Shorter Disease Duration Is Associated With Higher Rates of Response to Vedolizumab in Patients With Crohn's Disease But Not Ulcerative Colitis.

Background & aimsPatients with Crohn's disease (CD), but not ulcerative colitis (UC), of shorter duration have higher rates of response to tumor necrosis factor (TNF) antagonists than patients with longer disease duration. Little is known about the association between disease duration and response to other biologic agents. We aimed to evaluate response of patients with CD or UC to vedolizumab, stratified by disease duration.MethodsWe analyzed data from a retrospective, multicenter, consortium of patients with CD (n = 650) or UC (n = 437) treated with vedolizumab from May 2014 through December 2016. Using time to event analyses, we compared rates of clinical remission, corticosteroid-free remission (CSFR), and endoscopic remission between patients with early-stage (≤2 years duration) and later-stage (>2 years) CD or UC. We used Cox proportional hazards models to identify factors associated with outcomes.ResultsWithin 6 months initiation of treatment with vedolizumab, significantly higher proportions of patients with early-stage CD, vs later-stage CD, achieved clinical remission (38% vs 23%), CSFR (43% vs 14%), and endoscopic remission (29% vs 13%) (P < .05 for all comparisons). After adjusting for disease-related factors including previous exposure to TNF antagonists, patients with early-stage CD were significantly more likely than patients with later-stage CD to achieve clinical remission (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.02-2.49), CSFR (aHR, 3.39; 95% CI, 1.66-6.92), and endoscopic remission (aHR, 1.90; 95% CI, 1.06-3.39). In contrast, disease duration was not a significant predictor of response among patients with UC.ConclusionsPatients with CD for 2 years or less are significantly more likely to achieve a complete response, CSFR, or endoscopic response to vedolizumab than patients with longer disease duration. Disease duration does not associate with response vedolizumab in patients with UC

Active and Passive Radiative Transfer Modeling of the Olympic Mountains Experiment

Sensor forward models are an important tool for interpreting remote sensing observations of geophysical phenomena. By implementing a three-dimensional framework, we can simulate and analyze observations from various sensors on disparate platforms. To demonstrate our model framework, we simulate observations from the Olympic Mountains Experiment (OLYMPEX). The use of cloud model simulations allows us to understand sensor response to cloud ice, falling snow, and other processes and features, and the application of model tools to observations allows us to quantify precipitation.MIIST 3D Forward ModelThe Multi-Instrument Inverse Solver Testbed(MIIST) uses the Atmospheric Radiative TransferSimulator (ARTS) for solving the vector radiativetransfer (RT) equation in up to three spatialdimensions within a spherical geometry Gas absorptiono Line-by-line calculationso Fast transmittance tables Hydrometeor scattering solverso Discrete ordinateo RT4 (Evans, 1D)o Radar Single Scattering (1D or 3D)o Monte Carlo (3D)Scattering TablesHigh-fidelity hydrometeor scatteringtables are necessary for accurateand consistent forward modeling ofmulti-frequency observations Requires full Stokes matriceso And absorption vector Randomly oriented particleso Discrete Dipole Approximationo Characteristic Basis Function Method(coming soon) Horizontally-oriented plateso Invariant Imbedding T-matrix MethodCloud Resolving SimulationsCloud resolving simulations (e.g.,NU-WRF) supply output consistentwith ARTS needs Atmospheric Informationo Temperatureo Pressure / heighto Water vapor Hydrometeor Profileso ARTS architecture ripe for explicit binmicrophysics Examples use Morrison 2M schemeThe Olympic Mountains Experiment (OLYMPEX)Validation for GPM of mid-latitudefrontal systems approaching nearcoastalmountains from the ocean Large collection of ground-based andairborne sensorso Radarso Radiometerso In situ Contemporaneous with RADEXo Two sets of radar at same frequenciesRadiometer Simulation (3 km NUWRF, 20151203, 15:00)2018.12.14 7Simulate 166 GHz polarizationdifference Corresponds to the presence of aligned icecrystals Look at trends for both simulations andobservations Simulations can tolerate lower resolutiono Larger domainSimulations from Observations: OLYMPEXSimulate sensor response usinggeophysical retrievals as input Single frequency radar retrievals Multiple scattering enhancementapparent at W band Spatially dependent phenomenonModeling Application: 1D Retrievals03 December 2015 DC-8 and ER-2 flightso Focus on APR-3 (DC-8) Citationo Stacked microphysics legso Qualitative comparisonso Range of frozen habitso Presence of supercooledliquid cloudsResults Retrievals match probeso Good qualitative match Bands of increasedreflectivity correspond tolarge Dm and highaggregate fraction Significant amounts ofsupercooled liquid wate

Reduction in intraoperative bacterial contamination of peripheral intravenous tubing through the use of a novel device

Background: Hand hygiene is a vital intervention to reduce health-care associated infections, but compliance remains low. The authors hypothesized that improvements in intraoperative hand hygiene compliance would reduce transmission of bacteria to surgical patients and reduce the incidence of postsurgical healthcare-associated infections. Methods: The authors performed a controlled before-andafter study over 2 consecutive months. One hundred fourteen operative cases were enrolled. Two predesignated sites on the anesthesia machine were selected, decontaminated, and cultured via aseptic technique. These sites and the peripheral intravenous stopcock were cultured again after completion of the surgery. The treatment phase used a novel personal handdecontamination device capable of recording hand-decontamination events. Results: There were no significant differences in patient location, age, or case duration and procedure type between groups. Use of the Sprixx GJ device (Harbor Medical Inc., Santa Barbara, CA) increased hourly hand decontamination events by 27-fold as compared with baseline rates (P < 0.002; 95% confidence interval, 3.3-13.4). Use of the device was associated with a reduction in contamination in the anesthesia work area and peripheral intravenous tubing. Intravenous tubing contamination was identified in 32.8% of cases in the control group versus 7.5% in the treatment group (odds ratio, 0.17; 95% confidence interval, 0.06 -0.51; P < 0.01). Healthcare-associated infections rates were reduced in the device group (3.8%) as compared with the control group (17.2%) (odds ratio, 0.19; 95% confidence interval, 0.00 -0.81; P ‫؍‬ 0.02). Conclusions: Improved hand hygiene compliance through the use of a novel hand sanitation strategy reduces the risk of intraoperative bacterial transmission. The interventio

How Do Microbial Pathogens Make CENs?

This article does not have an abstract

miRNA Expression Profiling in Migrating Glioblastoma Cells: Regulation of Cell Migration and Invasion by miR-23b via Targeting of Pyk2

Glioblastoma (GB) is the most common and lethal type of primary brain tumor. Clinical outcome remains poor and is essentially palliative due to the highly invasive nature of the disease. A more thorough understanding of the molecular mechanisms that drive glioma invasion is required to limit dispersion of malignant glioma cells.We investigated the potential role of differential expression of microRNAs (miRNA) in glioma invasion by comparing the matched large-scale, genome-wide miRNA expression profiles of migrating and migration-restricted human glioma cells. Migratory and migration-restricted cell populations from seven glioma cell lines were isolated and profiled for miRNA expression. Statistical analyses revealed a set of miRNAs common to all seven glioma cell lines that were significantly down regulated in the migrating cell population relative to cells in the migration-restricted population. Among the down-regulated miRNAs, miR-23b has been reported to target potential drivers of cell migration and invasion in other cell types. Over-expression of miR-23b significantly inhibited glioma cell migration and invasion. A bioinformatics search revealed a conserved target site within the 3' untranslated region (UTR) of Pyk2, a non-receptor tyrosine kinase previously implicated in the regulation of glioma cell migration and invasion. Increased expression of miR-23b reduced the protein expression level of Pyk2 in glioma cells but did not significantly alter the protein expression level of the related focal adhesion kinase FAK. Expression of Pyk2 via a transcript variant missing the 3'UTR in miR-23b-expressing cells partially rescued cell migration, whereas expression of Pyk2 via a transcript containing an intact 3'UTR failed to rescue cell migration.Reduced expression of miR-23b enhances glioma cell migration in vitro and invasion ex vivo via modulation of Pyk2 protein expression. The data suggest that specific miRNAs may regulate glioma migration and invasion to influence the progression of this disease

Increased Glucose Availability Sensitizes Pancreatic Cancer to Chemotherapy

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose

Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex

Viral genetic tools to target specific brain cell types in humans and non-genetic model organisms will transform basic neuroscience and targeted gene therapy. Here we used comparative epigenetics to identify thousands of human neuronal subclass-specific putative enhancers to regulate viral tools, and 34% of these were conserved in mouse. We established an AAV platform to evaluate cellular specificity of functional enhancers by multiplexed fluorescent in situ hybridization (FISH) and single cell RNA sequencing. Initial testing in mouse neocortex yields a functional enhancer discovery success rate of over 30%. We identify enhancers with specificity for excitatory and inhibitory classes and subclasses including PVALB, LAMP5, and VIP/LAMP5 cells, some of which maintain specificity in vivo or ex vivo in monkey and human neocortex. Finally, functional enhancers can be proximal or distal to cellular marker genes, conserved or divergent across species, and could yield brain-wide specificity greater than the most selective marker genes

The Mating Type Locus (MAT) and Sexual Reproduction of Cryptococcus heveanensis: Insights into the Evolution of Sex and Sex-Determining Chromosomal Regions in Fungi

Mating in basidiomycetous fungi is often controlled by two unlinked, multiallelic loci encoding homeodomain transcription factors or pheromones/pheromone receptors. In contrast to this tetrapolar organization, Cryptococcus neoformans/Cryptococcus gattii have a bipolar mating system, and a single biallelic locus governs sexual reproduction. The C. neoformans MAT locus is unusually large (>100 kb), contains >20 genes, and enhances virulence. Previous comparative genomic studies provided insights into how this unusual MAT locus might have evolved involving gene acquisitions into two unlinked loci and fusion into one contiguous locus, converting an ancestral tetrapolar system to a bipolar one. Here we tested this model by studying Cryptococcus heveanensis, a sister species to the pathogenic Cryptococcus species complex. An extant sexual cycle was discovered; co-incubating fertile isolates results in the teleomorph (Kwoniella heveanensis) with dikaryotic hyphae, clamp connections, septate basidia, and basidiospores. To characterize the C. heveanensis MAT locus, a fosmid library was screened with C. neoformans/C. gattii MAT genes. Positive fosmids were sequenced and assembled to generate two large probably unlinked MAT gene clusters: one corresponding to the homeodomain locus and the other to the pheromone/receptor locus. Strikingly, two divergent homeodomain genes (SXI1, SXI2) are present, similar to the bE/bW Ustilago maydis paradigm, suggesting one or the other homeodomain gene was recently lost in C. neoformans/C. gattii. Sequencing MAT genes from other C. heveanensis isolates revealed a multiallelic homeodomain locus and at least a biallelic pheromone/receptor locus, similar to known tetrapolar species. Taken together, these studies reveal an extant C. heveanensis sexual cycle, define the structure of its MAT locus consistent with tetrapolar mating, and support the proposed evolutionary model for the bipolar Cryptococcus MAT locus revealing transitions in sexuality concomitant with emergence of a pathogenic clade. These studies provide insight into convergent processes that independently punctuated evolution of sex-determining loci and sex chromosomes in fungi, plants, and animals