Model-Based Systems Engineering in Concurrent Engineering Centers

Concurrent Engineering Centers (CECs) are specialized facilities with a goal of generating and maturing engineering designs by enabling rapid design iterations. This is accomplished by co-locating a team of experts (either physically or virtually) in a room with a focused design goal and a limited timeline of a week or less. The systems engineer uses a model of the system to capture the relevant interfaces and manage the overall architecture. A single model that integrates other design information and modeling allows the entire team to visualize the concurrent activity and identify conflicts more efficiently, potentially resulting in a systems model that will continue to be used throughout the project lifecycle. Performing systems engineering using such a system model is the definition of model-based systems engineering (MBSE); therefore, CECs evolving their approach to incorporate advances in MBSE are more successful in reducing time and cost needed to meet study goals. This paper surveys space mission CECs that are in the middle of this evolution, and the authors share their experiences in order to promote discussion within the community

Model-Based Systems Engineering in Concurrent Engineering Centers

Concurrent Engineering Centers (CECs) are specialized facilities with a goal of generating and maturing engineering designs by enabling rapid design iterations. This is accomplished by co-locating a team of experts (either physically or virtually) in a room with a narrow design goal and a limited timeline of a week or less. The systems engineer uses a model of the system to capture the relevant interfaces and manage the overall architecture. A single model that integrates other design information and modeling allows the entire team to visualize the concurrent activity and identify conflicts more efficiently, potentially resulting in a systems model that will continue to be used throughout the project lifecycle. Performing systems engineering using such a system model is the definition of model-based systems engineering (MBSE); therefore, CECs evolving their approach to incorporate advances in MBSE are more successful in reducing time and cost needed to meet study goals. This paper surveys space mission CECs that are in the middle of this evolution, and the authors share their experiences in order to promote discussion within the community

Perioperative nursing: maintaining momentum and staying safe.

Perioperative practice underpins one of the key activities of many healthcare services but the work of perioperative nurses is little known. A better understanding of their work is important to enable articulation of their contribution to clinical practice. This study observed the practice of perioperative nurses and explored how they described their role. Using ethnographic observation and interview, eighty-five hours observation of eleven nurses were undertaken and eight nurses were interviewed. Thematic analysis was undertaken enabling themes to emerge with two being identified. The first, 'maintaining momentum', described the need to keep people and equipment moving. The second, ‘accounting for safety’, referred to the need to keep the patient safe during this dangerous period. Tension between these two phenomena was apparent. Perioperative nurses describe one of their key roles as maintaining the momentum of the patient’s journey through the operating theatre but having to balance this with the need to ensure the patient’s safety. A core component of the perioperative nurse’s work is thus management of the tension between these. This study illuminated how these nurses understand their practice

Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors

The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK-MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC. Significance: Compensatory upregulation of IGF1R and ERK- MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.Peer reviewe

Diagnosing tuberculosis in the 21st century – Dawn of a genomics revolution?

Tuberculosis (TB) ranks alongside HIV as the leading cause of death worldwide, killing 1.5 million people in 2014. Traditional laboratory techniques do not provide sufficiently rapid results to inform clinicians on appropriate treatment, especially in the face of increasingly prevalent drug-resistant TB. Rapid molecular methods such as PCR and LAMP are vital tools in the fight against TB, however, rapid advances in next generation sequencing (NGS) technology are allowing increasingly rapid and accurate sequencing of entire bacterial genomes at ever decreasing cost, providing unprecedented depth of information. These advances mean NGS stands to revolutionise the diagnosis and epidemiological study of Mycobacterium tuberculosis infection. This review focuses on current applications of NGS for TB diagnosis including sequencing cultured isolates to predict drug resistance and, more desirably, direct diagnostic metagenomic sequencing of clinical samples. Also discussed is the potential impact of NGS on the epidemiological study of TB and some of the key challenges that need to be overcome to enable this promising technology to be translated into routine use

Iron and zinc nutrition in the economically-developed world : a review

This review compares iron and zinc food sources, dietary intakes, dietary recommendations, nutritional status, bioavailability and interactions, with a focus on adults in economically-developed countries. The main sources of iron and zinc are cereals and meat, with fortificant iron and zinc potentially making an important contribution. Current fortification practices are concerning as there is little regulation or monitoring of intakes. In the countries included in this review, the proportion of individuals with iron intakes below recommendations was similar to the proportion of individuals with suboptimal iron status. Due to a lack of population zinc status information, similar comparisons cannot be made for zinc intakes and status. Significant data indicate that inhibitors of iron absorption include phytate, polyphenols, soy protein and calcium, and enhancers include animal tissue and ascorbic acid. It appears that of these, only phytate and soy protein also inhibit zinc absorption. Most data are derived from single-meal studies, which tend to amplify impacts on iron absorption in contrast to studies that utilize a realistic food matrix. These interactions need to be substantiated by studies that account for whole diets, however in the interim, it may be prudent for those at risk of iron deficiency to maximize absorption by reducing consumption of inhibitors and including enhancers at mealtimes.<br /

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.