Tau overexpression exacerbates neuropathology after repeated mild head impacts in male mice.

Repeated mild traumatic brain injury (rmTBI) can lead to development of chronic traumatic encephalopathy (CTE), which is characterized by progressive neurodegeneration with presence of white matter damage, gliosis and hyper-phosphorylated tau. While animal models of rmTBI have been documented, few characterize the molecular pathogenesis and expression profiles of relevant injured brain regions. Additionally, while the usage of transgenic tau mice in rmTBI is prevalent, the effects of tau on pathological outcomes has not been well studied. Here we characterized a 42-impact closed-head rmTBI paradigm on 3-4 month old male C57BL/6 (WT) and Tau-overexpressing mice (Tau58.4). This injury paradigm resulted in chronic gliosis, T-cell infiltration, and demyelination of the optic nerve and associated white matter tracts at 1-month post-injury. At 3-months post-injury, Tau58.4 mice showed progressive neuroinflammation and neurodegeneration in multiple brain regions compared to WT mice. Corresponding to histopathology, RNAseq of the optic nerve tract at 1-month post-injury showed significant upregulation of inflammatory pathways and downregulation of myelin synthetic pathways in both genotypes. However, Tau58.4 mice showed additional changes in neurite development, protein processing, and cell stress. Comparisons with published transcriptomes of human Alzheimer's Disease and CTE revealed common signatures including neuroinflammation and downregulation of protein phosphatases. We next investigated the demyelination and T-cell infiltration phenotypes to determine whether these offer potential avenues for therapeutic intervention. Tau58.4 mice were treated with the histamine H3 receptor antagonist GSK239512 for 1-month post-injury to promote remyelination of white matter lesions. This restored myelin gene expression to sham levels but failed to repair the histopathologic lesions. Likewise, injured T-cell-deficient Rag2/Il2rg (R2G2) mice also showed evidence for inflammation and loss of myelin. However, unlike immune-competent mice, R2G2 mice had altered myeloid cell gene expression and fewer demyelinated lesions. Together this data shows that rmTBI leads to chronic white matter inflammatory demyelination and axonal loss exacerbated by human tau overexpression but suggests that immune-suppression and remyelination alone are insufficient to reverse damage.

Comparisons of potentially inappropriate medications and outcomes in older adults admitted to intensive care unit: A retrospective cohort study.

OBJECTIVES: To comparatively assess potentially inappropriate medication (PIM) use and subsequent impact on clinical outcomes among older adults admitted to the intensive care unit (ICU) by means of 3 different screening criteria for PIMs. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: DCH Regional Medical Center ICU. Patients 65 years of age and older admitted to the medical ICU in 2014 (n = 346). MAIN OUTCOME MEASURES: PIMs were identified with the use of the Beers criteria (2015 and 2012 versions) and the Screening Tool of Older People's Potentially Inappropriate Prescriptions (STOPP). The proportions of PIM use at admission and discharge and proportions of in-hospital mortality and ICU and hospital readmission within 2014 among patients with PIM use were compared among the 3 criteria. Multivariable Poisson regression models assessed the associations of PIMs at admission with hospital and ICU length of stay (LOS). Statistical significance was considered to be indicated at P < 0.05. RESULTS: The proportions of patients with at least 1 PIM identified through 3 different criteria (2015 Beers, 2012 Beers, and STOPP, respectively; at admission: 68.5%, 58.1%, and 44.5%; at discharge: 77.4%, 63.6%, and 42.9%) were significantly different from each other (2012/2015 Beers vs. STOPP: P < 0.01). PIM use at admission as determined by STOPP was significantly associated with longer ICU stay (relative risk [RR] 1.24, 95% CI 1.11-1.38) and hospital LOS (RR 1.24, 95% CI 1.16-1.33). However, PIMs identified through the Beers criteria (2015 and 2012 versions) were associated with shorter ICU and hospital LOS. No differences were found in proportions of in-hospital mortality and ICU and hospital readmission among patients with PIM use identified through the 3 different criteria. CONCLUSION: Although the Beers criteria demonstrated the ability to identify PIMs more frequently in the ICU setting, PIM use identified by means of STOPP was associated with longer ICU and hospital LOS. Clinical interventions aiming to reduce PIMs identified by STOPP in inpatient or ICU settings may decrease patients' inpatient or ICU LOS.