A general method for chemogenetic control of peptide function.

Natural or engineered peptides serve important biological functions. A general approach to achieve chemical-dependent activation of short peptides will be valuable for spatial and temporal control of cellular processes. Here we present a pair of chemically activated protein domains (CAPs) for controlling the accessibility of both the N- and C-terminal portion of a peptide. CAPs were developed through directed evolution of an FK506-binding protein. By fusing a peptide to one or both CAPs, the function of the peptide is blocked until a small molecule displaces them from the FK506-binding protein ligand-binding site. We demonstrate that CAPs are generally applicable to a range of short peptides, including a protease cleavage site, a dimerization-inducing heptapeptide, a nuclear localization signal peptide, and an opioid peptide, with a chemical dependence up to 156-fold. We show that the CAPs system can be utilized in cell cultures and multiple organs in living animals.

Venous thromboembolism in patients with reduced estimated GFR: a population-based perspective.

BACKGROUND: An increased frequency of venous thromboembolism (VTE) has been shown in patients with decreased kidney function measured by decreased estimated glomerular filtration rate (eGFR). However, present practices with respect to VTE prevention and management in patients with decreased eGFR in general population settings are uncertain. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: Community investigation of 1,509 metropolitan Worcester, MA, residents with a validated VTE in 1999, 2001, and 2003 with further follow-up for up to 3 years. PREDICTOR: Patients with VTE classified further according to eGFR on presentation: <30, 30-59, 60-89, or ≥90 mL/min/1.73 m(2) (reference group). OUTCOMES: Recurrent VTE, major bleeding episodes, and all-cause mortality. MEASUREMENTS: Demographic and clinical characteristics, treatment practices, and study outcomes were extracted from patients' hospital and outpatient medical records; eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Patients with VTE with eGFR <30 mL/min/1.73 m(2) were at increased risk of recurrent VTE (HR, 1.83; 95% CI, 1.03-3.25), major bleeding episodes (HR, 2.30; 95% CI, 1.28-4.16), and all-cause mortality (HR, 1.70; 95% CI, 1.12-2.57) during a 3-year follow-up. Patients with decreased eGFR also presented with more comorbid conditions and were less likely to be discharged on any form of anticoagulant therapy (72.6%, 81.0%, 82.1%, and 87.3% for eGFR <30, 30-59, 60-89, and ≥90 mL/min/1.73 m(2), respectively; P < 0.001). LIMITATIONS: Decreased eGFR status is presumed based on creatinine values on clinical presentation. The impact of drug dosage, timing, type of anticoagulant therapy, and medication adherence on study outcomes could not be evaluated. CONCLUSIONS: Severe decreases in eGFR are associated with increased risk of long-term recurrent VTE, bleeding, and total mortality in patients with VTE. A greater frequency of serious comorbid conditions, difficulties implementing available management strategies, and suboptimal VTE prophylaxis during hospital admissions likely contributed to our findings.

Venous thromboembolism in patients with prior stroke.

Patients with prior stroke are susceptible to venous thromboembolism (VTE). We studied patients with stroke in the Worcester VTE study of 2488 consecutive patients hospitalized with VTE. In all, 288 (11.6%) had a clinical history of stroke and 2200 (88.4%) did not. Patients with stroke were more likely to die inhospital (9.2% vs 4%) and within 30 days of VTE diagnosis (16.7% vs 6.9%) compared with patients without stroke (all P < .001). Recent immobilization (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.15-4.09) and inferior vena cava (IVC) filter insertion (adjusted OR 2.1; 95% CI 1.15-3.83) were associated with a doubling of inhospital death. Recent immobilization (adjusted OR 1.84; 95% CI 1.19-2.83) and IVC filter insertion (adjusted OR 1.94; 95% CI 1.2-3.14) were associated with an increased risk of death within 30 days of VTE. In conclusion, patients with VTE and prior stroke were more than twice as likely to die while hospitalized and within 30 days of VTE diagnosis.

Venous thromboembolism in patients with diabetes mellitus.

PURPOSE: The majority of epidemiological studies demonstrate an increased risk of venous thromboembolism among diabetic patients. Our aim was to compare clinical characteristics, prophylaxis, treatment, and outcomes of venous thromboembolism in patients with and without previously diagnosed diabetes. METHODS: We studied diabetic patients in the population-based Worcester Venous Thromboembolism Study of 2488 consecutive patients with validated venous thromboembolism. RESULTS: Of 2488 venous thromboembolism patients, 476 (19.1%) had a clinical history of diabetes. Thromboprophylaxis was omitted in more than one third of diabetic patients who had been hospitalized for non-venous-thromboembolism-related illness or had undergone major surgery within 3 months before diagnosis. Patients with diabetes were more likely than nondiabetic patients to have a complicated course after venous thromboembolism. Patients with diabetes were more likely than patients without diabetes to suffer recurrent deep vein thrombosis (14.9% vs 10.7%) and long-term major bleeding complications (16.4% vs 11.7%) (all P=.01). Diabetes was associated with a significant increase in the risk of recurrent deep vein thrombosis (adjusted odds ratio [AOR] 1.74; 95% confidence interval [CI], 1.21-2.51). Aspirin therapy at discharge (AOR 1.59; 95% CI, 1.1-2.3) and chronic kidney disease (AOR 2.19; 95% CI, 1.44-3.35) were independent predictors of long-term major bleeding. CONCLUSION: Patients with diabetes who developed venous thromboembolism were more likely to suffer a complicated clinical course. Diabetes was an independent predictor of recurrent deep vein thrombosis. We observed a low rate of thromboprophylaxis in diabetic patients. Further studies should focus on venous thromboembolism prevention in this vulnerable population.

Venous thromboembolism in patients with chronic obstructive pulmonary disease.

OBJECTIVE: Our aim was to compare the clinical characteristics, prophylaxis, treatment, and outcomes of venous thromboembolism in patients with and without previously diagnosed chronic obstructive pulmonary disease. METHODS: We analyzed the population-based Worcester Venous Thromboembolism Study of 2488 consecutive patients with validated venous thromboembolism to compare clinical characteristics, prophylaxis, treatment, and outcomes in patients with and without chronic obstructive pulmonary disease. RESULTS: Of 2488 patients with venous thromboembolism, 484 (19.5%) had a history of clinical chronic obstructive pulmonary disease and 2004 (80.5%) did not. Patients with chronic obstructive pulmonary disease were older (mean age 68 vs 63 years) and had a higher frequency of heart failure (35.5% vs 12.9%) and immobility (53.5% vs 43.3%) than patients without chronic obstructive pulmonary disease (all P<.0001). Patients with chronic obstructive pulmonary disease were more likely to die in hospital (6.8% vs 4%, P=.01) and within 30 days of venous thromboembolism diagnosis (12.6% vs 6.5%, P<.0001). Patients with chronic obstructive pulmonary disease demonstrated increased mortality despite a higher frequency of venous thromboembolism prophylaxis. Immobility doubled the risk of in-hospital death (adjusted odds ratio, 2.21; 95% confidence interval, 1.35-3.62) and death within 30 days of venous thromboembolism diagnosis (adjusted odds ratio, 2.04; 95% confidence interval, 1.43-2.91). CONCLUSION: Patients with chronic obstructive pulmonary disease have an increased risk of dying during hospitalization and within 30 days of venous thromboembolism diagnosis. Immobility in patients with chronic obstructive pulmonary disease is an ominous risk factor for adverse outcomes.

Venous thromboembolism in patients with symptomatic atherosclerosis.

Patients with atherosclerosis have an increased risk of venous thromboembolism (VTE). We studied patients in the population-based Worcester VTE Study of 1,822 consecutive patients with validated VTE to compare clinical characteristics, prophylaxis, treatment, and outcomes of VTE in patients with and without symptomatic atherosclerotic cardiovascular disease, defined as history of ischaemic heart disease, history of positive cardiac catheterisation, percutaneous coronary intervention, or coronary artery bypass graft surgery, or history of peripheral artery disease. Of the 1,818 patients with VTE, 473 (26%) had a history of symptomatic atherosclerosis. Patients with atherosclerosis were significantly older (mean age 71.9 years vs. 61.6 years) and were more likely to have immobility (57.2% vs. 46.7%), prior heart failure (36.9% vs. 10.7%), chronic lung disease (26.4% vs. 15.5%), cerebrovascular disease (18.1% vs. 9.8%), and chronic kidney disease (4.9% vs. 1.9%) (all p<0.001) compared with non-atherosclerosis patients. Thromboprophylaxis was omitted in more than one-third of atherosclerosis patients who had been hospitalised for non-VTE-related illness or had undergone major surgery within the three months prior to VTE. Patients with atherosclerosis were significantly more likely to suffer in-hospital major bleeding (7.6% vs. 3.8%, p=0.0008). In conclusion, patients with atherosclerosis and VTE are more likely to suffer a complicated hospital course. Despite a high frequency of comorbid conditions contributing to the risk of VTE, we observed a low rate of thromboprophylaxis in patients with symptomatic atherosclerosis.

Venous thromboembolism in heart failure: preventable deaths during and after hospitalization.

OBJECTIVE: Our aim was to compare the clinical characteristics, prophylaxis, treatment, and outcomes of patients with venous thromboembolism with and without heart failure. METHODS: We studied patients with heart failure in the population-based Worcester Venous Thromboembolism Study of 1822 consecutive patients with validated venous thromboembolism. RESULTS: Of the 1822 patients with venous thromboembolism, 319 (17.5%) had a history of clinical heart failure and 1503 (82.5%) did not. Patients with heart failure were older (mean age 75 vs 62 years, P<.0001) and more likely to have been immobilized (65.2% vs 46.1%, P<.0001). Thromboprophylaxis was omitted in approximately one third of patients with heart failure who had been hospitalized for non-venous thromboembolism-related illness or had undergone major surgery within the 3 months before diagnosis. Patients with heart failure had a higher frequency of in-hospital death (9.7% vs 3.3%, P<.0001) and death within 30 days of venous thromboembolism diagnosis (15.6% vs 6.4%, P<.0001). Heart failure (adjusted odds ratio [OR] 2.04; 95% confidence interval [CI], 1.15-3.62) and immobility (adjusted OR 4.37; 95% CI, 2.42-7.9) were associated with an increased risk of in-hospital death. Heart failure (adjusted OR 1.57; 95% CI, 1.01-2.43) and immobility (adjusted OR 3.05; 95% CI, 2.01-4.62) also were independent predictors of death within 30 days of venous thromboembolism diagnosis. CONCLUSION: High mortality was observed among patients with heart failure and venous thromboembolism both during and after hospitalization. Heart failure and immobility are potent risk factors for in-hospital death and death within 30 days in patients with venous thromboembolism.