An EWMA control chart for the multivariate coefficient of variation

This is the peer reviewed version of the following article: Giner-Bosch, V, Tran, KP, Castagliola, P, Khoo, MBC. An EWMA control chart for the multivariate coefficient of variation. Qual Reliab Engng Int. 2019; 35: 1515-1541, which has been published in final form at https://doi.org/10.1002/qre.2459. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Monitoring the multivariate coefficient of variation over time is a natural choice when the focus is on stabilising the relative variability of a multivariate process, as is the case in a significant number of real situations in engineering, health sciences, and finance, to name but a few areas. However, not many tools are available to practitioners with this aim. This paper introduces a new control chart to monitor the multivariate coefficient of variation through an exponentially weighted moving average (EWMA) scheme. Concrete methodologies to calculate the limits and evaluate the performance of the chart proposed and determine the optimal values of the chart's parameters are derived based on a theoretical study of the statistic being monitored. Computational experiments reveal that our proposal clearly outperforms existing alternatives, in terms of the average run length to detect an out-of-control state. A numerical example is included to show the efficiency of our chart when operating in practice.Generalitat Valenciana, Grant/Award Number: BEST/2017/033 and GV/2016/004; Ministerio de Economia y Competitividad, Grant/Award Number: MTM2013-45381-PGiner-Bosch, V.; Tran, KP.; Castagliola, P.; Khoo, MBC. (2019). An EWMA control chart for the multivariate coefficient of variation. Quality and Reliability Engineering International. 35(6):1515-1541. https://doi.org/10.1002/qre.2459S15151541356Kang, C. W., Lee, M. S., Seong, Y. J., & Hawkins, D. M. (2007). 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Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

Analysis of queries sent to PubMed at the point of care: Observation of search behaviour in a medical teaching hospital

Contains fulltext : 69801.pdf ( ) (Open Access)BACKGROUND: The use of PubMed to answer daily medical care questions is limited because it is challenging to retrieve a small set of relevant articles and time is restricted. Knowing what aspects of queries are likely to retrieve relevant articles can increase the effectiveness of PubMed searches. The objectives of our study were to identify queries that are likely to retrieve relevant articles by relating PubMed search techniques and tools to the number of articles retrieved and the selection of articles for further reading. METHODS: This was a prospective observational study of queries regarding patient-related problems sent to PubMed by residents and internists in internal medicine working in an Academic Medical Centre. We analyzed queries, search results, query tools (Mesh, Limits, wildcards, operators), selection of abstract and full-text for further reading, using a portal that mimics PubMed. RESULTS: PubMed was used to solve 1121 patient-related problems, resulting in 3205 distinct queries. Abstracts were viewed in 999 (31%) of these queries, and in 126 (39%) of 321 queries using query tools. The average term count per query was 2.5. Abstracts were selected in more than 40% of queries using four or five terms, increasing to 63% if the use of four or five terms yielded 2-161 articles. CONCLUSION: Queries sent to PubMed by physicians at our hospital during daily medical care contain fewer than three terms. Queries using four to five terms, retrieving less than 161 article titles, are most likely to result in abstract viewing. PubMed search tools are used infrequently by our population and are less effective than the use of four or five terms. Methods to facilitate the formulation of precise queries, using more relevant terms, should be the focus of education and research

Temperature influence on DXA measurements: bone mineral density acquisition in frozen and thawed human femora

<p>Abstract</p> <p>Background</p> <p>Determining bone mineral density (BMD) with dual-energy x-ray absorptiometry (DXA) is an established and widely used method that is also applied prior to biomechanical testing. However, DXA is affected by a number of factors. In order to delay decompositional processes, human specimens for biomechanical studies are usually stored at about -20°C; similarly, bone mineral density measurements are usually performed in the frozen state. The aim of our study was to investigate the influence of bone temperature on the measured bone mineral density.</p> <p>Methods</p> <p>Using DXA, bone mineral density measurements were taken in 19 fresh-frozen human femora, in the frozen and the thawed state. Water was used to mimic the missing soft tissue around the specimens. Measurements were taken with the specimens in standardized internal rotation. Total-BMD and single-BMD values of different regions of interest were used for evaluation.</p> <p>Results</p> <p>Fourteen of the 19 specimens showed a decrease in BMD after thawing. The measured total-BMD of the frozen specimens was significantly (1.4%) higher than the measured BMD of the thawed specimens.</p> <p>Conclusion</p> <p>Based on our findings we recommend that the measurement of bone density, for example prior to biomechanical testing, should be standardized to thawed or frozen specimens. Temperature should not be changed during measurements. When using score systems for data interpretation (e.g. T- or Z-score), BMD measurements should be performed only on thawed specimens.</p

Heterogeneous Glycation of Cancellous Bone and Its Association with Bone Quality and Fragility

Non-enzymatic glycation (NEG) and enzymatic biochemical processes create crosslinks that modify the extracellular matrix (ECM) and affect the turnover of bone tissue. Because NEG affects turnover and turnover at the local level affects microarchitecture and formation and removal of microdamage, we hypothesized that NEG in cancellous bone is heterogeneous and accounts partly for the contribution of microarchitecture and microdamage on bone fragility. Human trabecular bone cores from 23 donors were subjected to compression tests. Mechanically tested cores as well as an additional 19 cores were stained with lead-uranyl acetate and imaged to determine microarchitecture and measure microdamage. Post-yield mechanical properties were measured and damaged trabeculae were extracted from a subset of specimens and characterized for the morphology of induced microdamage. Tested specimens and extracted trabeculae were quantified for enzymatic and non-enzymatic crosslink content using a colorimetric assay and Ultra-high Performance Liquid Chromatography (UPLC). Results show that an increase in enzymatic crosslinks was beneficial for bone where they were associated with increased toughness and decreased microdamage. Conversely, bone with increased NEG required less strain to reach failure and were less tough. NEG heterogeneously modified trabecular microarchitecture where high amounts of NEG crosslinks were found in trabecular rods and with the mechanically deleterious form of microdamage (linear microcracks). The extent of NEG in tibial cancellous bone was the dominant predictor of bone fragility and was associated with changes in microarchitecture and microdamage

Heterogeneous reaction of ClONO2_{2} with TiO2_{2} and SiO2_{2} aerosol particles: implications for stratospheric particle injection for climate engineering

Deliberate injection of aerosol particles into the stratosphere is a potential climate engineering scheme. Particles injected into the stratosphere would scatter solar radiation back to space, thereby reducing the temperature at the Earth's surface and hence the impacts of global warming. Minerals such as TiO$_{2}$ or SiO$_{2}$ are among the potentially suitable aerosol materials for stratospheric particle injection due to their greater light-scattering ability than stratospheric sulfuric acid particles. However, the heterogeneous reactivity of mineral particles towards trace gases important for stratospheric chemistry largely remains unknown, precluding reliable assessment of their impacts on stratospheric ozone, which is of key environmental significance. In this work we have investigated for the first time the heterogeneous hydrolysis of ClONO$_{2}$ on TiO$_{2}$ and SiO$_{2}$ aerosol particles at room temperature and at different relative humidities (RHs), using an aerosol flow tube. The uptake coefficient, γ(ClONO$_{2}$), on TiO$_{2}$ was ∼ 1.2 × 10$^{-3}$ at 7 % RH and remained unchanged at 33 % RH, and increased for SiO$_{2}$ from ∼ 2 × 10$^{-4}$ at 7 % RH to  ∼ 5 × 10$^{-4}$ at 35 % RH, reaching a value of  ∼ 6 × 10$^{-4}$ at 59 % RH. We have also examined the impacts of a hypothetical TiO$_{2}$ injection on stratospheric chemistry using the UKCA (United Kingdom Chemistry and Aerosol) chemistry–climate model, in which heterogeneous hydrolysis of N$_{2}$O$_{5}$ and ClONO$_{2}$ on TiO$_{2}$ particles is considered. A TiO$_{2}$ injection scenario with a solar-radiation scattering effect very similar to the eruption of Mt Pinatubo was constructed. It is found that, compared to the eruption of Mt Pinatubo, TiO$_{2}$ injection causes less ClO$_{x}$ activation and less ozone destruction in the lowermost stratosphere, while reduced depletion of N$_{2}$O$_{5}$ and NO$_{x}$ in the middle stratosphere results in decreased ozone levels. Overall, no significant difference in the vertically integrated ozone abundances is found between TiO$_{2}$ injection and the eruption of Mt Pinatubo. Future work required to further assess the impacts of TiO$_{2}$ injection on stratospheric chemistry is also discussed.Financial support provided by EPSRC grant EP/I01473X/1 and the Isaac Newton Trust (Trinity College, University of Cambridge, UK) is acknowledged. We thank NCAS-CMS for modelling support. Model integrations have been performed using the ARCHER UK National Supercomputing Service. We acknowledge the ERC for support through the ACCI project (project number: 267760). M. J. Tang would like to thank the CAS Pioneer Hundred Talents programme and State Key Laboratory of Organic Geochemistry for providing starting grants

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte– endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro- thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations

High Diversity of vacA and cagA Helicobacter pylori Genotypes in Patients with and without Gastric Cancer

BACKGROUND: Helicobacter pylori is associated with chronic gastritis, peptic ulcers, and gastric cancer. The aim of this study was to assess the topographical distribution of H. pylori in the stomach as well as the vacA and cagA genotypes in patients with and without gastric cancer. METHODOLOGY/PRINCIPAL FINDINGS: Three gastric biopsies, from predetermined regions, were evaluated in 16 patients with gastric cancer and 14 patients with dyspeptic symptoms. From cancer patients, additional biopsy specimens were obtained from tumor centers and margins; among these samples, the presence of H. pylori vacA and cagA genotypes was evaluated. Positive H. pylori was 38% and 26% in biopsies obtained from the gastric cancer and non-cancer groups, respectively (p = 0.008), and 36% in tumor sites. In cancer patients, we found a preferential distribution of H. pylori in the fundus and corpus, whereas, in the non-cancer group, the distribution was uniform (p = 0.003). A majority of the biopsies were simultaneously cagA gene-positive and -negative. The fundus and corpus demonstrated a higher positivity rate for the cagA gene in the non-cancer group (p = 0.036). A mixture of cagA gene sizes was also significantly more frequent in this group (p = 0.003). Ninety-two percent of all the subjects showed more than one vacA gene genotype; s1b and m1 vacA genotypes were predominantly found in the gastric cancer group. The highest vacA-genotype signal-sequence diversity was found in the corpus and 5 cm from tumor margins. CONCLUSION/SIGNIFICANCE: High H. pylori colonization diversity, along with the cagA gene, was found predominantly in the fundus and corpus of patients with gastric cancer. The genotype diversity observed across systematic whole-organ and tumor sampling was remarkable. We find that there is insufficient evidence to support the association of one isolate with a specific disease, due to the multistrain nature of H. pylori infection shown in this work