Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program

CONTEXT: Safety concerns regarding premature mortality, diabetes, neoplasia and cerebrovascular disease in association with growth hormone (GH) therapy have been raised. OBJECTIVE: To assess incidence of key safety outcomes. DESIGN: Prospective, multinational, observational study (1999-2015). SETTING: 22,311 GH-treated children from 827 investigative sites in 30 countries. PATIENTS: Children with growth disorders. INTERVENTIONS: GH treatment. MAIN OUTCOME MEASURES: Standardized mortality (SMR) and incidence (SIR) ratios with 95% confidence intervals (CI) for mortality, diabetes, and primary cancer, using general population registries. RESULTS: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean±SD follow-up of 4.2±3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with SMR (95% CI) of 0.61 (0.44-0.82); the SMR was elevated for patients with cancer-related organic GH deficiency (5.87 [3.21-9.85]). Based on 18 cases, Type 2 diabetes (T2DM) risk was elevated (SIR 3.77 [2.24-5.96]), but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed (SIR 0.71 [0.39-1.20]). Second neoplasms occurred in 31/622 (5.0%) cancer survivors (10.7 [7.5-15.2] cases/1000 PY), and intracranial tumor recurrences in 67/823 (8.1%) tumor survivors (16.9 [13.3-21.5] cases/1000 PY). All 3 hemorrhagic stroke cases had risk factors. CONCLUSIONS: GeNeSIS data support the favourable safety profile of pediatric GH treatment. Overall risk for death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared to the general population, but most cases had diabetes risk factors

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

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

Dark Energy from Mass Varying Neutrinos

We show that mass varying neutrinos (MaVaNs) can behave as a negative pressure fluid which could be the origin of the cosmic acceleration. We derive a model independent relation between the neutrino mass and the equation of state parameter of the neutrino dark energy, which is applicable for general theories of mass varying particles. The neutrino mass depends on the local neutrino density and the observed neutrino mass can exceed the cosmological bound on a constant neutrino mass. We discuss microscopic realizations of the MaVaN acceleration scenario, which involve a sterile neutrino. We consider naturalness constraints for mass varying particles, and find that both ev cutoffs and ev mass particles are needed to avoid fine-tuning. These considerations give a (current) mass of order an eV for the sterile neutrino in microscopic realizations, which could be detectable at MiniBooNE. Because the sterile neutrino was much heavier at earlier times, constraints from big bang nucleosynthesis on additional states are not problematic. We consider regions of high neutrino density and find that the most likely place today to find neutrino masses which are significantly different from the neutrino masses in our solar system is in a supernova. The possibility of different neutrino mass in different regions of the galaxy and the local group could be significant for Z-burst models of ultra-high energy cosmic rays. We also consider the cosmology of and the constraints on the ``acceleron'', the scalar field which is responsible for the varying neutrino mass, and briefly discuss neutrino density dependent variations in other constants, such as the fine structure constant.Comment: 26 pages, 3 figures, refs added, typos corrected, comment added about possible matter effect