Case-matched comparison of cardiovascular outcome in Loeys-Dietz syndrome versus Marfan syndrome

Background: Pathogenic variants in TGFBR1, TGFBR2 and SMAD3 genes cause Loeys-Dietz syndrome, and pathogenic variants in FBN1 cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Methods: Three expert centers performed a case-matched comparison of cardiovascular outcomes. The Loeys-Dietz group comprised 43 men and 40 women with a mean age of 34 +/- 18 years. Twenty-six individuals had pathogenic variants in TGFBR1, 40 in TGFBR2, and 17 in SMAD3. For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. Results: In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus (p = 0.014) was more prevalent, the craniofacial score was higher (p < 0.001), the systemic score lower (p < 0.001), and mitral valve prolapse less frequent (p = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 +/- 3 versus 73 +/- 2 years; p = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 +/- 4 versus 48 +/- 3 years; p = 0.589), distal aortic repair (72 +/- 3 versus 67 +/- 2 years; p = 0.777), mitral valve surgery (75 +/- 4 versus 65 +/- 3 years; p = 0.108), and reintervention (20 +/- 3 versus 14 +/- 2 years; p = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748; p < 0.001), where receiver operating characteristic analysis identified <= 33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502; p = 0.001), and higher systemic score points at least marginally (HR = 1.175; p = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Conclusions: Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery

Global standards of Constitutional law : epistemology and methodology

Just as it led the philosophy of science to gravitate around scientific practice, the abandonment of all foundationalist aspirations has already begun making political philosophy into an attentive observer of the new ways in which constitutional law is practiced. Yet paradoxically, lawyers and legal scholars are not those who understand this the most clearly. Beyond analyzing the jurisprudence that has emerged from the expansion of constitutional justice, and taking into account the development of international and regional law, the ongoing globalization of constitutional law requires comparing the constitutional laws of individual nations. Following Waldron, the product of this new legal science can be considered as ius gentium. This legal science is not as well established as one might like to think. But it can be developed on the grounds of the practice that consists in ascertaining standards. As abstract types of best “practices” (and especially norms) of constitutional law from around the world, these are only a source of law in a substantive, not a formal, sense. They thus belong to what I should like to call a “second order legal positivity.” In this article I will undertake, both at a methodological and an epistemological level, the development of a model for ascertaining global standards of constitutional law

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)