Optically Enhanced Bonding Workstation for Robust Bonding

Process control is one of the methods recommended by the FAA to reduce risk in fabrication of structurally bonded composite joints for aircraft structure based on guidance provided in circular AC-107B for certification of structurally bonded joints. An Optically Enhanced Bonding Workstation is presented here that reduces the risk in bonded joint fabrication. Results will be presented demonstrating the benefits of process monitoring and its ability to reduce risk in performing pre-bond composite surface preparation steps. This supports reduction in the timeline to certification of bonded composite structures through development of a robust bonding process upstream of any part certification steps. Sanding surface preparation has been identified as a high risk process step that is known to impact bond performance. Control of sanding during surface preparation can be performed using portable surface analysis tools previously identified including included gloss, color, Fourier Transform Infrared spectroscopy (FTIR) and optically stimulated electron emissions (OSEE). Threshold limits for the surface analysis tool measurements were determined based on an example objective bonding system utilizing a common EA9394 paste adhesive measured using standard double cantilever beam fracture toughness testing. The patented Optically Enhanced Bonding Workstation (OEBW), was tailored to monitor and control the epoxy composite surface preparation step. Surface analysis tool threshold limits were incorporated into the OEBW to demonstrate improved composite bond performance through process control. The surface analysis tools investigated here can easily be incorporated into an automated system due to their applicability to rapidly quantify the composite sanded surface treatment and their portability

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system. One Sentence Summary: We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

INTRODUCTION: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that often presents in young adults. Over the past decade, certain elements of the genetic architecture of susceptibility have gradually emerged, but most of the genetic risk for MS remained unknown. RATIONALE: Earlier versions of the MS genetic map had highlighted the role of the adaptive arm of the immune system, implicating multiple different T cell subsets. We expanded our knowledge of MS susceptibility by performing a genetic association study in MS that leveraged genotype data from 47,429 MS cases and 68,374 control subjects. We enhanced this analysis with an in-depth and comprehensive evaluation of the functional impact of the susceptibility variants that we uncovered. RESULTS: We identified 233 statistically independent associations with MS susceptibility that are genome-wide significant. The major histocompatibility complex (MHC) contains 32 of these associations, and one, the first MS locus on a sex chromosome, is found in chromosome X. The remaining 200 associations are found in the autosomal non-MHC genome. Our genome-wide partitioning approach and large-scale replication effort allowed the evaluation of other variants that did not meet our strict threshold of significance, such as 416 variants that had evidence of statistical replication but did not reach the level of genome-wide statistical significance. Many of these loci are likely to be true susceptibility loci. The genome-wide and suggestive effects jointly explain ~48% of the estimated heritability for MS. Using atlases of gene expression patterns and epigenomic features, we documented that enrichment for MS susceptibility loci was apparent in many different immune cell types and tissues, whereas there was an absence of enrichment in tissue-level brain profiles. We extended the annotation analyses by analyzing new data generated from human induced pluripotent stem cell–derived neurons as well as from purified primary human astrocytes and microglia, observing that enrichment for MS genes is seen in human microglia, the resident immune cells of the brain, but not in astrocytes or neurons. Further, we have characterized the functional consequences of many MS susceptibility variants by identifying those that influence the expression of nearby genes in immune cells or brain. Last, we applied an ensemble of methods to prioritize 551 putative MS susceptibility genes that may be the target of the MS variants that meet a threshold of genome-wide significance. This extensive list of MS susceptibility genes expands our knowledge more than twofold and highlights processes relating to the development, maturation, and terminal differentiation of B, T, natural killer, and myeloid cells that may contribute to the onset of MS. These analyses focus our attention on a number of different cells in which the function of MS variants should be further investigated. Using reference protein-protein interaction maps, these MS genes can also be assembled into 13 communities of genes encoding proteins that interact with one another; this higher-order architecture begins to assemble groups of susceptibility variants whose functional consequences may converge on certain protein complexes that can be prioritized for further evaluation as targets for MS prevention strategies. CONCLUSION: We report a detailed genetic and genomic map of MS susceptibility, one that explains almost half of this disease’s heritability. We highlight the importance of several cells of the peripheral and brain resident immune systems—implicating both the adaptive and innate arms—in the translation of MS genetic risk into an auto-immune inflammatory process that targets the CNS and triggers a neurodegenerative cascade. In particular, the myeloid component highlights a possible role for microglia that requires further investigation, and the B cell component connects to the narrative of effective B cell–directed therapies in MS. These insights set the stage for a new generation of functional studies to uncover the sequence of molecular events that lead to disease onset. This perspective on the trajectory of disease onset will lay the foundation for developing primary prevention strategies that mitigate the risk of developing MS

Ofatumumab versus Teriflunomide in Multiple Sclerosis

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.)