Prevalence estimation of celiac disease in the general adult population of Latvia using serology and HLA genotyping

BACKGROUND: Prevalence estimates for celiac disease (CD) depend on the method used. The role of deamidated gliadin peptide (DGP) and genetic testing in epidemiological studies and diagnostic settings of celiac disease (CD) has still to be established. OBJECTIVES: The objective of this article is to assess the prevalence of CD in Latvia by combining serological tests with DQ2.5/DQ8 testing. METHODS: A total of 1444 adults from a randomly selected cross-sectional general population sample were tested by ELISA for tTG IgA, DGP IgA and IgG antibodies (QUANTA Lite®, Inova Diagnostics Inc). Samples with tTG IgA ≥20U were tested for EMA IgA by indirect immunofluorescence assay, and all specimens with tTG IgA ≥15U were tested by QUANTA-Flash® chemiluminescent assays (CIA) (Inova Diagnostics Inc) for tTG IgA, DGP IgA and IgG. DQ2.5/8 was detected in individuals with any positive ELISA test and a subgroup of controls. RESULTS: Forty-three individuals (2.98%; 95% CI: 2.10–3.86%) tested positive by at least one ELISA test; 41.86% of the serology-positive individuals (any test above the cutoff) were DQ positive. Six individuals (0.42%; 95% CI: 0.09–0.75%) were triple ELISA positive, and DQ2.5 or DQ8 was positive in all; 0.35% (95% CI: 0.05–0.65%) were tTG IgA and EMA positive. Two tTG IgA-negative cases were both DGP IgG and IgA positive, both being DQ positive; including them in the “serology-positive” group would increase the prevalence to 0.49% (95% CI: 0.13–0.85%). CIA tests revealed 2 tTG IgA-positive and EMA-negative cases with a positive genotype. DQ2.5 or DQ8 genotype was positive in 28.6% of the serology-negative population. CONCLUSIONS: Estimates of the prevalence of CD in Latvia based on the serogenetic testing approach range from 0.35% to 0.49% depending on the criteria used. There is a rationale for combining serological tests and DQ2.5/8 genotyping

Diagnostic and clinical significance of Crohn’s disease-specific anti-MZGP2 pancreatic antibodies by a novel ELISA:New anti-MZGP2 ELISA in Crohn’s

The recent identification of the pancreas major zymogen granule membrane glycoprotein 2 (MZGP2) as the major autoantigen of pancreatic autoantibody (PAB) has led to the appreciation of anti-MZGP2 antibodies as specific markers of Crohn’s disease (CrD). We have recently developed new, robust, highly sensitive and specific IgA and IgG anti-MZGP2 antibody ELISAs and assessed their clinical relevance in the largest inflammatory bowel disease (IBD) cohort tested to date for anti-MZGP2 antibodies. In contrast to currently available anti-MZGP2 ELISAs, the new QUANTA Lite® MZGP2 ELISA (INOVA Diagnostics, San Diego, CA) utilizes the eukaryotically-expressed specific isoform 4 of human GP2 UniProtKB: P55259. A total of 832 sera were studied including 617 consecutive IBD patients (323 CrD and 294 UC) under regular follow-up in a tertiary centre, 112 patients with various diseases, and 103 healthy blood donors. The new ELISA’s calculated AUC was 0.5968, 95% CI (0.5552, 0.6383) for IgA anti-MZGP2 [CD vs non-CD (UC plus controls)] and 0.6236, 95% CI (0.5813, 0.6659) for IgG anti-MZGP2. The sensitivity of IgA anti-MZGP2 for CrD in the IBD population was 15% and the specificity was 98% (95, 99), while the sensitivity and specificity of IgG anti-MZGP2 was 27% and 97%. IgA and IgG anti-MZGP2 combined testing led to a sensitivity of 31% and specificity of 96%. Positivity for either ASCA (IgA or IgG) or anti-MZGP2 (IgA or IgG) showed a sensitivity of 75% (70, 80) and specificity of 84% (79, 89). Of clinical relevance, IgA anti- MZGP2 antibodies were more prevalent in patients with early disease onset (Montreal classification A1, p=0.011), while patients with localised colonic disease were less likely to be IgG anti-MZGP2 positive. Anti-MZGP2 positive patients more frequently had extensive disease with ileal involvement and stricture formation. Patients with longer disease duration were more likely to have IgG anti-MZGP2 or IgA ASCA antibodies. In conclusion, the new IgA and IgG anti-MZGP2 antibody ELISAs allow accurate autoantibody determination, and can be used as a tool to study the clinical significance and utility of these autoantibodies in patients with IBD

...And Eat It Too: High Read Performance in Write-Optimized HPC I/O Middleware File Formats (CMU-PDL-09-111)

As HPC applications run on increasingly high process counts on larger and larger machines, both the frequency of checkpoints needed for fault tolerance and the resolution and size of Data Analysis Dumps are expected to increase proportionally. In order to maintain an acceptable ratio of time spent performing useful computation work to time spent performing I/O, write bandwidth to the underlying storage system must increase proportionally to this increase in the checkpoint and computation size. Unfortunately, popular scientific self-describing file formats such as netCDF and HDF5 are designed with a focus on portability and exibility. Extra care and careful crafting of the output structure and API calls is required to optimize for write performance using these APIs. To provide sufficient write bandwidth to continue to support the demands of scientific applications, the HPC community has developed a number of I/O middleware layers, that structure output into write-optimized file formats. However, the obvious concern with any write optimized file format would be a corresponding penalty on reads. In the log-structured filesystem, for example, a file generated by random writes could be written efficiently, but reading the file back sequentially later would result in very poor performance. Simulation results require efficient read-back for visualization and analytics, and though most checkpoint files are never used, the efficiency of a restart is very important in the face of inevitable failures. The utility of write speed improving middleware would be greatly diminished if it sacrificed acceptable read performance. In this paper we examine the read performance of two write-optimized middleware layers on large parallel machines and compare it to reading data natively in popular file formats

APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types

The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. Video Abstract: [Figure presented] By generating and characterizing isogenic APOE3- or APOE4-carrying human brain cell types, Lin et al. show that the APOE4 variant can lead to extensive gene expression alterations, and multiple cellular phenotypes potentially related to AD pathogenesis, in neurons, astrocytes, and microglia.National Institutes of Health (NIH) (Grants RF1-AG048056, RC1-AG036106, and RF1-AG048029

Whose shoe fits best? Dubious physics and power politics in the TMD footprint controversy

Apparent design breakthroughs in short-range missile defense systems such as Theater High-Altitude Air Defense (THAAD) have prompted questions about the legality of such systems under the 1972 Antiballistic Missile (ABM) Treaty. Prominent physicists have used computer “footprint” methodology to prove that if engineered to specifications, THAAD might exceed ABM Treaty performance limits banning highly effective missile defense systems. In response, missile defense officials commissioned Sparta, Inc. to conduct secret research casting doubt on the validity of such findings. The substantial diplomatic issues at stake and the interesting rhetorical dynamics involved in this dispute warrant close scholarly analysis. Attention to the iterative relationship between the interpenetrating spheres of public argument and scientific practice in this case yields novel insight about the processes in which technical knowledge of defense systems is forged and raises fresh issues for the “closure project” in science and technology controversy studies