the hypothesis that the dominant component of LIRG population has changed from large, gas rich spirals at z$>0.5$ to major-mergers at z=0. The stellar mass of z=0.6 UV galaxies of \rm L_{FUV} \leq 10^{10.2} L_\sun is about a factor 2 less than their local counterparts of the same luminosity, indicating growth of these galaxies. The mass of z=0.6 UV lunmous galaxies (UVLGs: \rm L_{FUV} > 10^{10.2} L_\sun) and IR selected galaxies, which are nearly exclusively LIRGs and ULIRGs, is the same as their local counterparts.Comment: 27 pages, 8 figures, to be published in the Astrophysical Journal Supplement series dedicated to GALEX result