Fibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies.

Objective. To estimate cause of death and to identify factors associated with risk of inhospital mortality among patients with T2D. Methods. Prospective cohort study performed in a referral public hospital in Lima, Peru. The outcome was time until event, elapsed from hospital admission to discharge or death, and the exposure was the cause of hospital admission. Cox regression was used to evaluate associations of interest reporting Hazard Ratios (HR) and 95% confidence intervals. Results. 499 patients were enrolled. Main causes of death were exacerbation of chronic renal failure (38.1%), respiratory infections (35.7%), and stroke (16.7%). During hospital stay, 42 (8.4%) patients died. In multivariable models, respiratory infections (HR = 6.55, p < 0.001), stroke (HR = 7.05, p = 0.003), and acute renal failure (HR = 16.9, p = 0.001) increased the risk of death. In addition, having 2+ (HR = 7.75, p < 0.001) and 3+ (HR = 21.1, p < 0.001) conditions increased the risk of dying. Conclusion. Respiratory infections, stroke, and acute renal disease increased the risk of inhospital mortality among hospitalized patients with T2D. Infections are not the only cause of inhospital mortality. Certain causes of hospitalization require standardized and aggressive management to decrease mortality.

Objective: Neuroendocrine differentiation of prostate cancer can result in ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) and Cushing syndrome. The aim of this report is to highlight this unusual mechanism of hypercortisolism and its management. Methods: We report a 73-year-old patient with a history of prostate adenocarcinoma who presented with severe weakness, hyperglycemia, and hypokalemia caused by EAS. Results: Diagnostic workup showed elevated 24-hour urine cortisol and ACTH levels consistent with EAS. Fluorodeoxyglucose positron emission tomographycomputed tomography revealed a hypermetabolic mass in the prostate and metastatic lesions to the liver and bones. Liver biopsy was consistent with small cell carcinoma with positive immunostaining for ACTH. Pleural fluid analysis was consistent with high-grade neuroendocrine carcinoma. The patient underwent chemotherapy with carboplatin and etoposide. Hypercortisolism was treated with ketoconazole, metyrapone, mifepristone, and spironolactone. He suffered complications including opportunistic infections, deep venous thrombosis, and delirium. Given his poor prognosis and clinical decline, the patient opted for comfort measures only in a hospice facility. Conclusion: Treatment-related neuroendocrine differentiation of prostate cancer is an emerging entity that may be associated with paraneoplastic syndromes including EAS. (AACE Clinical Case Rep. 2019;5:e192-e196) Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; EAS = ectopic adrenocorticotrophic hormone syndrome; FDG = fluorodeoxyglucose; SCPC = small cell prostate carcinoma

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