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Background: Fibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published GWAS, highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP., Methods: We performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n=120,246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, consisting of European ancestry samples and CRP (n=363,228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n=148,164). We also performed colocalization analysis to compare the associations in identified loci for the two traits and Genotype-Tissue Expression (GTEx) data., Results: We identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS., Conclusion: Bivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease., Methods: Computationally predicted damaging or loss-of-function (REVEL>0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595)., Results: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10 -5 ) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10 -4 ) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers., Conclusions: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach., Competing Interests: Conflicts of Interest: The other authors have nothing to declare.

Objective: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D)., Research Design and Methods: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD., Results: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16)., Conclusions: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D., (© 2024 by the American Diabetes Association.)

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( ARSE and MMP16 ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease., Competing Interests: Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Leslie S. Emery is now an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, or interpretation of this study. Nathan O. Stitziel has received research funding from Regeneron Pharmaceuticals, unrelated to this work. Karine A. Viaud-Martinez is an employee at Illumina Inc. Ryan W. Kim is an employee at Psomagen Inc. Roxona Mehran reports institutional research grants from Abbott Laboratories, Abiomed, Applied Therapeutics, AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich; consultant fees from Abbott Laboratories, Boston Scientific, CardiaWave, Chiesi, Janssen Scientific Affairs, Medscape/WebMD, Medtelligence (Janssen Scientific Affairs), Roivant Sciences, Sanofi, Siemens Medical Solutions; consultant fees paid to the institution from Abbott Laboratories, Bristol-Myers Squibb; advisory board, funding paid to the institution from Spectranetics/Philips/Volcano Corp; consultant (spouse) from Abiomed, The Medicines Company, Merck; Equity <1% from Claret Medical, Elixir Medical; DSMB Membership fees paid to the institution from Watermark Research Partners; consulting (no fee) from Idorsia Pharmaceuticals Ltd., Regeneron Pharmaceuticals; Associate Editor for ACC, AMA. Rajeev Malhotra is a consultant for MyoKardia (now owned by BMS), Epizon Pharma, Renovacor, and Third Pole, a co-founder of Patch and Angea Biotherapeutics, and has received research funding from Angea Biotherapeutics, Bayer Pharmaceuticals, and Amgen. Adrienne M. Stilp receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. Pradeep Natarajan reports grants from Amgen, Apple, Boston Scientific, AstraZeneca, Allelica, Novartis, and Genentech, consulting income from GV, Blackstone Life Sciences, Foresite Labs, Apple, AstraZeneca, Allelica, Novartis, HeartFlow, and Genentech, is a scientific advisor to Esperion Therapeutics, Preciseli, and TenSixteen Bio, is a scientific co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. Clint L. Miller received a research grant from AstraZeneca for an unrelated project. The remaining authors declare no competing interests.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D., Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test., Results: Using a Bonferroni-corrected significance threshold of P <1.6×10 -4 , we identified 3 genes ( ATP1B1 , ARVCF , and LIPG ) associated with CAC and 2 genes ( ABCG8 and EIF2B2 ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis., Conclusions: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC., Competing Interests: Disclosures Dr Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Raffield is a consultant for the Trans-Omics for Precision Medicine (TOPMed) Administrative Coordinating Center (through WeStat). Dr Malhotra receives research funding from Aeglea BioTherapeutics and Amgen and serves as a consultant for Myokardia/Bristol Myers Squibb, Renovacor, Epizon Pharma, and Third Pole. The other authors report no conflicts.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains insufficiently researched. It is also unclear whether associations of the CHD and IS PRS with ASCVD are independent of subclinical atherosclerosis measures. 7,286 White and 2,016 Black participants from the population-based Atherosclerosis Risk in Communities study who were free of cardiovascular disease and type 2 diabetes at baseline were included. We computed previously validated CHD and IS PRS consisting of 1,745,179 and 3,225,583 genetic variants, respectively. Cox proportional hazards models were used to test the association between each PRS and ASCVD, adjusting for traditional risk factors, ankle-brachial index, carotid intima media thickness, and carotid plaque. The hazard ratios (HR) for the CHD and IS PRS were significant with HR of 1.50 (95% CI: 1.36-1.66) and 1.31 (95% CI: 1.18-1.45) respectively for the risk of incident ASCVD per standard deviation increase in CHD and IS PRS among White participants after adjusting for traditional risk factors. The HR for the CHD PRS was not significant with an HR of 0.95 (95% CI: 0.79-1.13) for the risk of incident ASCVD in Black participants. The HR for the IS PRS was significant with an HR of 1.26 (95%CI: 1.05-1.51) for the risk of incident ASCVD in Black participants. The association of the CHD and IS PRS with ASCVD was not attenuated in White participants after adjustment for ankle-brachial index, carotid intima media thickness, and carotid plaque. The CHD and IS PRS do not cross-predict well, and predict better the outcome for which they were created than the composite ASCVD outcome. Thus, the use of the composite outcome of ASCVD may not be ideal for genetic risk prediction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry., Article Highlights: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions., (© 2023 by the American Diabetes Association.)

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits., (© 2022. The Author(s).)

Background: Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify remaining lifetime risk and years free of CHD according to polygenic risk and the American Heart Association's Life's Simple 7 (LS7) guidelines in a population-based cohort study., Methods: Our analysis included data from participants of the ARIC (Atherosclerosis Risk in Communities) study: 8372 White and 2314 Black participants; 45 years of age and older; and free of CHD at baseline examination. A polygenic risk score (PRS) comprised more than 6 million genetic variants was categorized into low (<20th percentile), intermediate, and high (>80th percentile). An overall LS7 score was calculated at baseline and categorized into "poor," "intermediate," and "ideal" cardiovascular health. Lifetime risk and CHD-free years were computed according to polygenic risk and LS7 categories., Results: The overall remaining lifetime risk was 27%, ranging from 16.6% in individuals with an ideal LS7 score to 43.1% for individuals with a poor LS7 score. The association of PRS with lifetime risk differed according to ancestry. In White participants, remaining lifetime risk ranged from 19.8% to 39.3% according to increasing PRS categories. Individuals with a high PRS and poor LS7 had a remaining lifetime risk of 67.1% and 15.9 fewer CHD-free years than did those with intermediate polygenic risk and LS7 scores. In the high-PRS group, ideal LS7 was associated with 20.2 more CHD-free years compared with poor LS7. In Black participants, remaining lifetime risk ranged from 19.1% to 28.6% according to increasing PRS category. Similar lifetime risk estimates were observed for individuals of poor LS7 regardless of PRS category. In the high-PRS group, an ideal LS7 score was associated with only 4.5 more CHD-free years compared with a poor LS7 score., Conclusions: Ideal adherence to LS7 recommendations was associated with lower lifetime risk of CHD for all individuals, especially in those with high genetic susceptibility. In Black participants, adherence to LS7 guidelines contributed to lifetime risk of CHD more so than current PRSs. Improved PRSs are needed to properly evaluate genetic susceptibility for CHD in diverse populations.

Objective: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed., Research Design and Methods: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD)., Results: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway., Conclusions: Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes., (© 2022 by the American Diabetes Association.)

Aims: Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information has not been presented, and the extent to which a normal body weight can offset a high lifetime genetic risk is unknown., Methods: We used data from 15,671 diabetes-free participants of European ancestry aged 45 years and older from the prospective population-based ARIC study and Rotterdam Study (RS). We quantified the remaining lifetime risk of diabetes stratified by genetic risk and quantified the effect of normal weight in terms of relative and lifetime risks in low, intermediate and high genetic risk., Results: At age 45 years, the lifetime risk of type 2 diabetes in ARIC in the low, intermediate and high genetic risk category was 33.2%, 41.3% and 47.2%, and in RS 22.8%, 30.6% and 35.5% respectively. The absolute lifetime risk for individuals with normal weight compared to individuals with obesity was 24% lower in ARIC and 8.6% lower in RS in the low genetic risk group, 36.3% lower in ARIC and 31.3% lower in RS in the intermediate genetic risk group, and 25.0% lower in ARIC and 29.4% lower in RS in the high genetic risk group., Conclusions: Genetic variants for type 2 diabetes have value in estimating the lifetime risk of type 2 diabetes. Normal weight mitigates partly the deleterious effect of high genetic risk., (© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Quantifying nurses' perceptions of workload burden when managing critically ill patients is essential for designing interventions to ease nurses' workday., Objectives: To explore pediatric intensive care unit (PICU) nurses' perceptions of their workload when caring for critically ill patients and managing protocolized therapies., Methods: This study was embedded in a multicenter randomized clinical trial where participants were assigned to receive either lower-target or higher-target glucose control. Nurses from 35 participating PICUs completed a baseline survey containing questions about their perceptions of PICU workload in general. They completed an intervention survey after caring for a study patient. Two workload measurement instruments, the Subjective Workload Assessment Technique (SWAT) and the National Aeronautics and Space Administration-Task Load Index (NASA-TLX), were embedded in these surveys., Results: Baseline surveys were completed by 1476 PICU nurses, predominantly female with a bachelor's degree and a median (interquartile range) of 6 (3-11) years of nursing experience and 4 (2-9) years of PICU experience. Most nurses (65%) rated time burden as the most important component of their workload, followed by cognitive (22%) or psychological stress (13%) burden. Work performance was selected most often as contributing to workload, followed by cognitive demand, time pressure, effort, and physical demand. Intervention surveys were completed by 73% of enrolled participants (505 of 693). Nurses managing the lower glucose target group reported higher levels of workload burden as measured by the SWAT (P = .002) and NASA-TLX (P < .001)., Conclusions: This study describes the workload burden perceived by PICU nurses when managing critically ill patients in general and when managing protocolized therapies., (©2021 American Association of Critical-Care Nurses.)

Purpose: The purpose of this study was to describe medical device-related pressure injuries (MDRPIs) in hospitalized pediatric patients., Design: A prospective, descriptive study., Sample/subjects and Setting: The sample comprised 625 patients cared for in 8 US pediatric hospitals. Participants were aged preterm to 21 years, on bed rest for at least 24 hours, and had a medical device in place., Methods: Two nursing teams, blinded to the other's assessments, worked in tandem to assess pressure injury risk, type of medical devices in use, and preventive interventions for each medical device. They also identified the presence, location, and stage of MDRPI. Subjects were observed up to 8 times over 4 weeks, or until discharge, whichever occurred first., Results: Of 625 enrolled patients, 42 (7%) developed 1 or more MDRPIs. Two-thirds of patients with MDRPIs were younger than 8 years. Patients experiencing MDRPIs had higher acuity scores on hospital admission, were more frequently cognitively and/or functionally impaired, or were extreme in body mass index. Respiratory devices caused the most injuries (6.19/1000 device-days), followed by immobilizers (2.40/1000 device-days), gastric tubes (2.24/1000 device-days), and external monitoring devices (1.77/1000 device-days). Of the 6336 devices in place, 36% did not have an MDRPI preventive intervention in place. Clinical variables contributing to MDRPI development included intensive care unit care (odds ratio [OR] 8.9, 95% confidence interval [CI] 1.9-43.6), use of neuromuscular blockade (OR 3.7, 95% CI 1.7-7.8), and inotropic/vasopressor medications (OR 2.7, 95% CI 1.7-4.3). Multivariable analysis indicated that Braden QD scores alone predicted MDRPI development., Conclusion: Medical devices are common in hospitalized infants and children and these medical devices place patients at risk for MDRPI.

Objectives: The impact of early enteral nutrition on clinical outcomes in critically ill children has not been adequately described. We hypothesized that early enteral nutrition is associated with improved clinical outcomes in critically ill children., Design: Secondary analysis of the Heart and Lung Failure-Pediatric Insulin Titration randomized controlled trial., Setting: Thirty-five PICUs., Patients: Critically ill children with hyperglycemia requiring inotropic support and/or invasive mechanical ventilation who were enrolled for at least 48 hours with complete nutrition data., Interventions: Subjects received nutrition via guidelines that emphasized enteral nutrition and were classified into early enteral nutrition (enteral nutrition within 48 hr of study randomization) and no early enteral nutrition (enteral nutrition after 48 hr of study randomization, or no enteral nutrition at any time)., Measurements and Main Results: Of 608 eligible subjects, 331 (54%) received early enteral nutrition. Both early enteral nutrition and no early enteral nutrition groups had similar daily caloric intake over the first 8 study days (median, 36 vs 36 kcal/kg/d; p = 0.93). After controlling for age, body mass index z scores, primary reason for ICU admission, severity of illness, and mean Vasopressor-Inotrope Score at the time of randomization, and adjusting for site, early enteral nutrition was associated with lower 90-day hospital mortality (8% vs 17%; p = 0.007), more ICU-free days (median, 20 vs 17 d; p = 0.02), more hospital-free days (median, 8 vs 0 d; p = 0.003), more ventilator-free days (median, 21 vs 19 d; p = 0.003), and less organ dysfunction (median maximum Pediatric Logistic Organ Dysfunction, 11 vs 12; p < 0.001)., Conclusions: In critically ill children with hyperglycemia requiring inotropic support and/or mechanical ventilation, early enteral nutrition was independently associated with better clinical outcomes.

Objectives: To investigate adaptive skills, behavior, and quality health-related quality of life in children from 32 centers enrolling in the Heart And Lung Failure-Pediatric INsulin Titration randomized controlled trial., Study Design: This prospective longitudinal cohort study compared the effect of 2 tight glycemic control ranges (lower target, 80-100 mg/dL vs higher target, 150-180 mg/dL) 1-year neurobehavioral and health-related quality of life outcomes. Subjects had confirmed hyperglycemia and cardiac and/or respiratory failure. Patients aged 2-16 years old enrolled between April 2012 and September 2016 were studied at 1 year after intensive care discharge. The primary outcome, adaptive skills, was assessed using the Vineland Adaptive Behavior Scale. Behavior and health-related quality of life outcomes were assessed as secondary outcomes using the Pediatric Quality of Life and Child Behavior Checklist at baseline and 1-year follow-up. Group differences were evaluated using regression models adjusting for age category, baseline overall performance, and risk of mortality., Results: Of 369 eligible children, 358 survived after hospital discharge and 214 (60%) completed follow-up. One-year Vineland Adaptive Behavior Scale-II composite scores were not different (mean ± SD, 79.9 ± 25.5 vs 79.4 ± 26.9, lower vs higher target; P = .20). Improvement in Pediatric Quality of Life total health from baseline was greater in the higher target group (adjusted mean difference, 8.2; 95% CI, 1.1-15.3; P = .02)., Conclusions: One-year adaptive behavior in critically ill children with lower vs higher target glycemic control did not differ. The higher target group demonstrated improvement from baseline in overall health. This study affirms the lack of benefit of lower glucose targeting., Trial Registration: ClinicalTrials.gov: NCT01565941., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To explore the prevalence, location, and clinical factors associated with hospital-acquired pressure injuries among pediatric patients with congenital heart disease., Design: Secondary analysis of data from a multicenter prospective cohort study of pediatric pressure injury risk, including patients with congenital heart disease., Setting: Eight acute care academic pediatric hospitals., Patients: Patients were preterm to 21 years old with congenital heart disease and on bed rest for at least 24 hours after hospital admission with a medical device attached to or traversing the skin or mucous membrane., Interventions: None., Measurements and Main Results: Patients were evaluated for a maximum of eight observations during a 4-week period to identify Braden QD risk and pressure injury development. Hospital-acquired pressure injuries were staged according to the National Pressure Ulcer Advisory Panel guidelines. Stepwise logistic regression was used to explore risk factors associated with hospital-acquired pressure injuries development, accounting for site as a cluster variable using generalized estimating equations. Overall, 279 pediatric cardiac patients provided 919 observations (median, 2 per patient [interquartile range, 2-5 per patient]). Thirty-eight hospital-acquired pressure injuries occurred in 27 patients (9.7%). Most injuries (28/38 [74%]) were related to medical devices. The most common medical devices that caused injury were oxygen saturation probes. The remaining hospital-acquired pressure injuries were immobility-related pressure injuries (10/38 [26%]) located primarily on the buttock, sacrum, or coccyx (5/10 [50%]). In multivariable analyses, being non-Hispanic white (odds ratio, 3.54; 95% CI, 2.15-5.84), experiencing operating room time greater than 4 hours (odds ratio, 2.91; 95% CI, 1.13-7.49), having oxygen saturation levels less than 85% (odds ratio, 2.65; 95% CI, 1.01-6.96), and having worse Braden QD scores (odds ratio, 1.25 per 1 point increase; 95% CI, 1.17-1.34) were significantly associated with hospital-acquired pressure injuries development., Conclusions: In this multicenter observational study of pediatric patients with congenital heart disease, we describe a hospital-acquired pressure injury prevalence of 9.7% with approximately 75% of injuries related to medical devices. These data can be used to inform practice and target interventions to decrease pressure injury risk and prevent pressure injuries in this vulnerable pediatric population.

Objective: To describe the development and initial testing of the Braden QD Scale to predict both immobility-related and medical device-related pressure injury risk in pediatric patients., Study Design: This was a multicenter, prospective cohort study enrolling hospitalized patients, preterm to 21 years of age, on bedrest for at least 24 hours with a medical device in place. Receiver operating characteristic curves using scores from the first observation day were used to characterize Braden QD Scale performance, including areas under the curve (AUC) with 95% CIs., Results: Eight centers enrolled 625 patients. A total of 86 hospital-acquired pressure injures were observed in 49 (8%) patients: 22 immobility-related pressure injuries in 14 (2%) patients and 64 medical device-related pressure injuries in 42 (7%) patients. The Braden QD Scale performed well in predicting immobility-related and medical device-related pressure injuries in the overall sample, with an AUC of 0.78 (95% CI 0.73-0.84). At a cutoff score of 13, the AUC was 0.72 (95% CI 0.67-0.78), providing a sensitivity of 0.86 (95% CI 0.76-0.92), specificity of 0.59 (95% CI 0.55-0.63), positive predictive value of 0.15 (95% CI 0.11-0.19), negative predictive value of 0.98 (95% CI 0.97-0.99), and a positive likelihood ratio of 2.09 (95% CI 0.95-4.58)., Conclusions: The Braden QD Scale reliably predicts both immobility-related and device-related pressure injuries in the pediatric acute care environment and will be helpful in monitoring care and in guiding resource use in the prevention of hospital-acquired pressure injuries., (Copyright © 2017 Elsevier Inc. All rights reserved.)