Genetic epidemiology of motor neuron disease-associated variants in the Scottish population

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population

Meta-analysis of the heritability of human traits based on fifty years of twin studies

Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool

Peri-intubation adverse events in the critically ill child after hematopoietic cell transplant

Objectives: Mechanically ventilated children post-hematopoietic cell transplant (HCT) have increased morbidity and mortality compared with other mechanically ventilated critically ill children. Tracheal intubation-associated adverse events (TIAEs) and peri-intubation hypoxemia universally portend worse outcomes. We investigated whether adverse peri-intubation associated events occur at increased frequency in patients with HCT compared with non-HCT oncologic or other PICU patients and therefore might contribute to increased mortality. Design: Retrospective cohort between 2014 and 2019. Setting: Single-center academic noncardiac PICU. Patients: Critically ill children who underwent tracheal intubation (TI). Interventions: None. Measurements and main results: Data from the local airway management quality improvement databases and Virtual Pediatric Systems were merged. These data were supplemented with a retrospective chart review for HCT-related data, including HCT indication, transplant-related comorbidity status, and patient condition at the time of TI procedure. The primary outcome was defined as the composite of hemodynamic TIAE (hypo/hypertension, arrhythmia, cardiac arrest) and/or peri-intubation hypoxemia (oxygen saturation < 80%) events. One thousand nine hundred thirty-one encounters underwent TI, of which 92 (4.8%) were post-HCT, while 319 (16.5%) had history of malignancy without HCT, and 1,520 (78.7%) had neither HCT nor malignancy. Children post-HCT were older more often had respiratory failure as an indication for intubation, use of catecholamine infusions peri-intubation, and use of noninvasive ventilation prior to intubation. Hemodynamic TIAE or peri-intubation hypoxemia were not different across three groups (HCT 16%, non-HCT with malignancy 10%, other 15). After adjusting for age, difficult airway feature, provider type, device, apneic oxygenation use, and indication for intubation, we did not identify an association between HCT status and the adverse TI outcome (odds ratio, 1.32 for HCT status vs other; 95% CI, 0.72-2.41; p = 0.37). Conclusions: In this single-center study, we did not identify an association between HCT status and hemodynamic TIAE or peri-intubation hypoxemia during TI

The Use and Duration of Preintubation Respiratory Support Is Associated With Increased Mortality in Immunocompromised Children With Acute Respiratory Failure

Objectives: To determine the association between preintubation respiratory support and outcomes in patients with acute respiratory failure and to determine the impact of immunocompromised (IC) diagnoses on outcomes after adjustment for illness severity. Design: Retrospective multicenter cohort study. Setting: Eighty-two centers in the Virtual Pediatric Systems database. Patients: Children 1 month to 17 years old intubated in the PICU who received invasive mechanical ventilation (IMV) for greater than or equal to 24 hours. Interventions: None. Measurements and main results: High-flow nasal cannula (HFNC) or noninvasive positive-pressure ventilation (NIPPV) or both were used prior to intubation in 1,825 (34%) of 5,348 PICU intubations across 82 centers. When stratified by IC status, 50% of patients had no IC diagnosis, whereas 41% were IC without prior hematopoietic cell transplant (HCT) and 9% had prior HCT. Compared with patients intubated without prior support, preintubation exposure to HFNC (adjusted odds ratio [aOR], 1.33; 95% CI, 1.10-1.62) or NIPPV (aOR, 1.44; 95% CI, 1.20-1.74) was associated with increased odds of PICU mortality. Within subgroups of IC status, preintubation respiratory support was associated with increased odds of PICU mortality in IC patients (HFNC: aOR, 1.50; 95% CI, 1.11-2.03; NIPPV: aOR, 1.76; 95% CI, 1.31-2.35) and HCT patients (HFNC: aOR, 1.75; 95% CI, 1.07-2.86; NIPPV: aOR, 1.85; 95% CI, 1.12-3.02) compared with IC/HCT patients intubated without prior respiratory support. Preintubation exposure to HFNC/NIPPV was not associated with mortality in patients without an IC diagnosis. Duration of HFNC/NIPPV greater than 6 hours was associated with increased mortality in IC HCT patients (HFNC: aOR, 2.41; 95% CI, 1.05-5.55; NIPPV: aOR, 2.53; 95% CI, 1.04-6.15) and patients compared HCT patients with less than 6-hour HFNC/NIPPV exposure. After adjustment for patient and center characteristics, both preintubation HFNC/NIPPV use (median, 15%; range, 0-63%) and PICU mortality varied by center. Conclusions: In IC pediatric patients, preintubation exposure to HFNC and/or NIPPV is associated with increased odds of PICU mortality, independent of illness severity. Longer duration of exposure to HFNC/NIPPV prior to IMV is associated with increased mortality in HCT patients

The Use and Duration of Preintubation Respiratory Support Is Associated With Increased Mortality in Immunocompromised Children With Acute Respiratory Failure

OBJECTIVESTo determine the association between preintubation respiratory support and outcomes in patients with acute respiratory failure and to determine the impact of immunocompromised (IC) diagnoses on outcomes after adjustment for illness severity. DESIGNRetrospective multicenter cohort study. SETTINGEighty-two centers in the Virtual Pediatric Systems database. PATIENTSChildren 1 month to 17 years old intubated in the PICU who received invasive mechanical ventilation (IMV) for greater than or equal to 24 hours. INTERVENTIONSNone. MEASUREMENTS AND MAIN RESULTSHigh-flow nasal cannula (HFNC) or noninvasive positive-pressure ventilation (NIPPV) or both were used prior to intubation in 1,825 (34%) of 5,348 PICU intubations across 82 centers. When stratified by IC status, 50% of patients had no IC diagnosis, whereas 41% were IC without prior hematopoietic cell transplant (HCT) and 9% had prior HCT. Compared with patients intubated without prior support, preintubation exposure to HFNC (adjusted odds ratio [aOR], 1.33; 95% CI, 1.10-1.62) or NIPPV (aOR, 1.44; 95% CI, 1.20-1.74) was associated with increased odds of PICU mortality. Within subgroups of IC status, preintubation respiratory support was associated with increased odds of PICU mortality in IC patients (HFNC: aOR, 1.50; 95% CI, 1.11-2.03; NIPPV: aOR, 1.76; 95% CI, 1.31-2.35) and HCT patients (HFNC: aOR, 1.75; 95% CI, 1.07-2.86; NIPPV: aOR, 1.85; 95% CI, 1.12-3.02) compared with IC/HCT patients intubated without prior respiratory support. Preintubation exposure to HFNC/NIPPV was not associated with mortality in patients without an IC diagnosis. Duration of HFNC/NIPPV greater than 6 hours was associated with increased mortality in IC HCT patients (HFNC: aOR, 2.41; 95% CI, 1.05-5.55; NIPPV: aOR, 2.53; 95% CI, 1.04-6.15) and patients compared HCT patients with less than 6-hour HFNC/NIPPV exposure. After adjustment for patient and center characteristics, both preintubation HFNC/NIPPV use (median, 15%; range, 0-63%) and PICU mortality varied by center. CONCLUSIONSIn IC pediatric patients, preintubation exposure to HFNC and/or NIPPV is associated with increased odds of PICU mortality, independent of illness severity. Longer duration of exposure to HFNC/NIPPV prior to IMV is associated with increased mortality in HCT patients

Mutation analysis of CHCHD10 in different neurodegenerative diseases

A recent study by Bannwarth et al. (2014) implicated CHCHD10 as a novel gene for amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTLD), reporting a p.S59L substitution (c.176C > T; NM_213720.2) in a large French kindred. Affected family members were presented with a complex phenotype that included symptoms of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), cerebellar ataxia, Parkinson's disease and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range, including ALS/FTLD (p.S59L and p.P34S) (Bannwarth et al., 2014; Chaussenot et al., 2014), ALS (p.R15L and p.G66V) (Johnson et al., 2014; Muller et al., 2014), myopathy (p.R15S and p.G58R) (Ajroud-Driss et al., 2015) and late-onset spinal motor neuronopathy (p.G66V) (Penttila et al., 2015). All of them affect exon 2 (a mutational hotspot of CHCHD10).Fil: Zhang, Ming. University of Toronto; CanadáFil: Xi, Zhengrui. University of Toronto; CanadáFil: Zinman, Lorne. Sunnybrook Health Sciences Centre; Estados UnidosFil: Bruni, Amalia C.. Lamezia Terme. Regional Neurogenetic Centre; ItaliaFil: Maletta, Raffaele G.. Lamezia Terme. Regional Neurogenetic Centre; ItaliaFil: Curcio, Sabrina A. M.. Lamezia Terme. Regional Neurogenetic Centre; ItaliaFil: Rainero, Innocenzo. Università di Torino; ItaliaFil: Rubino, Elisa. Università di Torino; ItaliaFil: Pinessi, Lorenzo. Università di Torino; ItaliaFil: Nacmias, Benedetta. Universita Degli Studi Di Firenze; ItaliaFil: Sorbi, Sandro. Universita Degli Studi Di Firenze; ItaliaFil: Galimberti, Daniela. Università degli Studi di Milano; ItaliaFil: Lang, Anthony E.. Toronto Western Hospital University Of Toronto; Canadá. University of Toronto; CanadáFil: Fox, Susan. Toronto Western Hospital University Of Toronto; Canadá. University of Toronto; CanadáFil: Surace, Ezequiel Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: Ghani, Mahdi. University of Toronto; CanadáFil: Guo, Jing. University of Toronto; CanadáFil: Sato, Christine. University of Toronto; CanadáFil: Moreno, Danielle. University of Toronto; CanadáFil: Liang, Yan. University of Toronto; CanadáFil: Keith, Julia. Sunnybrook Health Sciences Centre; CanadáFil: Traynor, Bryan J.. National Institute on Aging. Laboratory of Neurogenetics. Neuromuscular Diseases Research Section; Estados UnidosFil: George-Hyslop, Peter St.. University of Toronto; Canadá. University of Cambridge; Reino UnidoFil: Rogaeva, Ekaterina. University of Toronto; Canad