The public health exposome and pregnancy-related mortality in the United States: a high-dimensional computational analysis.

BACKGROUND: Racial inequities in maternal mortality in the U.S. continue to be stark. METHODS: The 2015-2018, 4-year total population, county-level, pregnancy-related mortality ratio (PRM; deaths per 100,000 live births; National Center for Health Statistics (NCHS), restricted use mortality file) was linked with the Public Health Exposome (PHE). Using data reduction techniques, 1591 variables were extracted from over 62,000 variables for use in this analysis, providing information on the relationships between PRM and the social, health and health care, natural, and built environments. Graph theoretical algorithms and Bayesian analysis were applied to PHE/PRM linked data to identify latent networks. RESULTS: PHE variables most strongly correlated with total population PRM were years of potential life lost and overall life expectancy. Population-level indicators of PRM were overall poverty, smoking, lack of exercise, heat, and lack of adequate access to food. CONCLUSIONS: In this high-dimensional analysis, overall life expectancy, poverty indicators, and health behaviors were found to be the strongest predictors of pregnancy-related mortality. This provides strong evidence that maternal death is part of a broader constellation of both similar and unique health behaviors, social determinants and environmental exposures as other causes of death.

PUMA-V: Optimizing Parallel Code Performance Through Interactive Visualization.

Performance optimization for parallel loop-oriented programs compromises between parallelism and locality. We present a visualization interface that allows programmers to assist the compiler in generating optimal code. It greatly improves the user's understanding of the transformations that took place and aids in making additional transformations in a visually intuitive way.

Identifying common components across biological network graphs using a bipartite data model.

The GeneWeaver bipartite data model provides an efficient means to evaluate shared molecular components from sets derived across diverse species, disease states and biological processes. In order to adapt this model for examining related molecular components and biological networks, such as pathway or gene network data, we have developed a means to leverage the bipartite data structure to extract and analyze shared edges. Using the Pathway Commons database we demonstrate the ability to rapidly identify shared connected components among a diverse set of pathways. In addition, we illustrate how results from maximal bipartite discovery can be decomposed into hierarchical relationships, allowing shared pathway components to be mapped through various parent-child relationships to help visualization and discovery of emergent kernel driven relationships. Interrogating common relationships among biological networks and conventional GeneWeaver gene lists will increase functional specificity and reliability of the shared biological components. This approach enables self-organization of biological processes through shared biological networks.

Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis.

BACKGROUND: The transcription factor (TF) IRF4 is involved in the regulation of Th1, Th2, Th9, and Th17 cells, and animal studies have indicated an important role in allergy. However, IRF4 and its target genes have not been examined in human allergy. METHODS: IRF4 and its target genes were examined in allergen-challenged CD4(+) cells from patients with IAR, using combined gene expression microarrays and chromatin immunoprecipitation chips (ChIP-chips), computational target prediction, and RNAi knockdowns. RESULTS: IRF4 increased in allergen-challenged CD4(+) cells from patients with IAR, and functional studies supported its role in Th2 cell activation. IRF4 ChIP-chip showed that IRF4 regulated a large number of genes relevant to Th cell differentiation. However, neither Th1 nor Th2 cytokines were the direct targets of IRF4. To examine whether IRF4 induced Th2 cytokines via one or more downstream TFs, we combined gene expression microarrays, ChIP-chips, and computational target prediction and found a putative intermediary TF, namely ETS1 in allergen-challenged CD4(+) cells from allergic patients. ETS1 increased significantly in allergen-challenged CD4(+) cells from patients compared to controls. Gene expression microarrays before and after ETS1 RNAi knockdown showed that ETS1 induced Th2 cytokines as well as disease-related pathways. CONCLUSIONS: Increased expression of IRF4 in allergen-challenged CD4(+) cells from patients with intermittent allergic rhinitis leads to activation of a complex transcriptional program, including Th2 cytokines.

A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis.

We performed a network-based analysis of DNA microarray data from allergen-challenged CD4(+) T cells from patients with seasonal allergic rhinitis. Differentially expressed genes were organized into a functionally annotated network using the Ingenuity Knowledge Database, which is based on manual review of more than 200,000 publications. The main function of this network is the regulation of lymphocyte apoptosis, a role associated with several genes of the tuber necrosis factor superfamily. The expression of TNFRSF4, one of the genes in this family, was found to be 48 times higher in allergen-challenged cells than in diluent-challenged cells. TNFRSF4 is known to inhibit apoptosis and to enhance Th2 proliferation. Examination of a different material of allergen-stimulated peripheral blood mononuclear cells showed a higher number of interleukin-4(+) type 2 CD4(+) T (Th2) cells in patients than in controls (P<0.01), as well as a higher number of non-apoptotic Th2 cells in patients (P<0.01). The number of Th2 cells expressing TNFRSF4, TNFSF7 and TNFRSF1B was also significantly higher in patients. Treatment with anti-TNFSF4 resulted in a significantly decreased number of Th2 cells (P<0.05). A logical inference from all this is that the proliferation of allergen-challenged Th2 cells is associated with a decreased apoptosis of Th2 cells and an increase in TNFRSF4 signalling.

Evaluation of the gel system for ABO grouping and D typing.

BACKGROUND: The gel agglutination assay has been approved by the Food and Drug Administration as an alternative to the tube assay for the detection of red cell antibodies. It has also been approved recently by the Food and Drug Administration for ABO blood grouping and D typing. STUDY DESIGN AND METHODS: Tube and gel agglutination assays were compared for ABO grouping and D typing of 100 donor and 100 patient specimens. ABO grouping of 14 specimens of known ABO groups and D typing of 10 specimens with weak D were also compared. When antigen typing or isohemagglutinin results differed, gel testing was repeated by the use of modified incubation times, reagent or specimen volumes, and red cell concentrations. RESULTS: ABO grouping and D typing in all patient and donor specimens concurred. B isohemagglutinins were not detected in seven group A specimens. Six of seven discrepancies were resolved when gel tests were incubated at room temperature with increased serum or plasma volume. Weak D was detected in all 10 specimens tested by both assays. When weak A and/or B were tested with monoclonal antibody reagents, the correct phenotypes were identified in 9 specimens by gel assay and in 10 by tube assay. Using human antisera, 6 specimens were correctly phenotyped by gel assay and 7 by tube assay. CONCLUSION: The gel assay performed as well as the tube assay in detection of A, B, and D, but the tube assay was slightly better at detecting B isohemagglutinins. The gel assay can be used in place of the tube assay for ABO blood grouping and D typing.

Mental health values of clergy: effects of open-mindedness, religious affiliation, and education in counseling.

Multivariate analyses of variance indicated that both religious affiliation and education in counseling of 44 Episcopal and 51 Catholic clergy had over-all effects on their scores on the Mental Health Values Questionnaire. In separate univariate analyses, significant effects were found on six of eight mental health value subscales. On all subscales in which significant interactions occurred, much of the variance was found among the clergy who were least well educated in counseling. As education in counseling increased, perceptions of mental health values became more consistent between affiliations. Mental health values of clergy were similar to those of a sample of psychotherapists, with Self-acceptance and Good Interpersonal Relations being the highest scored values for both groups.

Spectral analysis of activation time sequences.

Adequate spatial resolution of local activation is fundamental for the correct depiction of myocardial activation during ablative treatment of ventricular tachycardia. The widest allowable distances between recording sites that provide an accurate description of the field potential distribution is dictated by the Nyquist sampling theorem. Activation times are derived from the field potentials. However, because of noise intrinsic in activation detection algorithms, closer recording sites may be required than those theoretically computed. The purpose of this study is to examine the spatial frequency spectrum of epicardial activation time sequences computed by common activation detection algorithms, determine which algorithm is least noisy, and derive the recording site density necessary to avoid distortion of the epicardial activation map. Using 40 to 80 electrode linear arrays, monopolar and bipolar electrograms from the epicardium were recorded vertically (base to apex) and horizontally in 11 dogs. Activation times for bipolar electrograms were estimated using Peak, Fastest Zero Crossing, and Morphological algorithms. Activation times for monopolar electrograms were set equal to the time of the fastest negative deflection. Activation time sequences were analyzed using conventional Fourier techniques. Anomalous activation times from serially adjacent bipolar electrograms, which constitute algorithm noise, were studied. Horizontal and vertical interelectrode distances are 3.2 mm and 2.4 mm, respectively. Of the bipolar algorithms, the Morphological algorithm produced the fewest anomalous activation times. Mapping systems having more than 256 channels are required for accurate representation of epicardial activation in a typical 20-kg dog. The endocardial electrode spacing is unknown, but is expected to be at least as dense. Large global mapping systems or regionally dense arrays may offer advantages during catheter ablations for ventricular tachycardia and for studies into the mechanisms of ventricular tachycardia by accurately defining the cardiac activation pattern.

Response of glioblastoma cell lines to low dose rate irradiation.

Glioblastoma U251 and U87 cells irradiated with single fraction high dose rate radiation (1.1 Gy/min) were relatively insensitive to inactivation of colony forming ability, similar to other glioblastoma cell lines. Initial rates of cell kill with continuous low dose rate irradiation (0.075 Gy/hr to 0.49 Gy/hr) were low, but at times greater than 20 hours and with dose rates of 0.25 Gy/hr or higher, the rate of cell kill increased. Population doubling times for these cell lines were about 24 hours, suggesting that cell cycle redistribution may be responsible for the increased sensitivity. DNA histograms obtained by flow cytometry support this hypothesis, with cells accumulating in the G2 and M phases of the cell cycle. These results suggest that low dose rate irradiation may be effective in treating glioblastomas. Optimization of time intervals between radiation treatments as well as dose rates used for glioblastoma patients may be influenced by these findings, resulting in better integration of continuous low-dose-rate irradiation (radioactive antibodies and implants) and high-dose-rate irradiation (fractionated external beam) into therapeutic programs.

Cardiovascular responses to vasoactive intestinal contractor, a novel endothelin-like peptide.

Cardiovascular and pulmonary responses to vasoactive intestinal contractor (VIC), an endothelin (ET)-like peptide from the murine gastrointestinal tract, were investigated in the cat. VIC (0.1-1.0 nmol/kg iv) decreased or elicited biphasic changes in arterial pressure (AP) and increased central venous pressure, cardiac output, pulmonary arterial pressure, and left atrial pressure. VIC produced biphasic changes in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). VIC increased heart rate (HR) and, at the 1 nmol/kg dose, a secondary decrease was observed. Hexamethonium blocked the changes in HR in response to VIC, whereas the ganglionic blocker, meclofenamate, or glybenclamide had no effect on changes in AP, SVR, and PVR elicited by the peptide. VIC caused small changes in right ventricular contractile force and increased distal aortic and carotid artery blood flow at all doses, with secondary decreases at the higher doses. VIC decreased superior mesenteric artery flow and decreased renal blood flow at the 1 nmol/kg dose. The changes in AP in response to VIC, ET-1, and ET-2 were similar, whereas those elicited by ET-3 and sarafotoxin 6b were similar. The present data show that VIC can produce both vasodilation and vasoconstriction in the systemic vascular bed and biphasic changes in PVR in the cat. These data show that VIC can produce complex cardiovascular responses similar to those elicited by the ET peptides and that these responses are largely independent of autonomic reflexes, release of cyclooxygenase products, and activation of ATP-regulated potassium channels. We conclude that VIC may act as an ET-like peptide.

Clinical syndrome of variant angina with normal coronary arteriogram.

We compared patients with variant angina (ST-segment elevation during pain) who had normal or near normal coronary arteriograms (Group 1) with 20 in whom variant angina occurred in the presence of obstructive coronary lesions (Group 2). A long history of nonexertional angina without angina of effort or previous infarction was the rule in Group 1, whereas recent-onset unstable angina preceded by effort angina and infarction predominated in Group 2 (P less than 0.001). Normal electrocardiograms at rest, with ischemic ST-segment elevation in the inferior leads, and ischemia-induced heart block and bradycardia, characterized Group 1, whereas abnormal electrocardiograms, ischemic involvement or fibrillation were more common in Group 2 (P less than 0.001). Variant angina with normal coronary arteriogram generally has a benign course and is probably unrelated to atherosclerosis.

ST-segment isolation and quantification as a means of improving diagnostic accuracy in treadmill stress testing.

A new method of ST-segment analysis utilizing computer-analytic techniques has been employed in treadmill exercise testing, with the aim of enhancing diagnostic sensitivity and specificity. One hundred thirty-three individuals were studied, including 62 normal subjects (Group I), 29 patients with coronary disease and clear, "ischemic" ST-segment responses to exercise testing (Group II), and 42 patients with coronary disease but normal or nondiagnostic exercise tests (Group III). The techniques used included: computer averaging, to minimize motion artifact and baseline drift; a means of isolating the ST-segment from the T-wave and quantifying ST-amplitude and slope (the isolated ST integral, IST); and the relating of the IST to a given heart rate, thus taking cognizance of the dependency of ST-depression on heart rate and level of exercise. These methods resulted in a test specificity exceeding 90 per cent and a sensitivity of over 85 per cent. Further evidence of the improved sensitivity achieved using these techniques included a 79 per cent (33 of 42) recognition of abnormalities in Group III, patients having normal or nondiagnostic visually interpreted treadmill stress tests (i.e., no flat or downsloping ST-segments of 1 mm. or greater). Moreover, 15 of 29 patients in Group II (52 per cent) manifested abnormal IST's before development of a typical "ischemic" ST, and in 17 patients (59 per cent), the IST continued to remain positive after disappearance of the characteristic flat or downsloping ST-segment. It is concluded that this type of computation analysis adds appreciable diagnostic sensitivity and specificity to treadmill stress testing.

Effect of clofibrate on progression of coronary disease: a prospective angiographic study in man.

Lowering blood lipids has been invoked as a means of controlling future coronary events. In this prospective study, the effect of a lipid-reducing agent clofibrate (2 gm. daily) on extent of coronary artery disease was investigated. Forty patients, 32 having aortocoronary bypass, six having Vineberg operations, two having neither, were placed double-blind in placebo (24 patients) and clofibrate (16 patients) groups, and restudied by selective coronary angiography one year later. An additional 24 patients dropped from the study due to adverse drug reactions in eight. Each patient's right, left, anterior descending, and circumflex coronary arteries (with their branches) were separately rated according to degree of obstruction. The clofibrate group showed a significantly greater fall in triglyceride than did the placebo group (minus 13.7 per cent versus plus 2.3 per cent; p equal to 0.45). In the clofibrate group, 19 out of 64 coronary arteries (29.6 per cent) showed progressive coronary narrowing, not significantly different from the placebo group (24 out of 96 coronary arteries narrowed, 25 per cent; p equal to 0.26). No significant differences between drug groups emerged when the data were corrected for degree of fall of blood lipids, initial lipoprotein type, or effect in bypassed versus nonbypassed vessels (p always greater than 0.2). Regression of coronary artery disease was not seen. We conclude that clofibrate did not significantly influence the rate of progression of coronary artery disease in a one-year period.

Enhanced rate of progression of coronary artery disease following aortocoronary saphenous vein bypass surgery.

To evaluate the fate of the boronary arteries after aortocoronary bypass, 40 patients underwent serial selective coronary angiographic studies 1 year apart, and the frequency of progression of coronary artery disease was estimated. Thirty-two had saphenous vein bypass surgery after the first procedure, six had Vineberg operations, and two had no interim operation. In each patient, the right, left, anterior descending and circumflex coronary arteries (including their branches) were separately evaluated. Progressive narrowing was evident in 31 of 50 (62 per cent) bypassed vessels and in only 11 to 113 (9.7 per cent) nonbypassed arteries (p less than 0.001). Coronary arteries with moderate to severe obstruction initially (50 to 99 per cent occluded) manifested progressive diseasee more frequently (33 of 70 arteries) than did arteries that were normal or mildly narrowed initially (4 of 71) (p less than 0.001. Considering only those vessels with 50 to 99 per cent obstruction initially, 27 of 35 (77 per cent) of the bypassed arteries and only 6 of 35 (17 per cent) of the nonbypassed arteries showed progression (p less than 0.001). We conclude that moderately or severely narrowed coronary arteries are more likely to show progressive narrowing than normal or mildly obstructed ones and that progression of coronary disease is greater in bypassed vessels than in nonbypassed vessels. In view of potential graft closure, the implications of these findings must be considered in selecting patients for aortocoronary bypass.