IMPORTANCE Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention.OBJECTIVE To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin. DESIGN, SETTING, AND PARTICIPANTSThis cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018.EXPOSURES Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure.MAIN OUTCOMES AND MEASURES All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort. RESULTS Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding.CONCLUSIONS AND RELEVANCE This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

Over-expression of the Hsp70 molecular chaperone prevents protein aggregation and ameliorates neurodegenerative disease phenotypes in model systems. We identified an Hsp70 activator, MAL1–271, that reduces α-synuclein aggregation in a Parkinson’s Disease model. We now report that MAL1–271 directly increases the ATPase activity of a eukaryotic Hsp70. Next, twelve MAL1–271 derivatives were synthesized and examined in a refined α-synuclein aggregation model as well as in an assay that monitors maturation of a disease-causing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutant, which is also linked to Hsp70 function. Compared to the control, MAL1–271 significantly increased the number of cells lacking α-synuclein inclusions and increased the steady-state levels of the CFTR mutant. We also found that a nitrile-containing MAL1–271 analog exhibited similar effects in both assays. None of the derivatives exhibited cellular toxicity at concentrations up to 100µM, nor were cellular stress response pathways induced. These data serve as a gateway for the continued development of a new class of Hsp70 agonists with efficacy in these and potentially other disease models.

BACKGROUND Prophylactic anticoagulation helps prevent postoperative venous thromboembolism (VTE) and time to initiation postcraniotomy has relied on clinical judgment and practice patterns. OBJECTIVE To compare risks of postoperative VTE and hemorrhage among patients undergoing tumor resection with initiation of prophylactic anticoagulation on postoperative day 1 (POD1) vs POD2. METHODS Adult patients undergoing craniotomy for tumor between 2008 and 2018 were retrospectively reviewed. Outcomes were recorded from the Electronic medical record (EMR) including deep vein thrombosis (DVT), pulmonary embolism (PE), and hemorrhage. RESULTS Of a total of 1168 patients undergoing craniotomy, 225 initiated anticoagulation on POD1 and 389 initiated on POD2. Of the 171 glioblastoma (GBM) cases, 64 initiated on POD1 and 107 on POD2. There were 9 DVTs (1.5%), 1 PE (0.20%), overall VTE rate of 1.6%, and 7 hemorrhagic complications (1.10%), 4 being clinically significant. The GBM cohort contained 4 DVTs (2.3%) and 3 hemorrhagic complications (1.80%). There was no increased risk of VTE or hemorrhage with anticoagulation initiated on POD2 compared to POD1 in either cohort. Multivariate analysis in both cohorts did not reveal a significant association between DVT, PE, or hemorrhagic complications with age, body mass index, GBM pathology, or extent of resection. Interestingly, glioma patients older than 70 with subtotal resection had a higher likelihood of suffering intracranial hemorrhage when anticoagulation was started on POD1 (odds ratio 12.98). CONCLUSION Risk of VTE or hemorrhagic complication did not significantly differ with prophylactic anticoagulation started on POD1 vs POD2. Early anticoagulation may certainly be considered in high risk cases; however, 1 group where risk may outweigh benefit is the elderly glioma population receiving a subtotal resection.

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