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

High-utilizing Crohn's disease patients under psychosomatic therapy*

<p>Abstract</p> <p>Objective</p> <p>Few studies have been published on health care utilization in Crohn's disease and the influence of psychological treatment on high utilizers.</p> <p>Methods</p> <p>The present sub study of a prospective multi center investigation conducted in 87 of 488 consecutive Crohn's disease (CD) patients was designed to investigate the influence of the course of Crohn's disease on health care utilization (hospital days (HD) and sick leave days (SLD) collected by German insurance companies) and to examine the conditions of high-utilizing patients. Predictors of health care utilization should be selected. Based on a standardized somatic treatment, high health care utilizing patients of the psychotherapy and control groups should be compared before and after a one-year treatment.</p> <p>Results</p> <p>Multivariate regression analysis identified disease activity at randomization as an important predictor of the clinical course (r²= 0.28, p < 0.01). Health care utilization correlated with duration of disease (p < 0.04), but the model was not significant (r²= 0.15, p = 0.09). The patients' level of anxiety, depression and lack of control at randomization predicted their health-related quality of life at the end of the study (r²= 0.51, p < 0.00001). Interestingly, steroid intake and depression (t1) predicted the combined outcome measure (clinical course, HRQL, health care utilization) of Crohn's disease at the end of the study (r²= 0.22, p < 0.001).</p> <p>Among high utilizers, a significantly greater drop in HD (p < 0.03) and in mean in SLD were found in the treatment compared to the control group.</p> <p>Conclusion</p> <p>The course of Crohn's disease is influenced by psychological as well as somatic factors; especially depression seems important here. A significant drop of health care utilization demonstrates the benefit of psychological treatment in the subgroup of high-utilizing CD patients. Further studies are needed to replicate the findings of the clinical outcome in this CD subgroup.</p

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Pressure-temperature evolution of primordial solar system solids during impact-induced compaction

Prior to becoming chondritic meteorites, primordial solids were a poorly consolidated mix of mm-scale igneous inclusions (chondrules) and high-porosity sub-μm dust (matrix). We used high-resolution numerical simulations to track the effect of impact-induced compaction on these materials. Here we show that impact velocities as low as 1.5 km s−1 were capable of heating the matrix to >1,000 K, with pressure–temperature varying by >10 GPa and >1,000 K over ~100 μm. Chondrules were unaffected, acting as heat-sinks: matrix temperature excursions were brief. As impact-induced compaction was a primary and ubiquitous process, our new understanding of its effects requires that key aspects of the chondrite record be re-evaluated: palaeomagnetism, petrography and variability in shock level across meteorite groups. Our data suggest a lithification mechanism for meteorites, and provide a ‘speed limit’ constraint on major compressive impacts that is inconsistent with recent models of solar system orbital architecture that require an early, rapid phase of main-belt collisional evolution

Hybrid speciation in Heliconius butterflies? A review and critique of the evidence

The evidence supporting the recent hypothesis of a homoploid hybrid origin for the butterfly species Heliconius heurippa is evaluated. Data from selective breeding experiments, mate-choice studies, and a wide variety of DNA markers are reviewed, and an alternative hypothesis for the origin of the species and its close relatives is proposed. A scenario of occasional red wing-pattern mutations in peripheral populations of Heliconius cydno with subsequent adaptive convergence towards sympatric mimicry rings involving H. melpomene and H. erato is offered as an alternative to the HHS hypothesis. Recent twists of this tale are addressed in a postscript

A Novel Three-Phase Model of Brain Tissue Microstructure

We propose a novel biologically constrained three-phase model of the brain microstructure. Designing a realistic model is tantamount to a packing problem, and for this reason, a number of techniques from the theory of random heterogeneous materials can be brought to bear on this problem. Our analysis strongly suggests that previously developed two-phase models in which cells are packed in the extracellular space are insufficient representations of the brain microstructure. These models either do not preserve realistic geometric and topological features of brain tissue or preserve these properties while overestimating the brain's effective diffusivity, an average measure of the underlying microstructure. In light of the highly connected nature of three-dimensional space, which limits the minimum diffusivity of biologically constrained two-phase models, we explore the previously proposed hypothesis that the extracellular matrix is an important factor that contributes to the diffusivity of brain tissue. Using accurate first-passage-time techniques, we support this hypothesis by showing that the incorporation of the extracellular matrix as the third phase of a biologically constrained model gives the reduction in the diffusion coefficient necessary for the three-phase model to be a valid representation of the brain microstructure

Growth hormone axis in chronic kidney disease

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD

Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy

Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1–48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization