Estimating and Reporting on the Quality of Inpatient Stroke Care by Veterans Health Administration Medical Centers

Background—Reporting of quality indicators (QIs) in Veterans Health Administration Medical Centers is complicated by estimation error caused by small numbers of eligible patients per facility. We applied multilevel modeling and empirical Bayes (EB) estimation in addressing this issue in performance reporting of stroke care quality in the Medical Centers. Methods and Results—We studied a retrospective cohort of 3812 veterans admitted to 106 Medical Centers with ischemic stroke during fiscal year 2007. The median number of study patients per facility was 34 (range, 12–105). Inpatient stroke care quality was measured with 13 evidence-based QIs. Eligible patients could either pass or fail each indicator. Multilevel modeling of a patient's pass/fail on individual QIs was used to produce facility-level EB-estimated QI pass rates and confidence intervals. The EB estimation reduced interfacility variation in QI rates. Small facilities and those with exceptionally high or low rates were most affected. We recommended 8 of the 13 QIs for performance reporting: dysphagia screening, National Institutes of Health Stroke Scale documentation, early ambulation, fall risk assessment, pressure ulcer risk assessment, Functional Independence Measure documentation, lipid management, and deep vein thrombosis prophylaxis. These QIs displayed sufficient variation across facilities, had room for improvement, and identified sites with performance that was significantly above or below the population average. The remaining 5 QIs were not recommended because of too few eligible patients or high pass rates with little variation. Conclusions—Considerations of statistical uncertainty should inform the choice of QIs and their application to performance reporting

Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers

It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (A beta)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer's disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (e4) non-carriers. In addition, in e4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of A beta 1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF A beta 1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased A beta 1-40 and A beta 1-42 fragments in a cell line model of A beta production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don't carry the e4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.National Institute on Aging (NIA); National Alzheimer's Coordinating Center (NACC) [U01 AG016976]; National Institute on Aging: Ruth Seemann, John Hopkins Alzheimer's Disease Research Center (NIA) [AG05146, P50 AG16570, AG05128]; NINDS [NS39764]; Glaxo Smith Kline [P50-AG053760, AG05144, P50AG05681, P50 AG05136, P30-AG13846, 211002]; Arizona Biomedical Research Commission [4001, 0011, 05_ 901]; Michael J. Fox Foundation [AG10161, HHSN-271-2013-00030C]; McGowan Endowment; Medical Research Council, local NHS trusts and Newcastle University; Medical Research Council; Safa Al-Sarraj; Netherlands Brain Bank; Stichting MS Research, Brain Net Europe; Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds; Internationale Stiching Alzheimer Onderzoek; NIH-NIA [R01-AG041232]; State of Arizona DHS (Arizona Alzheimer's Consortium) - NIH EUREKA [R01-AG034504]; NIH intramural funds; UK Dementia Research Institute; DRI Ltd - UK Medical Research Council; Alzheimer's Society; Alzheimer's Research UK - Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer'sAssociation; Alzheimer's Drug Discovery Foundation; Araclon Biotech; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Fujirebio; Johnson & Johnson Pharmaceutical Research & Development LLC.; Merck Co., Inc.; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Takeda Pharmaceutical Company; Canadian Institutes of Health Research isproviding funds; ADNI clinical sites in Canada; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; Laboratory for Neuro Imaging at the University of Southern CaliforniaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

24-Hour Rhythms of DNA Methylation and Their Relation with Rhythms of RNA Expression in the Human Dorsolateral Prefrontal Cortex

Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1–3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease

The Bekenstein Formula and String Theory (N-brane Theory)

A review of recent progress in string theory concerning the Bekenstein formula for black hole entropy is given. Topics discussed include p-branes, D-branes and supersymmetry; the correspondence principle; the D- and M-brane approach to black hole entropy; the D-brane analogue of Hawking radiation, and information loss; D-branes as probes of black holes; and the Matrix theory approach to charged and neutral black holes. Some introductory material is included.Comment: 53 pages, LaTeX. v3: Typos fixed, minor updates, references added, brief Note Added on AdS/CF

Gauge Theory and the Excision of Repulson Singularities

We study brane configurations that give rise to large-N gauge theories with eight supersymmetries and no hypermultiplets. These configurations include a variety of wrapped, fractional, and stretched branes or strings. The corresponding spacetime geometries which we study have a distinct kind of singularity known as a repulson. We find that this singularity is removed by a distinctive mechanism, leaving a smooth geometry with a core having an enhanced gauge symmetry. The spacetime geometry can be related to large-N Seiberg-Witten theory.Comment: 31 pages LaTeX, 2 figures (v3: references added

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E epsilon 4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.Mueller Family Charitable Trust; Arizona Department of Health Services; National Institutes of Health [R01-AG041232, R01-AG049465-05]; Flinn FoundationOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Human-specific histone methylation signatures at transcription start sites in prefrontal neurons

Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans

Transcriptome-Wide Assessment of Human Brain and Lymphocyte Senescence

Identifying biological pathways that vary across the age spectrum can provide insight into fundamental mechanisms that impact disease and frailty in the elderly. Few methodological approaches offer the means to explore this question on as broad a scale as gene expression profiling. Here, we have evaluated mRNA expression profiles as a function of age in two populations; one consisting of 191 individuals with ages-at-death ranging from 65-100 years and with post-mortem brain mRNA measurements of 13,216 genes and a second with 1240 individuals ages 15-94 and lymphocyte mRNA estimates for 18,519 genes.Among negatively correlated transcripts, an enrichment of mitochondrial genes was evident in both populations, providing a replication of previous studies indicating this as a common signature of aging. Sample differences were prominent, the most significant being a decrease in expression of genes involved in translation in lymphocytes and an increase in genes involved in transcription in brain, suggesting that apart from energy metabolism other basic cell processes are affected by age but in a tissue-specific manner. In assessing genomic architecture, intron/exon sequence length ratios were larger among negatively regulated genes in both samples, suggesting that a decrease in the expression of non-compact genes may also be a general effect of aging. Variance in gene expression itself has been theorized to change with age due to accumulation of somatic mutations and/or increasingly heterogeneous environmental exposures, but we found no evidence for such a trend here.Results affirm that deteriorating mitochondrial gene expression is a common theme in senescence, but also highlight novel pathways and features of gene architecture that may be important for understanding the molecular consequences of aging

Divergence of Arctic shrub growth associated with sea ice decline

Arctic sea ice extent (SIE) is declining at an accelerating rate with a wide range of ecological consequences. However, determining sea ice effects on tundra vegetation remains a challenge. In this study, we examined the universality or lack thereof in tundra shrub growth responses to changes in SIE and summer climate across the Pan-Arctic, taking advantage of 23 tundra shrub-ring chronologies from 19 widely distributed sites (56°N to 83°N). We show a clear divergence in shrub growth responses to SIE that began in the mid-1990s, with 39% of the chronologies showing declines and 57% showing increases in radial growth (decreasers and increasers, respectively). Structural equation models revealed that declining SIE was associated with rising air temperature and precipitation for increasers and with increasingly dry conditions for decreasers. Decreasers tended to be from areas of the Arctic with lower summer precipitation and their growth decline was related to decreases in the standardized precipitation evapotranspiration index. Our findings suggest that moisture limitation, associated with declining SIE, might inhibit the positive effects of warming on shrub growth over a considerable part of the terrestrial Arctic, thereby complicating predictions of vegetation change and future tundra productivity

Quantitative association tests of immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa.

There is now considerable evidence that host genetic factors are important in determining the outcome of infection with Mycobacterium tuberculosis (MTB). The aim of this study was to assess the role of several candidate genes in the variation observed in the immune responses to MTB antigens. In-vitro assays of T-cell proliferation, an in-vivo intradermal delayed hypersensitivity response; cytokine and antibody secretions to several mycobacterial peptide antigens were assessed in healthy, but exposed, West African twins. Candidate gene polymorphisms were typed in the NRAMP1, Vitamin D receptor, IL10, IL4, IL4 receptor and CTLA-4 genes. Variants of the loci IL10 (-1082 G/A), CTLA-4 (49 A/G) and the IL4 receptor (128 A/G) showed significant associations with immune responses to several antigens. T-cell proliferative responses and antibody responses were reduced, TNF-alpha responses were increased for subjects with the CTLA-4 G allele. The T-cell proliferative responses of subjects with IL10 GA and GG genotypes differed significantly. IL4 receptor AG and GG genotypes also showed significant differences in their T-cell proliferative responses to MTB antigens. These results yield a greater understanding of the genetic mechanisms that underlie the immune responses in tuberculosis and have implications for the design of therapeutic interventions