We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a ...confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.
It is widely assumed that genetic differences in gene expression underpin much of the difference among individuals and many of the quantitative traits of interest to geneticists. Despite this, there ...has been little work on genetic variability in human gene expression and almost none in the human brain, because tools for assessing this genetic variability have not been available. Now, with whole-genome SNP genotyping arrays and whole-transcriptome expression arrays, such experiments have become feasible. We have carried out whole-genome genotyping and expression analysis on a series of 193 neuropathologically normal human brain samples using the Affymetrix GeneChip Human Mapping 500K Array Set and Illumina HumanRefseq-8 Expression BeadChip platforms. Here we present data showing that 58% of the transcriptome is cortically expressed in at least 5% of our samples and that of these cortically expressed transcripts, 21% have expression profiles that correlate with their genotype. These genetic-expression effects should be useful in determining the underlying biology of associations with common diseases of the human brain and in guiding the analysis of the genomic regions involved in the control of normal gene expression.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), ...corticobasal degeneration (CBD) and Alzheimer’s disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts. We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies.
Background and Objectives: Fever is a common cause of hospitalization in infants under 8-weeks of age. Traditionally these patients have been admitted on empiric intravenous antibiotics for 48-72 ...hours pending culture results. Recent evidence suggests that it is safe to adopt a shorter period of antibiotic therapy of 24-36 hours. Aim: Reduce inpatient length of stay (LOS) of febrile infants less than 8 weeks of age by 12 hours within 2 years. Methods: This Quality Improvement (QI) project was implemented at two community hospitals affiliated with a children's hospital in a suburban, mid Atlantic community health system. We used a QI framework to identify barriers to reducing LOS for this cohort and prioritize solutions. Barriers included the lack of a rapid-resulting Herpes Simplex Virus (HSV) CSF PCR and a practice bias towards monitoring these patients for 48 hours. In cycle 1, we liaised with our laboratory and procured an in-house, rapid turn-around HSV CSF PCR. In cycle 2, we joined 126 other hospitals participating in Project REVISE (Reducing Excessive Variability in Infant Sepsis Evaluation), a QI collaborative of the AAP Value in Inpatient Pediatrics Network, to improve care of febrile neonates. As a part of this initiative, we adopted the discharge criteria recommended by our affiliated children's hospital Pathway for Treatment of the Febrile Young Infant. Results: The project included 118 patients, 28 pre-intervention (June 2015 - Feb 2016), and 90 post-intervention; 33 in cycle 1 (March 2016 - Dec 2016) and 57 in cycle 2 (Dec 2016 - Dec 2017). The median LOS decreased by approximately 14 hours, from 50.3 hours at baseline to 35.7 hours in cycle 2. There were no positive cultures (excluding contaminants) resulted after discharge and no re-admission for any serious bacterial infection including UTI, bacteremia, or meningitis within 7 days. Conclusions: LOS was successfully reduced in well appearing young febrile infants by using in-house HSV PCR and implementing an evidence-based clinical pathway. This initiative demonstrates high value care that safely reduces exposure to antimicrobials and allows patients and families to return home faster.
A sepsis workup is recommended in young infants 56 days or younger with fever to rule out a serious bacterial infection (SBI). Given the reduction in non-severe acute respiratory syndrome - ...coronavirus 2 viral infections observed in multiple studies during the coronavirus diseases 2019 (COVID-19) pandemic, we sought to determine if the reduction in viral infections led to a change in the incidence of SBI in this vulnerable patient population.
We performed a multicenter, retrospective study of infants 56 days or younger presenting with fever to emergency departments of 6 community hospitals. We compared the incidence of SBIs, viral meningitis, and viral bronchiolitis during March 2020 to February 2021 (pandemic year) with the same calendar months in the 2 preceding years (prepandemic years).
From March 2018 to February 2021, 543 febrile infants presented to the emergency departments, 95 during the pandemic year (March 2020 to February 2021) compared with 231 and 217 in the prepandemic years (March 2018 to February 2019 and March 2019 to February 2020, respectively).During the pandemic year, 28.4% of infants (27 of 95) were diagnosed with an SBI compared with 11.7% and 6.9% (P < 0.001) in the prepandemic years (27 of 231 and 15 of 217, respectively). Five patients were diagnosed with bacterial meningitis over the 3-year period, 4 of them during the pandemic year (4 of 95 4.2%). Positivity for viral cerebrospinal fluid polymerase chain reaction during the pandemic year was 6.4% (3 of 47) compared with 20.8% (25 of 120) and 20.4% (23 of 113) in prepandemic years (P = 0.070). During the pandemic year, 2.1% (2 of 95) febrile young infants were admitted with a comorbid diagnosis of bronchiolitis compared with 4.3% and 6.0% in the prepandemic years (P = 0.310).
The COVID-19 pandemic led to an increase in the incidence of SBIs in febrile infants 56 days or younger, likely a result of reduction in non-severe acute respiratory syndrome - coronavirus 2 viral infections. Greater vigilance is thus warranted in the evaluation of febrile infants during the COVID-19 pandemic.
The apolipoprotein E (
APOE
) ε4 allele is the best established genetic risk factor for late-onset Alzheimer’s disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide ...polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the
GRB
-associated binding protein 2 (
GAB2
) gene and a common haplotype encompassing the entire
GAB2
gene. SNP rs2373115 (p = 9 × 10
−11
) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with
APOE
ε4 to further modify risk.
GAB2
was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with
GAB2
gene expression increased tau phosphorylation. Our findings suggest that
GAB2
modifies LOAD risk in
APOE
ε4 carriers and influences Alzheimer’s neuropathology.
While the apolipoprotein E (APOE) epsilon allele is a well-established risk factor for late-onset Alzheimer's disease (AD), initial genome scans using microsatellite markers in late-onset AD failed ...to identify this locus on chromosome 19. Recently developed methods for the simultaneous assessment of hundreds of thousands of single nucleotide polymorphisms (SNPs) promise to help more precisely identify loci that contribute to the risk of AD and other common multigenic conditions. We sought here to demonstrate that more precise identification of loci that are associated with complex, multi-genic genetic disorders can be achieved using ultra-high-density whole-genome associations by demonstrating their ability to identify the APOE locus as a major susceptibility gene for late-onset AD, despite the absence of SNPs within the APOE locus itself, as well as to refine odds ratios (ORs) based on gold-standard phenotyping of the study population.
An individualized genome-wide association study using 502,627 SNPs was performed in 1086 his-topathologically verified AD cases and controls to determine the OR associated with genes predisposing to Alzheimer's disease.
As predicted, ultra-high-density SNP genotyping, in contrast to traditional microsatellite-based genome screening approaches, precisely identified the APOE locus as having a significant association with late-onset AD. SNP rs4420638 on chromosome 19, located 14 kilobase pairs distal to the APOE epsilon variant, significantly distinguished between AD cases and controls (Bonferroni corrected p value = 5.30 x 10(-34), OR = 4.01) and was far more strongly associated with the risk of AD than any other SNP of the 502,627 tested.
This study provides empirical support for the suggestion that the APOE locus is the major susceptibility gene for late-onset AD in the human genome, with an OR significantly greater than any other locus in the human genome. It also supports the feasibility of the ultra-high-density whole-genome association approach to the study of AD and other heritable phenotypes. These whole-genome association studies show great promise to identify additional genes that contribute to the risk of AD.
Introduction: The American Academy of Pediatrics recommends using isotonic intravenous fluids (IVF) for maintenance needs to decrease the risk of hyponatremia. We conducted a quality improvement ...project to increase the use of isotonic maintenance IVF in pediatric patients admitted to three sites in a community hospital network to >85% within 12 months. Methods: We used improvement methodology to identify causes of continued hypotonic fluid use, which involved provider behavior and systems factors. We implemented interventions to address these factors including: (1) education; (2) clinical decision support; and (3) stocking automated medication dispensing systems with isotonic IVF. We compared isotonic IVF use before and after interventions in all admitted patients aged 28 days to 18 years who received maintenance IVFs at the rate of at least 10 mL/hour. We excluded admissions of patients with active chronic medical conditions like diabetic ketoacidosis. Balancing measures were the occurrence of adverse events from hypo- or hypernatremia. Data were analyzed using Laney P′ statistical process control charts. Results: Isotonic IVF use among patients requiring maintenance fluids at all three sites surpassed the goal of >85% within 12 months. There were no reports of hypo- or hypernatremia or other adverse outcomes related to the use of isotonic IVF. Conclusion: A combination of interventions aimed at provider behavior and systems factors was critical to successfully adopting the American Academy of Pediatrics guideline regarding the use of maintenance isotonic IVF in hospitalized children.
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