Citations

Abstract Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10−6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10−6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.

Objectives: To assess—by literature review and expert consensus—workforce, workload, and burnout considerations among intensivists and advanced practice providers. Design: Data were synthesized from monthly expert consensus and literature review. Setting: Workforce and Workload section workgroup of the Academic Leaders in Critical Care Medicine Task Force. Measurements and Main Results: Multidisciplinary care teams led by intensivists are an essential component of critical care delivery. Advanced practice providers (nurse practitioners and physician assistants) are progressively being integrated into ICU practice models. The ever-increasing number of patients with complex, life-threatening diseases, concentration of ICU beds in few centralized hospitals, expansion of specialty ICU services, and desire for 24/7 availability have contributed to growing intensivist staffing concerns. Such staffing challenges may negatively impact practitioner wellness, team perception of care quality, time available for teaching, and length of stay when the patient to intensivist ratio is greater than or equal to 15. Enhanced team communication and reduction of practice variation are important factors for improved patient outcomes. A diverse workforce adds value and enrichment to the overall work environment. Formal succession planning for ICU leaders is crucial to the success of critical care organizations. Implementation of a continuous 24/7 ICU coverage care model in high-acuity, high-volume centers should be based on patient-centered outcomes. High levels of burnout syndrome are common among intensivists. Prospective analyses of interventions to decrease burnout within the ICU setting are limited. However, organizational interventions are felt to be more effective than those directed at individuals. Conclusions: Critical care workforce and staffing models are myriad and based on several factors including local culture and resources, ICU organization, and strategies to reduce burden on the ICU provider workforce. Prospective studies to assess and avoid the burnout syndrome among intensivists and advanced practice providers are needed.

Little is known about whether adolescent participation in sexual health research prompts adolescents and parents to have conversations about sensitive topics. One year after being presented with a hypothetical microbicide safety study, 248 adolescent–parent dyads were asked about conversations they may have had after their initial study visit. Sixty-three per cent of adolescents and 82% of parents reported having a conversation about the study. A launching conversation about broader topics (e.g. risk behaviours) was reported by 8% of adolescents and 17% of parents. Because there is evidence that conversations are occurring, researchers could provide guidance to help facilitate potentially sensitive discussions.

Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3–dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ–accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3+ CD4+ T cell proliferation, thereby amplifying organ inflammation. Consequently, Il3−/− mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.

Purpose: Neuroinvasive West Nile virus (WNV) is rare, occurring in less than 1% of those infected, and may manifest as meningitis, encephalitis, and/or acute flaccid paralysis. Patients may present initially with nonspecific symptoms including fevers. Although rare, neuroinvasive WNV is associated with significant morbidity and mortality. The mainstay of treatment is supportive care. Electroencephalography (EEG) allows for identification of nonconvulsive status epilepticus and other epileptiform and nonepileptiform patterns suggestive of underlying cognitive dysfunction. Our aim was to describe specific EEG patterns observed in WNV neuroinvasive disease. Methods: A retrospective chart review was conducted. West Nile virus was confirmed with serum and/or cerebrospinal fluid markers. Patients with a history of abnormal EEG were excluded. Electroencephalography reports were classified into categories based on the presence of epileptiform activity, focal slowing, generalized periodic discharges with triphasic morphology, and frontally predominant generalized rhythmic delta activity. Results: In our cohort of 34 patients, 60% of focal EEG abnormalities were anterior-predominant, seen as epileptiform discharges, focal slowing, or frontally predominant generalized rhythmic delta activity. Nonepileptiform EEG patterns included nonspecific slowing and generalized periodic discharges with triphasic morphology. Two patients had electrographic seizures, one arising from the frontocentral head region. Conclusions: EEGs are important in the evaluation of WNV infection to rule out seizures or alternative causes of encephalopathy, and because of the risk of nonconvulsive seizures or status epilepticus in encephalitis. Although an anterior predominance of EEG abnormalities was seen in our cohort, this most likely is more correlative to encephalopathy than WNV itself. Although a specific correlative EEG pattern may not accompany all cases of WNV neuroinvasive disease, WNV should be considered as a possible etiology in patients presenting with an encephalitic or meningitic syndrome in the presence of abnormal EEG findings including encephalopathic patterns, particularly those with anterior predominant EEG changes.

Male and female glioblastomas are biologically distinct, and improving outcomes may require sex-specific approaches to treatment.