Neonatal Fever in the COVID-19 Pandemic: Odds of a Serious Bacterial Infection.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Herpes zoster duplex bilateralis in an immunocompetent adolescent boy: a case report and literature review.

Simultaneous involvement of herpes zoster in multiple dermatomes is uncommon, and even more so in immunocompetent individuals. We report a case wherein a healthy adolescent boy presented with herpes zoster in two distinct dermatomes, raising concern for immunodeficiency, but he was found to be immunocompetent on further testing. A 14-year-old boy with no significant past medical history developed painless vesicular eruptions in two distinct distributions. Varicella zoster virus polymerase chain reaction was positive from unroofed vesicles in both regions. Initial laboratory studies disclosed abnormalities of unknown significance in natural killer (NK) cell percentage and function. The patient was treated with appropriate antiviral therapy. Repeat studies while healthy were not suggestive of an underlying NK cell defect. There are few case reports describing herpes zoster in two or more dermatomes in children. Previously described presentations most commonly occurred in the context of primary immunodeficiency, acquired immunodeficiency, or immunosuppressive medications. Because of the rarity of this presentation in immunocompetent patients, the authors recommend a thorough immune evaluation of all children presenting with isolated multidermatomal zoster.

Closing the Fluid Gap: Improving Isotonic Maintenance Intravenous Fluid Use in a Community Hospital Network.

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.

Genetic control of human brain transcript expression in Alzheimer disease.

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.

GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.

The apolipoprotein E (APOE) epsilon4 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 epsilon4 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 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 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 epsilon4 carriers and influences Alzheimer's neuropathology.

Successful Use of Quality Improvement Methodology to Reduce Inpatient Length of Stay in Bronchiolitis Through Judicious Use of Intermittent Pulse Oximetry.

BACKGROUND AND OBJECTIVES: The American Academy of Pediatrics 2014 bronchiolitis guidelines recommend against the routine use of continuous pulse oximetry (CPO) because it has been implicated in prolonging the length of stay (LOS). At our institution, infants admitted with bronchiolitis were monitored by using CPO during the entire hospital stay and intermittent desaturations <90% appeared to delay discharge. This quality improvement initiative was designed to reduce the LOS by decreasing the use of CPO in stable infants with nonsevere bronchiolitis. METHODS: The quality improvement project was implemented on the inpatient units of 2 community hospitals during the 2016 and 2017 bronchiolitis seasons. In cycle 1 (January 2016 to April 2016), the bronchiolitis pathway from the associated quaternary children's hospital was used to (1) limit the use of CPO to patients with severe bronchiolitis and those at high risk for apnea or severe disease, (2) discontinue CPO as patients improved and stabilized, and (3) standardize discharge criteria. In cycle 2 (November 2016 to April 2017), the clinical pathway was adopted. The main outcome measure was LOS, measured from the time of the admission order to the time of the discharge order. Process measures included compliance with the interventions. RESULTS: The project included 373 patients, 180 preintervention and 193 postintervention. The average LOS decreased by 20 hours, from 53 hours at baseline to 33 hours in cycle 2. No adverse events were noted, and there was no significant change in the number of emergency department revisits and readmissions within 7 days. CONCLUSIONS: In our study, LOS was successfully reduced in bronchiolitis patients by using a clinical pathway that limited CPO to patients with severe bronchiolitis and those at risk for severe disease or apnea.

Sorl1 as an Alzheimer's disease predisposition gene?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) epsilon4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval.

Blood culture contamination rates after skin antisepsis with chlorhexidine gluconate versus povidone-iodine in a pediatric emergency department.

OBJECTIVE: To determine blood culture contamination rates after skin antisepsis with chlorhexidine, compared with povidone-iodine. DESIGN: Retrospective, quasi-experimental study. SETTING: Emergency department of a tertiary care children's hospital. PATIENTS: Children aged 2-36 months with peripheral blood culture results from February 2004 to June 2008. Control patients were children younger than 2 months with peripheral blood culture results. METHODS: Blood culture contamination rates were compared using segmented regression analysis of time-series data among 3 patient groups: (1) patients aged 2-36 months during the 26-month preintervention period, in which 10% povidone-iodine was used for skin antisepsis before blood culture; (2) patients aged 2-36 months during the 26-month postintervention period, in which 3% chlorhexidine gluconate was used; and (3) patients younger than 2 months not exposed to the chlorhexidine intervention (ie, the control group). RESULTS: Results from 11,595 eligible blood cultures were reviewed (4,942 from the preintervention group, 4,274 from the postintervention group, and 2,379 from the control group). For children aged 2-36 months, the blood culture contamination rate decreased from 24.81 to 17.19 contaminated cultures per 1,000 cultures (P < .05) after implementation of chlorhexidine. This decrease of 7.62 contaminated cultures per 1,000 cultures (95% confidence interval, -0.781 to -15.16) represented a 30% relative decrease from the preintervention period and was sustained over the entire postintervention period. No change in contamination rate was observed in the control group (P = .337). CONCLUSION: Skin antisepsis with chlorhexidine significantly reduces the blood culture contamination rate among young children, as compared with povidone-iodine.

Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis.

For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.

Association of rapid head growth in children following tracheostomy tube placement.

INTRODUCTION: Our clinical observation indicates that some children who have a tracheostomy may experience increasing head circumference as they grow and develop. Accurate assessment and interpretation of growth parameters is an essential component of following child development. Appreciation for variations in growth is especially important in special populations, such as children with a tracheostomy. The aim of this study is to define head growth in children with a tracheostomy. METHOD: This retrospective cohort study includes children who underwent tracheostomy tube placement prior to 2 years of age in a respiratory rehabilitation unit within a children's hospital. Serial head circumference measurements were plotted against age on growth charts adjusted for gestational age. The percentage of patients with accelerated head growth, defined as increased head circumference across two major percentiles within 6 months following tracheostomy, was determined. RESULTS: Fifty-seven percent (20 out of 35 children) demonstrated increased head circumference across two major percentiles within 6 months following tracheostomy. DISCUSSION: Accelerated head growth is associated with the presence of a tracheostomy tube in children in this study. Further investigation is warranted to establish the relationship of head circumference to other growth parameters. In addition, the etiology of this phenomenon requires additional study. Understanding head growth in children with a tracheostomy will promote adequate growth assessment and may lead to improved patient care.

The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts.

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.

A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

A survey of genetic human cortical gene expression.

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.

Insulin-degrading enzyme haplotypes affect insulin levels but not dementia risk.

BACKGROUND: Insulin-degrading enzyme (IDE) polymorphism is hypothesized to regulate insulin levels as well as processes involved in neuronal compromise found in dementia. METHODS: We examined the association of IDE haplotypes with dementia and insulin levels in a single well-characterized cohort of Japanese-American men born between 1900 and 1919 and followed since 1965. In 1991, a fasting insulin was obtained; dementia cases were ascertained in 1991 and 1994 in a multi-stage procedure, diagnoses were made according to international guidelines. Five single-nucleotide polymorphisms were genotyped and used for haplotype analysis in a sample of 179 Alzheimer's disease cases, 104 vascular dementia cases and 516 controls nested in the total cohort. RESULTS: The global test for the haplotype effect on insulin levels was significant (p < 0.0001), adjusting for age, education, apolipoprotein epsilon4 status and fasting glucose. CONCLUSION: There was no association of IDE haplotypes with the risk of dementia. This study suggests IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimer's.

Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease.

Several studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD.