Efficacy, safety and patient reported outcomes (PROS) in adult patients with atopic dermatitis treated with dupilumab at week-52 in usual clinical practice

P15 Background: Dupilumab, an anti-interleikin-4-receptor-a monoclonal antibody, is a new treatment for atopic dermatitis in adults. Objective: To evaluate – at week 52 – patient reported outcomes, satisfaction, efficacy and safety, with dupilumab in adult patients with moderate-to-severe atopic dermatitis refractory to the usual treatments previously performed under conditions of usual clinical practice. Methods: Twelve patients were enrolled. Patients from our hospital, under routine clinical practice, were treated with subcutaneous dupilumab 300 mg every 2 weeks. The outcomes were evaluated at baseline, week 4, 8, 12, 16, 28 , 40 and week 52. The variables evaluated were: itch, difficulty to sleep, previous stressful life events, severity (SCORAD), anxiety and depression symptoms (HADS), quality of life (DLQI, EQ5D3L), satisfaction, adherence to the treatment, efficacy and safety. Results: At week 52 significant improvement was observed in severity, itch, difficulty to sleep, anxiety and depression symptoms, and quality of life. Satisfaction with dupilumab compared to previous treatments was significantly higher in all aspects assessed. No significant dupilumab-induced laboratory abnormalities were noted, and adverse events were mild and transient. Conclusions: Dupilumab used under routine clinical practice for 52 weeks improved atopic dermatitis signs and symptoms, with a good safety profile and patient satisfaction

Heteroepitaxial Beta-Ga2O3 on 4H-SiC for an FET With Reduced Self Heating

A method to improve thermal management of β-Ga 2 O 3 FETs is demonstrated here via simulation of epitaxial growth on a 4H-SiC substrate. Using a recently published device as a model, the reduction achieved in self-heating allows the device to be driven at higher gate voltages and increases the overall performance. For the same operating parameters an 18% increase in peak drain current and 15% reduction in lattice temperature are observed. Device dimensions may be substantially reduced without detriment to performance and normally off operation may be achieved

Processing of ultrafine-size particulate metal matrix composites by advanced shear technology

Copyright @ 2009 ASM International. This paper was published in Metallurgical & Materials Transactions A 40A(3) and is made available as an electronic reprint with the permission of ASM International. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplications of any material in this paper for a fee or for commercial purposes, or modification of the content of this paper are prohibited.Lack of efficient mixing technology to achieve a uniform distribution of fine-size reinforcement within the matrix and the high cost of producing components have hindered the widespread adaptation of particulate metal matrix composites (PMMCs) for engineering applications. A new rheo-processing method, the melt-conditioning high-pressure die-cast (MC-HPDC) process, has been developed for manufacturing near-net-shape components of high integrity. The MC-HPDC process adapts the well-established high shear dispersive mixing action of a twin-screw mechanism to the task of overcoming the cohesive force of the agglomerates under a high shear rate and high intensity of turbulence. This is followed by direct shaping of the slurry into near-net-shape components using an existing cold-chamber die-casting process. The results indicate that the MC-HPDC samples have a uniform distribution of ultrafine-sized SiC particles throughout the entire sample in the as-cast condition. Compared to those produced by conventional high-pressure die casting (HPDC), MC-HPDC samples have a much improved tensile strength and ductility.EP-SR

Red Tides In the Gulf of Mexico: Where, When, and Why?

Independent data from the Gulf of Mexico are used to develop and test the hypothesis that the same sequence of physical and ecological events each year allows the toxic dinoflagellate Karenia brevis to become dominant. A phosphorus-rich nutrient supply initiates phytoplankton succession, once deposition events of Saharan iron-rich dust allow Trichodesmium blooms to utilize ubiquitous dissolved nitrogen gas within otherwise nitrogen-poor sea water. They and the co-occurring K. brevis are positioned within the bottom Ekman layers, as a consequence of their similar diel vertical migration patterns on the middle shelf. Upon onshore upwelling of these near-bottom seed populations to CDOM-rich surface waters of coastal regions, light-inhibition of the small red tide of similar to 1 ug chl l(-1) of ichthytoxic K. brevis is alleviated. Thence, dead fish serve as a supplementary nutrient source, yielding large, self-shaded red tides of similar to 10 ug chl l(-1). The source of phosphorus is mainly of fossil origin off west Florida, where past nutrient additions from the eutrophied Lake Okeechobee had minimal impact. In contrast, the P-sources are of mainly anthropogenic origin off Texas, since both the nutrient loadings of Mississippi River and the spatial extent of the downstream red tides have increased over the last 100 years. During the past century and particularly within the last decade, previously cryptic Karenia spp. have caused toxic red tides in similar coastal habitats of other western boundary currents off Japan, China, New Zealand, Australia, and South Africa, downstream of the Gobi, Simpson, Great Western, and Kalahari Deserts, in a global response to both desertification and eutrophication

Dynamics of gene silencing during X inactivation using allele-specific RNA-seq

Background: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA-seq. Results: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X-inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. Also, the previously characterized gene clusters escaping XCI in human fibroblasts correlate with TADs. Conclusions: The gene silencing observed during XCI provides further insight in the establishment of the repressive complex formed by the inactive X chromosome. The association of e

Effect of skilled and unskilled training on nerve regeneration and functional recovery

The most disabling aspect of human peripheral nerve injuries, the majority of which affect the upper limbs, is the loss of skilled hand movements. Activity-induced morphological and electrophysiological remodeling of the neuromuscular junction has been shown to influence nerve repair and functional recovery. In the current study, we determined the effects of two different treatments on the functional and morphological recovery after median and ulnar nerve injury. Adult Wistar male rats weighing 280 to 330 g at the time of surgery (N = 8-10 animals/group) were submitted to nerve crush and 1 week later began a 3-week course of motor rehabilitation involving either “skilled” (reaching for small food pellets) or “unskilled” (walking on a motorized treadmill) training. During this period, functional recovery was monitored weekly using staircase and cylinder tests. Histological and morphometric nerve analyses were used to assess nerve regeneration at the end of treatment. The functional evaluation demonstrated benefits of both tasks, but found no difference between them (P > 0.05). The unskilled training, however, induced a greater degree of nerve regeneration as evidenced by histological measurement (P < 0.05). These data provide evidence that both of the forelimb training tasks used in this study can accelerate functional recovery following brachial plexus injury

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors