Faculty Bibliography

Purpose/UNASSIGNED:The purpose of this study was to compare hospital quality outcomes in patients over the age of 60 undergoing fixation of hip fracture based on their anticoagulation status. Materials and Methods/UNASSIGNED:Patients aged 60 and older with isolated hip fracture injuries treated operatively at 1 academic medical center between October 2014 and September 2016 were analyzed. Patients on the following medications were included in the anticoagulation cohort: warfarin, clopidogrel, aspirin 325 mg, rivaroxaban, apixaban, dabigatran, and dipyridamole/aspirin. We compared outcome measures including time to surgery, length of stay (LOS), transfusion rate, blood loss, procedure time, complication rate, need for intensive care unit (ICU)/step-down unit (SDU) care, discharge disposition, and cost of admission. Outcomes were controlled for age, Charlson comorbidity index (CCI), and anesthesia type. Results/UNASSIGNED:= .026). Lastly, there was no difference in cost of care. Conclusion/UNASSIGNED:This study highlights that anticoagulation status alone does not independently put patients at increased risk with respect to LOS, surgical outcomes, and cost of hospitalization.

BACKGROUND:Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer's disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. METHODS:In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts. RESULTS:Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD. CONCLUSIONS:The comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies.

The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo-electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the β and δ regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation.