DataSheet_1_Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.pdf

BackgroundInfluenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.MethodsWe measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR qResultsComparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.ConclusionThus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.</p

DataSheet_2_Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.xlsx

BackgroundInfluenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.MethodsWe measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR qResultsComparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.ConclusionThus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.</p

morton_2023_oi_221502_1674145740.31597.pdf

   Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD) but medical and sociodemographic factors explain only one third of variance in outcome.  Objective: To determine whether predicted damaging de novo variants (dDNV) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD. A post-hoc aim sought to determine whether some dDNV or rare predicted loss-of-function (pLOF) variants in specific gene categories are associated with outcomes.  Design: Prospective observational study from September 2017-June 2020.  Setting: Multicenter Participants: Participants were drawn from the Pediatric Cardiac Genomics Consortium (n=197) or Single Ventricle Reconstruction trial (n=24). Inclusion criteria were CHD, ≥ age 8 years, and available exome sequencing data. Individuals with pathogenic variants in known CHD- or neurodevelopmental-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. All 221 participants were included in post-hoc analyses, and 219 in case/control analysis.  Exposure: Participants were heterozygous for (cases) or lacked (controls) predicted dDNV in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNV or pLOF variants in four gene categories: chromatin-modifying, constrained, high-brain-expressed, and neurodevelopmental risk.  Main Outcomes and Measures: Neurodevelopmental and brain MRI metrics.  Results: Participants were median 15.0 years, interquartile range [IQR] 10.0-21.2; 50% (110/219) were male. Case and control participants had similar outcomes. dDNV/pLOF variants in chromatin-modifying genes were associated with worse verbal comprehension (n=16 vs. 200 participants, mean±SD: 91.4±20.4 vs. 103.4±17.8, p=0.01), social responsiveness (n=15 vs. 183, 57.3±17.2 vs. 49.4±11.2, p=0.03), and working memory (n=5 vs. 87, 73.8±16.4 vs. 97.3±15.7, p=0.03), as well as higher likelihood of autism spectrum disorder (4/14 vs. 8/153, 28.6% vs. 5.2%, p = 0.01). dDNV/pLOF variants in constrained genes were associated with impaired memory (immediated story memory: n=95 vs. 122, 9.7±3.7 vs. 10.7±3.0, p=0.03; immediate picture memory: n= 93 vs 116, 7.8±3.1 vs. 9.0±2.9, p=0.01). Adults with dDNV/pLOF variants in high-brain-expressed genes had greater hyperactivity symptoms (n=42 vs 33, 55.5±15.4 vs. 46.6±12.3, p=0.01).  Conclusions and Relevance: Neurodevelopmental outcomes are not associated with dDNV as a group, but may be worse in those with dDNV/pLOF variants in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific variants to brain function and structure.</p

Additional file 1: of Improving outcomes after pediatric cardiac arrest – the ICU-Resuscitation Project: study protocol for a randomized controlled trial

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