Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis : Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course

Objective To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. Study design We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level >= 50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level Results We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. Conclusions Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.Peer reviewe

Comparison of Three Clinical Trial Treatments for Autism Spectrum Disorder Through Multivariate Analysis of Changes in Metabolic Profiles and Adaptive Behavior

Several studies associate autism spectrum disorder (ASD) pathophysiology with metabolic abnormalities related to DNA methylation and intracellular redox homeostasis. In this regard, three completed clinical trials are reexamined in this work: treatment with (i) methylcobalamin (MeCbl) in combination with low-dose folinic acid (LDFA), (ii) tetrahydrobiopterin, and (iii) high-dose folinic acid (HDFA) for counteracting abnormalities in the folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) pathways and also for improving ASD-related symptoms and behaviors. Although effects of treatment on individual metabolites and behavioral measures have previously been investigated, this study is the first to consider the effect of interventions on a set of metabolites of the FOCM/TS pathways and to correlate FOCM/TS metabolic changes with behavioral improvements across several studies. To do so, this work uses data from one case–control study and the three clinical trials to develop multivariate models for considering these aspects of treatment. Fisher discriminant analysis (FDA) is first used to establish a model for distinguishing individuals with ASD from typically developing (TD) controls, which is subsequently evaluated on the three treatment data sets, along with one data set for a placebo, to characterize the shift of FOCM/TS metabolism toward that of the TD population. Treatment with MeCbl plus LDFA and, separately, treatment with tetrahydrobiopterin significantly shifted the metabolites toward the values of the control group. Contrary to this, treatment with HDFA had a lesser, though still noticeable, effect whilst the placebo group showed marginal, but not insignificant, variations in metabolites. A second analysis is then performed with non-linear kernel partial least squares (KPLS) regression to predict changes in adaptive behavior, quantified by the Vineland Adaptive Behavior Composite, from changes in FOCM/TS biochemical measurements provided by treatment. Incorporating the 74 samples receiving any treatment, including placebo, into the regression analysis yields an R2 of 0.471 after cross-validation when using changes in six metabolic measurements as predictors. These results are suggestive of an ability to effectively improve pathway-wide FOCM/TS metabolic and behavioral abnormalities in ASD with clinical treatment

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children

Background: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. Methods: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. Results: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. Conclusions: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.Peer reviewe

Optical imaging of the peri-tumoral inflammatory response in breast cancer

<p>Abstract</p> <p>Purpose</p> <p>Peri-tumoral inflammation is a common tumor response that plays a central role in tumor invasion and metastasis, and inflammatory cell recruitment is essential to this process. The purpose of this study was to determine whether injected fluorescently-labeled monocytes accumulate within murine breast tumors and are visible with optical imaging.</p> <p>Materials and methods</p> <p>Murine monocytes were labeled with the fluorescent dye DiD and subsequently injected intravenously into 6 transgenic MMTV-PymT tumor-bearing mice and 6 FVB/n control mice without tumors. Optical imaging (OI) was performed before and after cell injection. Ratios of post-injection to pre-injection fluorescent signal intensity of the tumors (MMTV-PymT mice) and mammary tissue (FVB/n controls) were calculated and statistically compared.</p> <p>Results</p> <p>MMTV-PymT breast tumors had an average post/pre signal intensity ratio of 1.8+/- 0.2 (range 1.1-2.7). Control mammary tissue had an average post/pre signal intensity ratio of 1.1 +/- 0.1 (range, 0.4 to 1.4). The p-value for the difference between the ratios was less than 0.05. Confocal fluorescence microscopy confirmed the presence of DiD-labeled cells within the breast tumors.</p> <p>Conclusion</p> <p>Murine monocytes accumulate at the site of breast cancer development in this transgenic model, providing evidence that peri-tumoral inflammatory cell recruitment can be evaluated non-invasively using optical imaging.</p

Precision measurements of A1N in the deep inelastic regime

We have performed precision measurements of the double-spin virtual-photon asymmetry A1A1 on the neutron in the deep inelastic scattering regime, using an open-geometry, large-acceptance spectrometer and a longitudinally and transversely polarized 3He target. Our data cover a wide kinematic range 0.277≤x≤0.5480.277≤x≤0.548 at an average Q2Q2 value of 3.078 (GeV/c)2, doubling the available high-precision neutron data in this x range. We have combined our results with world data on proton targets to make a leading-order extraction of the ratio of polarized-to-unpolarized parton distribution functions for up quarks and for down quarks in the same kinematic range. Our data are consistent with a previous observation of anA1n zero crossing near x=0.5x=0.5. We find no evidence of a transition to a positive slope in(Δd+Δd¯)/(d+d¯) up to x=0.548x=0.548

Flux: An Adaptive Partitioning Operator for Continuous Query Systems

The long-running nature of continuous queries poses new scalability challenges for dataflow processing. CQ systems execute pipelined dataflows that may be shared across multiple queries. The scalability of these dataflows is limited by their constituent, stateful operators -- e.g. windowed joins or grouping operators. To scale such operators, a natural solution is to partition them across a shared-nothing platform. But in the CQ context, traditional, static techniques for partitioned parallelism can exhibit detrimental imbalances as workload and runtime conditions evolve. Longrunning CQ dataflows must continue to function robustly in the face of these imbalances

Integrated management systems maturity : drivers and benefits in Indian SMEs

This study aims to assess the impact of the antecedents of Integrated Management System (IMS) implementation on the IMS maturity and its subsequent impact on operational performance in the context of Indian Small and Medium Enterprises (SMEs). Using Theory of Planned Behavior, this study develops research hypotheses linking challenges and motivation to implement IMS with IMS maturity and its impact on operational performance. Using Structural Equation Modelling to analyze the primary data collected from 144 SMEs in India, this study finds that intrinsic motivation drives firms towards higher levels of maturity while extrinsic motivation for implementation leads to lower levels of IMS maturity. This study not only empirically evaluates a comprehensive framework on IMS maturity but also contributes to growing literature on analysis of Developing Economy SMEs. The findings of this research may drive SMEs to focus on IMS maturity, as the results suggest that it is positively related to operational performance. © 2021 Elsevier Lt

Is Crowdfunding for All? A Study of Medical Crowdfunding to Examine the New Facets of Digital Divide

The outcome of a crowdfunding campaign has been a topic of special interest for Information Systems (IS) researchers. Despite the success of crowdfunding platforms, there have been questions raised about their egalitarian nature in sharing the benefits across participants. Crowdfunding campaigns especially in philanthropic domains like medical crowdfunding are becoming popular in developing countries. Given the varying rates of success of these campaigns, it is imperative to understand if crowdfunding platforms are level playing fields for all kind of fundraisers. This ongoing research makes an effort to address this concern by examining how the disparities in digital capabilities influence the participation and therefore the outcome of crowdfunding campaigns. We believe that the differences in the digital media capabilities of campaigners can influence the outcome of the campaign. We examine this phenomenon with the help of Language Expectancy Theory and Elaboration Likelihood Model using data extracted from a large medical crowdfunding platform