Background Higher tissue transcript levels of immune-related markers, including the recently discovered viral restriction factor interferon-induced transmembrane protein (IFITM) which inhibits viral entry and replication, have been reported in the prefrontal cortex in schizophrenia. Interestingly, mouse models of neuroinflammation have higher IFITM levels and deficits in GABA-related markers that are similar to findings in schizophrenia, suggesting that a shared pathogenetic process may underlie diverse cortical pathology in the disorder. However, the cell types that overexpress IFITM mRNA in schizophrenia are unknown, and it is unclear whether higher IFITM mRNA levels are associated with lower GABA-related marker levels in the same schizophrenia subjects. Methods We used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify IFITM mRNA levels in prefrontal cortex area 9 of 57 schizophrenia and 57 healthy comparison subjects and in antipsychotic-exposed monkeys. Results Quantitative PCR and in situ hybridization film analysis revealed markedly elevated IFITM mRNA levels (+114% and +117%, respectively) in prefrontal gray matter in schizophrenia. Interestingly, emulsion-dipped, Nissl-stained sections from schizophrenia and comparison subjects revealed IFITM mRNA expression in pia mater and blood vessels. IFITM grain density over blood vessels was 71% higher in schizophrenia. IFITM mRNA levels were negatively correlated with GABA-related mRNAs in the same schizophrenia subjects. Conclusions The finding that schizophrenia subjects with higher IFITM mRNA levels in cortical blood vessels have greater disturbances in cortical GABA neurons suggests that these cell-type distinct pathological disturbances may be influenced by a shared upstream insult that involves immune activation.
Adolescent cannabis use is associated with greater relative risk, increased symptom severity, and earlier age of onset of schizophrenia. We investigated whether this interaction may be partly attributable to disease-related disturbances in metabolism of the major cortical endocannabinoid 2-arachidonoylglycerol (2-AG). Transcript levels for the recently discovered 2-AG metabolizing enzyme, α-β-hydrolase domain 6 (ABHD6), were assessed using quantitative PCR in the prefrontal cortex of schizophrenia and healthy subjects (n = 84) and antipsychotic- or tetrahydrocannabinol-exposed monkeys. ABHD6 mRNA levels were elevated in schizophrenia subjects who were younger and had a shorter illness duration but not in antipsychotic- or tetrahydrocannabinol-exposed monkeys. Higher ABHD6 mRNA levels may increase 2-AG metabolism which may influence susceptibility to cannabis in the earlier stages of schizophrenia.
Introduction:In critically ill children, inappropriate urinary catheter (UC) utilization is associated with increased morbidity, including catheter-associated urinary tract infections (CAUTIs). Checklists are effective for reducing medical errors, but there is little data on their impact on device utilization in pediatric critical care. In this study, we evaluated UC utilization trends and CAUTI rate after implementing a daily rounding checklist.Methods:A retrospective review of our checklist database from 2006 through 2016 was performed. The study setting was a 36-bed pediatric intensive care unit in a quaternary-care pediatric hospital. Interventions included the “Daily QI Checklist” in 2006, ongoing education regarding device necessity, and a CAUTI prevention bundle in 2013. UC utilization and duration were assessed via auto-correlated time series models and Cochran-Armitage tests for trend. Changes in CAUTI rate were assessed via Poisson regression.Results:UC utilization decreased from 30% of patient-days in 2006 to 18% in 2016 (P < 0.0001, Cochran-Armitage trend test), while duration of UC use (median, 2.0 days; interquartile range, 1–4) did not change over time (P = 0.18). CAUTI rate declined from 9.49/1,000 UC-days in 2009 to 1.04 in 2016 (P = 0.0047).Conclusions:Implementation of the checklist coincided with a sustained 40% reduction in UC utilization. The trend may be explained by a combination of more appropriate selection of patients for catheterization and improved timeliness of UC discontinuation. We also observed an 89% decline in CAUTI rate that occurred after stabilization of UC utilization. These findings underscore the potential impact of a checklist on incorporating best practices into daily care of critically ill children.
Background: Neuropsychiatric symptoms and CSF cytokine, chemokine, and SARS-COV-2 antibody profiles are unknown in pediatric patients with COVID-19 or multisystem inflammatory syndrome (MIS-C), (NP-COVID-19). Methods: Children at a single pediatric institution quaternary referral center with laboratory-confirmed COVID-19 or MIS-C and neuropsychiatric symptoms were included in this retrospective case series. Clinical symptoms, ancillary testing data, treatments and outcomes are described. Multiplexed electrochemiluminescence assays for cytokines, chemokines and SARS-CoV-2 antibodies were tested in the CSF NP-COVID-19 patients compared to five controls and were analyzed using the Student's t-test. Results: Three of five NP-COVID-19 patients had psychiatric symptoms, and two patients had encephalopathy and seizures. All patients had full or near resolution of neuropsychiatric symptoms by discharge. One patient received intravenous steroids for treatment for psychiatric symptoms; 3/5 other patients received immunotherapy for MIS-C, including IVIG, high-dose steroids, anakinra, and tocilizumab. Pro-inflammatory chemokines, including MIG, MPC, MIP-1β, and TARC were significantly elevated in NP-COVID-19 patients compared to controls. Two of five patients had elevated CSF neurofilament light chain. CSF SARS-CoV-2 antibody titers to the full-length spike, receptor binding domain and N-terminal domain were significantly elevated. SARS-CoV-2 antibody titers strongly correlated with pro-inflammatory chemokines/cytokines, including IL-1β, IL-2, IL-8, TNF-α, and IFN-γ (P≤0.05 for all). Conclusions: A spectrum of neuropsychiatric clinical manifestations can occur in children with SARS-CoV-2 infection. CSF pro-inflammatory chemokines and SARS-CoV-2 antibodies may serve as biomarkers of SARS-CoV-2 mediated NP-COVID-19. Additional study is required to understand the pathophysiologic mechanisms of neuroinflammation in children with COVID-19 and MIS-C.
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