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Summary In complex tissues containing cells that are difficult to dissociate, single-nucleus RNA-sequencing (snRNA-seq) has become the preferred experimental technology over single-cell RNA-sequencing (scRNA-seq) to measure gene expression. To accurately model these data in downstream analyses, previous work has shown that droplet-based scRNA-seq data are not zero-inflated, but whether droplet-based snRNA-seq data follow the same probability distributions has not been systematically evaluated. Using pseudonegative control data from nuclei in mouse cortex sequenced with the 10x Genomics Chromium system and mouse kidney sequenced with the DropSeq system, we found that droplet-based snRNA-seq data follow a negative binomial distribution, suggesting that parametric statistical models applied to scRNA-seq are transferable to snRNA-seq. Furthermore, we found that the quantification choices in adapting quantification mapping strategies from scRNA-seq to snRNA-seq can play a significant role in downstream analyses and biological interpretation. In particular, reference transcriptomes that do not include intronic regions result in significantly smaller library sizes and incongruous cell type classifications. We also confirmed the presence of a gene length bias in snRNA-seq data, which we show is present in both exonic and intronic reads, and investigate potential causes for the bias.

Emerging data provide initial support for the concept that a single, minimally invasive liquid biopsy test, performed in conjunction with confirmatory radiologic or other diagnostic testing, when indicated, could be deployed on a broad scale to screen individuals for multiple types of cancer. Ideally, such a test could do this in a way that yields a clinically important percentage of true-positive indications of cancer while minimizing false-positive signals. Modern decision modeling approaches can and should be deployed to investigate the health and economic consequences of such multicancer early detection (MCED) testing within defined at-risk populations. In this paper, through small-scale analyses involving 3 hypothetical MCED-detectible cancers, the authors illustrate the potential for MCED testing to be cost-effective, along with the pivotal role of test-induced stage shift on results. The time is ripe for additional, prospective investigations of the clinical value of MCED testing, the benefits versus the risks for screened populations, and the overall projected impact on health outcomes and costs over time.

In complex tissues containing cells that are difficult to dissociate, single-nucleus RNA-sequencing (snRNA-seq) has become the preferred experimental technology over single-cell RNA-sequencing (scRNA-seq) to measure gene expression. To accurately model these data in downstream analyses, previous work has shown that droplet-based scRNA-seq data are not zero-inflated, but whether droplet-based snRNA-seq data follow the same probability distributions has not been systematically evaluated. Using pseudo-negative control data from nuclei in mouse cortex sequenced with the 10x Genomics Chromium system, we found that snRNA-seq data follow a negative binomial distribution, suggesting that parametric statistical models applied to scRNA-seq are transferable to snRNA-seq. Furthermore, we found that the quantification choices in adapting quantification mapping strategies from scRNA-seq to snRNA-seq can play a significant role in downstream analyses and biological interpretation. In particular, reference transcriptomes that do not include intronic regions result in significantly smaller library sizes and incongruous cell type classifications. We also confirmed the presence of a gene length bias in snRNA-seq data, which we show is present in both exonic and intronic reads, and investigate potential causes for the bias.

Background/Aims The preferential Janus kinase (JAK)-1 inhibitor filgotinib (FIL) is approved for treatment of moderately to severely active RA in Europe and Japan. We assessed efficacy and safety of FIL in patients (pts) with inadequate response to MTX (MTX-IR) who completed a Phase 3 trial (NCT02889796) and went on to enroll in a long-term extension (LTE; NCT03025308). Methods Pts who completed the parent study (PS) on study drug were eligible to enter the LTE. LTE data cutoff was June 1, 2020, and safety data are reported to that date, with median exposure 2.2 years. Efficacy data to W48 are reported for 4 treatment groups (all with background MTX): pts who received FIL 200mg (FIL200) or FIL 100mg (FIL100) in the PS and continued their dose in LTE (FIL200/FIL200, FIL100/FIL100) and ADA pts who were re-randomized, double blind, to FIL200 or FIL100 for LTE (ADA/FIL200, ADA/FIL100). ACR20/50/70 response rates, DAS28[CRP] ≤3.2 and Results As of June 1, 2020, 522/571 (91%) FIL200/FIL200, 502/570 (88%) FIL100/FIL100, 118/128 (92%) ADA/FIL200, and 115/130 (89%) ADA/FIL100 pts were still on study drug. LTE baseline (BL) disease characteristics were similar between groups: mean duration of RA was approximately 8.7 years; DAS28(CRP) was 2.55 and mean MTX dosage was 15.0 mg/week. Proportions of pts achieving ACR20/50/70, DAS28(CRP) ≤3.2, Conclusion During the LTE through W48, response rates were maintained for FIL/FIL and ADA/FIL pts. Though there were differences between LTE groups, safety was largely comparable and consistent with that observed in the PS and in previously reported results of safety data from 7 trials: rates of AESIs were low, and all confidence intervals were overlapping. Limitation: the LTE was not formally randomized for comparison between FIL/FIL and ADA/FIL treatment groups, the groups were of unequal size, and the switch from ADA to FIL for LTE was by design, rather than based on disease activity. Disclosure B. Combe: Consultancies; AbbVie; Eli Lilly & Co.; Gilead Sciences, Inc.; Janssen; Pfizer; Roche-Chugai; and Sanofi. Member of speakers’ bureau; for BMS; Eli Lilly & Co.; Gilead Sciences, Inc.; MSD; Pfizer; Roche- Chugai; and UCB. Grants/research support; Novartis, Pfizer, and Roche-Chugai. Y. Tanaka: Consultancies; Eli Lilly, Daiichi- Sankyo, Taisho, Ayumi, Sanofi, GSK, Abbvie. Member of speakers’ bureau; Daiichi- Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen. Grants/research support; Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo. P. Emery: Consultancies; AbbVie, BMS, Celltrion, Gilead, Lilly, Novartis, Roche, Samsung, and Sandoz. Grants/research support; AbbVie, BMS, Lilly, and Samsung. A. Pechonkina: Shareholder/stock ownership; employee and shareholder in Gilead Sciences, Inc. A. Kuo: Shareholder/stock ownership; employee and shareholder in Gilead Sciences, Inc. Q. Gong: Shareholder/stock ownership; employee and shareholder in Gilead Sciences, Inc. K. Van Beneden: Shareholder/stock ownership; employee of and shareholder in Galapagos, NV. V. Rajendran: Shareholder/stock ownership; employee of and shareholder in Galapagos, NV. H. Schulze-Koops: Consultancies; from AbbVie, Amgen, BMS, Celgene, Celltrion, Chugai, Gilead, Janssen, Eli Lilly and Company, Merck Sharp & Dohme, Novartis- Sandoz, Pfizer, Roche, Sanofi. Grants/research support; AbbVie and Novartis.

Determining the etiologic basis of the mutations that are responsible for cancer is one of the fundamental challenges in modern cancer research. Different mutational processes induce different types of DNA mutations, providing ‘mutational signatures’ that have led to key insights into cancer etiology. The most widely used signatures for assessing genomic data are based on unsupervised patterns that are then retrospectively correlated with certain features of cancer. We show here that supervised machine-learning techniques can identify signatures, called SuperSigs, that are more predictive than those currently available. Surprisingly, we found that aging yields different SuperSigs in different tissues, and the same is true for environmental exposures. We were able to discover SuperSigs associated with obesity, the most important lifestyle factor contributing to cancer in Western populations.

Item does not contain fulltext BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), intravenous fluid, pancreatic stents, or combinations of these have been evaluated in randomised controlled trials (RCTs) for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, but the comparative efficacy of these treatments remains unclear. Our aim was to do an exploratory network meta-analysis of previous RCTs to systematically compare the direct and indirect evidence and rank NSAIDs, intravenous fluids, pancreatic stents, or combinations of these to determine the most efficacious method of prophylaxis for post-ERCP pancreatitis. METHODS: We searched PubMed, Embase, and the Cochrane Central Register from inception to Nov 15, 2020, for full-text RCTs that evaluated the efficacy of NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for post-ERCP pancreatitis prevention in adult (aged ≥18 years) patients undergoing ERCP. Summary data from intention-to-treat analyses were extracted from published reports. We analysed incidence of post-ERCP pancreatitis across studies using network meta-analysis under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system for the confidence rating. This study is registered with PROSPERO, CRD42020172606. FINDINGS: We identified 1503 studies, of which 55 RCTs evaluating 20 interventions in 17 062 patients were included in the network meta-analysis. The mean incidence of post-ERCP pancreatitis in the placebo or active control group was 12·2% (95% CI 11·4-13·0). Normal saline plus rectal indometacin (OR 0·02, 95% CI 0·00-0·40), intramuscular diclofenac 75 mg (0·24, 0·09-0·69), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·30, 0·16-0·55), intravenous high-volume Ringer's lactate (0·31, 0·12-0·78), 5-7 Fr pancreatic stents (0·35, 0·26-0·48), rectal diclofenac 100 mg (0·36, 0·25-0·52), 3 Fr pancreatic stents (0·47, 0·26-0·87), and rectal indometacin 100 mg (0·60, 0·50-0·73) were all more efficacious than placebo for preventing post-ERCP pancreatitis in pairwise comparisons. 5-7 Fr pancreatic stents (0·59, 0·41-0·84), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·49, 0·26-0·94), intravenous standard-volume normal saline plus rectal indometacin 100 mg (0·04, 0·00-0·66), and rectal diclofenac 100 mg (0·59, 0·40-0·89) were more efficacious than rectal indometacin 100 mg. The GRADE confidence rating was low to moderate for 98·3% of the pairwise comparisons. INTERPRETATION: This systematic review and network meta-analysis summarises the available literature on NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for prophylaxis of post-ERCP pancreatitis. Rectal diclofenac 100 mg is the best performing rectal NSAID in this network meta-analysis. Combinations of prophylaxis might be more effective, but there is little evidence. These findings help to establish prophylaxis of post-ERCP pancreatitis for future research and practice, and could reduce costs and increase adoption of prophylaxis. FUNDING: None.

The single-bit charge loss of flash memory after stress has been investigated using TEM with selective chemical etching and TCAD simulation for the effect of silicon dopant profile and electrical failure analysis technique. However, the abnormal dopant profile on the drain-side of the failing bit observed in the TEM does not match the leakage behavior from the simulation. A qualitative model for the degradation process is proposed based on the electrical failure analysis results, it is suggested that the hole generated by avalanche breakdown captured by oxide traps on the drain-side during the stress is the source of leakage current.

Lean production and service means to improve the production and service management within an enterprise. Through several management techniques, the waste, the redundant things, and the expenses without added values can be cleared, and the production and service within an enterprise will become smoother, that is, the competitiveness of an enterprise will be enhanced. In this study, the data collected from experiment carried out in Toyota lean service simulation laboratory of China University of Technology are used for analysis. Data mining technique is used to investigate whether the result of lean production and service taken by enterprises can enhance the entire performance of production and service. In this study, Grey relational analysis is performed first and is used to judge whether the data collected in the experiment using lean production and service can enhance performance; then, clustering method is used to classify experimental data into two clusters based on service attitude and dish-serving efficiency; finally, three data mining techniques of Genetic Programming (GP), Back-propagation Artificial Neural Network and logistic regression are used to set up, respectively, lean service performance model and Employee Characteristic Analysis model. From the analysis result, it is shown that the result of lean production and service can indeed enhance the performance of entire production and service; and among the three data mining techniques, GP model has the best classification and forecast capability.

Taiwan’s economy recently gets a lot of vibration and instability due to the changing global economic environment. Meanwhile, some unsettlement problems might occur at the stock market given impacts from debts bankrupted on and caused by U.S. and European markets. These phenomena increase the risk of bankruptcy for many Taiwan’s enterprises where they failed to understand and manage the risk they have faced. Therefore, the managers really have to inspect the financial situation and characteristic of an enterprise well, and prevent in advance the operation risk possibly faced by the company. In this article, a comparison between normal and crisis companies from the profit force and growth force of financial characteristics was conducted. More specifically, the selected companies were then divided into two groups with the Self-Organized Map based on the ranks computed by the Grey Relational Analysis. Finally, three data mining techniques such as Grey Model Neural Network, Back-Propagation Neural Ne...

In recent years, global economic environmental are facing a fluctuated and unstable period. Due to the influence of subprime mortage crisis in USA and debt crisis in Europe, bankdruptcy of many large enterprises occurs one after another. In many countries, credit bankruptcy and violation of debt contract also occurs frequently, the violation of settlement in stock market can even be seen occasionally. This indicates that for many companies, not only risk is not well managed, but also the risk they are facing with is not well understood. To avoid possible business operation risk, the managers of a company really need to inspect the financial situation and characteristic of a company in advance. In this study, first, profitability force and growth force of financial five forces are used to the financial ratio data collected from the enterprises of China. Meanwhile, stability force and activity force is used to perform Grey Relational Analysis and the analysis results are sorted according to grey relational ...

In virtue of good generalization capability as well as Multiple Input and Multiple Output functions, the Neural Network has been extensively applied to various fields in recent years. Among neural networks, the General Regression Neural Network is frequently used in function approximation and classification forecast or continuous variables forecast. Thus, the General Regression Neural Network was intentionally adopted to predict closes in this study. In the first place, we took financial ratios of 37 Taiwanese listed private finance or insurance enterprises as sample data, and picked up the enterprises with their business performance ranking top two as the investment objectives by the Grey Relational Analysis. Next, for the purpose of choosing variables for one forecast model, the principal analysis was applied to technical indices as regards collected share prices. Finally, divided into training data and testing data, the data for variables selected was employed to develop the General Regression...

In recent years, data mining technology has been extensively applied to researches for investment related issues. And application methods include decision tree and artificial neural network, etc. Nevertheless, instead of relying on methods in the past, this research adopts genetic programming planning to conduct domestic stock market investment strategy researches. This thesis takes three approaches in strategic sense respectively: Call, put and hold. First of all, it collects daily information and relevant factors which could influence the stock price one day ahead of the actual trading for China Steel stocks. These factors include aspects in the stock's fundamental, share volume, technical performance in addition to Dow Jones average plus processing these information and subsequent normalization. Lastly, genetic programming planning is applied to construct investment model accordingly, in addition to conducting comparison analyses regarding the investment strategy classification capabilities for the dec...

PurposeTo solve problems of overdue loans and bad debts, the research establishes the internal performance measures to monitor and enhance the operational qualities of the employees in the lending department.Design/methodology/approachThe research utilizes the value‐added approach to analyze the lending production process and derive the internal performance measures to add value to lending activities.FindingsCompared with final measures (data envelopment analysis, benchmark, and productivity measures), the internal performance measures proposed in this research would be more effective for evaluating the job performance of employees in lending activities. A comprehensive analytical framework that will improve the accuracy of analyzing a borrower's capacity and condition has also been constructed in this research.Research limitations/implicationsThe conclusions in this research have been derived from deductive method. Some empirical study in confirmation of the conclusions in this research could be the direction for future research.Practical implicationsThe practical implication of using internal measure to monitor the output quality of the employees in lending department is a reduction in the likelihood of employee's moral hazard behavior.Originality/valueThe past researches in measuring the performance of bank lending have focused on the final measures that are incapable of solving the problems of overdue loans and bad debts. The value of the internal performance measure approach would ease the lending operational risk that is one of the main purpose of Basel II.

Partial hepatectomy is a major upper abdominal operation associated with certain stress to the patient. Successful adaptation to such stress is a prerequisite for survival. Donor hepatectomy with maximal safety is a principal concern during living donor liver transplantation. The purpose of the study was to compare the stress response by assessing cytokines and the acute-phase response induced by hepatectomy in patients with a healthy liver and those with a diseased liver. Fourteen patients undergoing partial right hepatectomy were enrolled in this study. Seven of them were donors for living related liver transplantation (group 1, or GI); the other seven were patients with hepatocellular carcinoma due to chronic hepatitis B (Child's class A) (GII). Blood samples for interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and C-reactive protein (CRP) assays were collected before the operation, at the beginning and end of the operation, and 24 and 48 hours after the operation. The data were analyzed and compared in the same group using the Friedman test and between groups using the Mann-Whitney U-test. A value of p0.05 was regarded as significant. Results showed that resection of the liver in patients with both healthy and disease livers leads to significant increases in IL-6 and CPR but not TNFalpha. Significantly lower levels of IL-6 before and after operation in GI patients compared to those in GII patients suggests that GI patients adapted to surgical stress more easily than did the GII patients.

In this work, gate bias-temperature-stress (VG-BTS) induced off-state leakage current (Ioff) has been comprehensively studied. During long-term operation in word-line driver of flash memory, the STI SiN-liner trapped charge which lowered the threshold voltage of STI-edge parasitic MOSFETs lead to off-state leakage or so-called word-line leakage. Both unipolar and bipolar AC stresses are performed for the phenomenon of relaxation and recovery. The H2 diffusion (Ea=0.6eV) is major cause of interface trapping between STI oxide and nitride and also attributes to the leakage. By long-term stress results, it is shown that the dependence of lifetime and gate voltage can be described by power law V-model. Moreover, we provide the design solutions to eliminate this unexpected leakage for the reliable memory production in the future.

The reliability assessments of tungsten via to copper interconnect were investigated. Three layout schemes of full-landing, just-landing and un-landing via structure showed similar characteristics of electromigration: The activation energy is about 0.8 eV and current density exponent is about 1.9, which means the failure symptoms of interfacial diffusivity and line depletion stress. In this paper, we discussed the relations between mean-time-to-failure and line-end-extension. The lifetime of electromigration is proportional to logarithm of extended spacing, which is attributed to difference of mechanical stress by performing stressmigration test. The model was provided a simple reliability assessment of via landing structure for definition of process pitch during technology development that could reduce the chip size and keep good reliability in the same time.

The reliability assessment of tungsten via to copper interconnect were investigated. Just-landing and un-landing via structure showed similar EM characteristics to full-landing structure. The activation energy of EM is about 0.86 and current density exponent is about 1.9, which means the mechanisms of interfacial diffusivity and line depletion stress. The resistance shifting of all splits was no more than 1% after 1000H SM test. The un-landing via of over-etching formation showed good resistivity and reliability that might be one of the solutions for gaining the process pitch in low-cost memory applications.

Spatial ‘intermittency’ in the velocity field fine-structure of fully turbulent flow regions, first observed by Batchelor & Townsend (1949), is studied further here in grid-generated nearly isotropic turbulence and on the axis of a round jet. At large enough Reynolds numbers, appropriately filtered hot-wire anemometer signals appear intermittent as the turbulent patterns are convected past the hot wire by the mean flow. Measurements show that there is a decrease in the relative fluid volume (equal to the ‘intermittency factor’) occupied by fine-structure of given size as the turbulence Reynolds number is increased. They show also that, for a fixed Reynolds number, the relative volume is smaller for smaller fine-structure. The average linear dimension of the fine-structure regions turns out to be much larger than the sizes of fine-structure therein. At Rλ, = 110, for example, the ratio ranges from 15 to 30, decreasing with decreasing ‘eddy’ size. It appears to be approaching an asymptote with increasing Rλ.The flatness factors and probability distributions of the first derivative, the second derivative, band-passed and high-passed velocity fluctuation signals were also measured. The turbulence Reynolds numbers Rλ ranged from 12 to 830. The flatness factors of the first and the second derivatives increase monotonically with Rλ. Those of the second derivative vary with Rλ0.25 for Rλ < 100, and with Rλ0.75 for Rλ > 300. No indication of asymptotic constant values was observed for Rλ up to the order of one thousand.The probability distributions of velocity fluctuations and large-scale signals are nearly normal, while the small-scale signals are not. The flatness factor of the filtered band-pass velocity signal increases with increasing frequency.At the larger Reynolds numbers, the square of the signal associated with large wave-numbers may be approximated by a log-normal probability distribution for amplitudes when probabilities fall between 0·3 and 0·95, in limited agreement with the theory of Kolmogorov (1962), Oboukhov (1962), Gurvich & Yaglom (1967).

A structural test program of typical aircraft structural configurations was conducted to assess the current Air Force damage tolerance design requirements defined in MIL-A-83444. The specimens, made of 2024-T3XX and 7075-T6XX, were subjected to randomized flight-by-flight spectra, representative of fighter/trainer and bomber/cargo type loading spectra, respectively, and to a constant amplitude loading spectrum. A total of two-hundred fifty-six specimens were tested. The test results were correlated with analytical predictions using crack growth and crack initiation methods. As a result of this study, recommendation is provided to the validity of MIL-A-83444, to develop guidelines for selection of critical crack locations, and to assess the state-of-the art analytical capabilities in predicting crack growth and crack initiation time. This report presents the user's manual of the computer program DAMGRO. This program has been developed in conjuction with this contract, and used to predict the crack growth and crack initiation of the structural test specimens.

An attempt has been made to identify the geometric character of the random fine-structure regions dispersed in fully turbulent fluid. The technique was measure-ment of two-position coincidence functions for the presence of velocity fine-structure. In this primitive approach, we tried to distinguish among only three possible categories for the random shapes: (a) ‘blobs’, (b) ‘rods’ and (c) 'slabs’, depending on whether three mean orthogonal dimensions of the domains were such that (a) all were of the same order, (b) one was an order larger than the other two, or (c) one was an order smaller than the other two.Highly idealized paradigms for these three categories were studied analytically: the two-position coincidence functions were computed for the cases of (a) spheres, (b) circular cylinders and (c) plane slabs, each field containing randomly sized elements distributed randomly in space with a homogeneous and isotropic distribution. Comparison of the measured coincidence functions with these three paradigms suggests that the fine-structure regions are more nearly of ‘rod-like’ geometry than like either of the other two. No attempt was made to distinguish shapes which might be called 'strips’.