Thermodynamically accessible titanium clusters TiN, N = 2-32

We have performed a genetic algorithm search on the tight-binding interatomic potential energy surface (PES) for small TiN (N = 2-32) clusters. The low energy candidate clusters were further refined using density functional theory (DFT) calculations with the PBEsol exchange-correlation functional and evaluated with the PBEsol0 hybrid functional. The resulting clusters were analysed in terms of their structural features, growth mechanism and surface area. The results suggest a growth mechanism that is based on forming coordination centres by interpenetrating icosahedra, icositetrahedra and Frank-Kasper polyhedra. We identify centres of coordination, which act as centres of bulk nucleation in medium sized clusters and determine the morphological features of the cluster

Antimigraine medication use and associated health care costs in employed patients

Migraine is under diagnosed and suboptimally treated in the majority of patients, and also associated with decreased productivity in employees. The objective of this retrospective study is to assess the antimigraine medication use and associated resource utilization in employed patients. Patients with primary diagnosis of migraine or receiving antimigraine prescription drugs were identified from an employer-sponsored health insurance plan in 2010. Medical utilization and health care costs were determined for the year of 2010. Generalized linear regression was applied to evaluate the association between health care costs and the use of antimigraine medications by controlling covariates. Of 465 patients meeting the study criteria, nearly 30% that had migraine diagnosis were prescribed antimigraine medications, and 20% that had migraine diagnosis were not prescribed antimigraine medications. The remaining 50% were prescribed antimigraine medications but did not have migraine diagnosis. Patients with antimigraine medication prescriptions showed lower frequency of emergency department visits than those without antimigraine medication prescriptions. Regression models indicated an increase in migraine-related health care costs by 86% but decreases in all-cause medical costs and total health care costs by 42 and 26%, respectively, in the antimigraine medication use group after adjusting for covariates. Employed patients experienced inadequate pharmacotherapy for migraine treatment. After controlling for covariates, antimigraine prescription drug use was associated with lower total medical utilization and health care costs. Further studies should investigate patient self-reported care and needs to manage headache and develop effective intervention to improve patient quality of life and productivity

Widespread Epigenetic Abnormalities Suggest a Broad DNA Methylation Erasure Defect in Abnormal Human Sperm

Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis.We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm.This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line

Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study

Objective: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. Methods: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. Results: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. Significance: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy

Multi-Modal Proteomic Analysis of Retinal Protein Expression Alterations in a Rat Model of Diabetic Retinopathy

As a leading cause of adult blindness, diabetic retinopathy is a prevalent and profound complication of diabetes. We have previously reported duration-dependent changes in retinal vascular permeability, apoptosis, and mRNA expression with diabetes in a rat model system. The aim of this study was to identify retinal proteomic alterations associated with functional dysregulation of the diabetic retina to better understand diabetic retinopathy pathogenesis and that could be used as surrogate endpoints in preclinical drug testing studies.A multi-modal proteomic approach of antibody (Luminex)-, electrophoresis (DIGE)-, and LC-MS (iTRAQ)-based quantitation methods was used to maximize coverage of the retinal proteome. Transcriptomic profiling through microarray analysis was included to identify additional targets and assess potential regulation of protein expression changes at the mRNA level. The proteomic approaches proved complementary, with limited overlap in proteomic coverage. Alterations in pro-inflammatory, signaling and crystallin family proteins were confirmed by orthogonal methods in multiple independent animal cohorts. In an independent experiment, insulin replacement therapy normalized the expression of some proteins (Dbi, Anxa5) while other proteins (Cp, Cryba3, Lgals3, Stat3) were only partially normalized and Fgf2 and Crybb2 expression remained elevated.These results expand the understanding of the changes in retinal protein expression occurring with diabetes and their responsiveness to normalization of blood glucose through insulin therapy. These proteins, especially those not normalized by insulin therapy, may also be useful in preclinical drug development studies