Objective Delirium occurs frequently in adults, and is an independent predictor of mortality. However, the epidemiology and outcomes of pediatric delirium are not well-characterized. The primary objectives of this study were to describe the incidence of delirium in critically ill children, its duration, associated risk factors, and effect on in-hospital outcomes, including mortality. Secondary objectives included determination of delirium subtype, and effect of delirium on duration of mechanical ventilation (MV), and length of hospital stay (LOS). Design Prospective longitudinal cohort study. Setting Urban academic tertiary care pediatric intensive care unit (PICU). Patients All consecutive admissions from September 2014 through August 2015. Intervention Children were screened for delirium twice daily throughout their ICU stay. Measurements and Main Results Of 1547 consecutive patients, delirium was diagnosed in 267 (17%), and lasted a median of two days (IQR 1,5). Seventy-eight percent of children with delirium developed it within the first three PICU days. Most cases of delirium were of the hypoactive (46%) and mixed (45%) subtypes; only 8% of delirium episodes were characterized as hyperactive delirium. In multivariable analysis, independent predictors of delirium included age ≤2 years, developmental delay, severity of illness, prior coma, mechanical ventilation, and receipt of benzodiazepines and anticholinergics. PICU LOS was increased in children with delirium (adjusted relative LOS 2.3, CI= 2.1, 2.5, p<0.001), as was duration of MV (median 4 vs. 1 day, p<0.001). Delirium was a strong and independent predictor of mortality (adjusted OR 4.39, CI= 1.96–9.99, p<0.001). Conclusions Delirium occurs frequently in critically ill children and is independently associated with mortality. Some in-hospital risk factors for delirium development are modifiable. Interventional studies are needed to determine best practices to limit delirium exposure in at-risk children.

IMPORTANCETo our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated.OBJECTIVE To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. DESIGN, SETTING, AND PARTICIPANTSWe performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. MAIN OUTCOMES AND MEASURESThe diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes.RESULTS With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy-related genes (4 families) and collagen myopathy-related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for "trios" (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease-related gene panel did not improve our diagnostic yield. CONCLUSIONS AND RELEVANCEWith WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples.

This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Objective To determine the costs associated with delirium in critically ill children. Design Prospective observational study. Setting An urban, academic, tertiary-care pediatric intensive care unit (PICU) in New York City. Patients Four-hundred and sixty-four consecutive PICU admissions between 9/2/2014 and 12/19/2014. Interventions None. Measurements and Main Results All children were assessed for delirium daily throughout their PICU stay. Hospital costs were analyzed using cost-to-charge ratios, in 2014 dollars. Median total PICU costs were higher in patients with delirium than in patients who were never delirious ($18,832 vs. $4,803, p<0.0001). Costs increased incrementally with number of days spent delirious (median cost of $9,173 for 1 day with delirium, $19,682 for 2–3 days with delirium, and $75,833 for >3 days with delirium, p<0.0001); this remained highly significant even after adjusting for PICU length of stay (p<0.0001). After controlling for age, gender, severity of illness, and PICU length of stay, delirium was associated with an 85% increase in PICU costs (p<0.0001). Conclusions Pediatric delirium is associated with a major increase in PICU costs. Further research directed at prevention and treatment of pediatric delirium is essential to improve outcomes in this population, and could lead to substantial healthcare savings.

Benzodiazepines are an independent and modifiable risk factor for development of delirium in critically ill children, even after carefully controlling for time-dependent covariates, with a dose-response effect. This temporal relationship suggests causality between benzodiazepine exposure and pediatric delirium and supports limiting the use of benzodiazepines in critically ill children.

Summary Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Aim:  To assess the extent of Listeria monocytogenes in causation of human spontaneous abortions by isolation methods and PCR analysis for the presence of virulence‐associated genes. Methods and Results:  A total of 305 samples comprising blood, urine, placental bits, faecal and vaginal swabs were collected from 61 patients with spontaneous abortions. Listeria spp. were isolated from 10 samples collected from nine (14·8%) patients. Confirmation of these isolates was based on biochemical tests, haemolysis on blood agar, CAMP test, phosphatidylinositol‐specific phospholipase C (PI‐PLC) assay followed by in vivo pathogenicity tests and multiplex PCR to detect virulence‐associated genes (prfA, plcA, hlyA, actA and iap). Three isolates were confirmed as L. monocytogenes. Of these, two isolates turned out to be pathogenic and found to posses all five genes. However, the remaining two haemolytic L. monocytogenes isolates lacking the plcA gene and activity in the PI‐PLC assay were found to be nonpathogenic by in vivo tests. Conclusions:  The occurrence of pathogenic L. monocytogenes in cases of spontaneous abortions was 3·3%. It seems that the plcA gene and its expression have an important role as essential virulence determinants in pathogenic Listeria spp. Significance and Impact of the Study:  The recovery of pathogenic L. monocytogenes isolates from cases of spontaneous abortion indicates the significance of listeric infection in pregnant women.

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis.