bluuebunny/crossref_metadata_2025 huggingface dataset:
Conceptualizing the Lessons Learned Process in Delivery Projects: Detecting Knowledge Flow Barriers
Authors: Ahmad Banaz , Bergsjö Dag
Published: September 2021

Knowledge is vital intellectual property and is one of the most significant assets of an organization. Notably, it needs to be highly prioritized and managed strategically to enhance continuous improvement by capturing and reusing knowledge. Technology enterprises are associated with innovation, productivity, a collaboration of multidisciplinary professionals, tight budgets, and challenging time‐schedules. These factors combined are often what leads to challenges with knowledge management. Frequent disappointments with past knowledge management initiatives have motivated organizations to gain a new understanding of the complex mechanism of knowledge, which governs the effectiveness of an enterprise. This study elaborated on identifying knowledge flow barriers and handling knowledge by lessons learned (LL) practice in a case company and identify changes to ameliorate the flow. Albeit, the observations revealed that the difficulties related to finding LL documents were not the main issue, it was the contribution of the leaders. The case company demonstrated a discrepancy between what they said they do, and what they actually do. Besides these barriers, the research also detected divergence in the fundamental understanding of the theoretical aspects within knowledge management and LL, which indicates confusion and absence of awareness for the project managers and the leaders. Implementation of Systems Engineering (SE) methods, such as Communities of Practice (CoP) or triple loop lessons learned may fill both the gaps in the company but also in the literature when it comes to improving knowledge flow in large‐sized delivery projects.
Architecture Literacy
Authors: Kumar Anand , Lokku Doji Samson , Natarajan Swaminathan
Published: September 2021

Architecture as a discipline is gaining prominence in dealing with the size, sophistication, and complexity of human‐made entities. The architectures of these entities are expressed by architecture descriptions that depict how stakeholder concerns are addressed. Often, many stakeholders find it difficult to understand the underlying architectural concepts, properties, and principles and make decisions that affect the human‐made entity without understanding the consequences of their actions. Organizations often deal with the ripple effects of these uninformed decisions. In this paper, a few fundamental architecture concepts, principles, and properties are presented with the expectation that it will help individuals understand and make better architecture related decisions.
Broadening the Definition of Breadth in Systems Engineering
Authors: Armstrong James R.
Published: September 2021

Breadth versus depth is an aspect of systems engineering that is often referred to but seldom fully defined. This paper presents results of recent research that defines multiple aspects of depth that should be considered and discusses their value. The set of nine dimensions expands beyond the usual view of breadth defined as multiple systems engineering areas and can be applied to growth paths for systems engineers in their expertise development.
Betulinic acid exerts antigenotoxic and anticarcinogenic activities via inhibition of COX‐2 and PCNA in rodents
Authors: Ferreira Natália H. , Cunha Nayanne L. , de Melo Matheus R. S. , Fernandes Fernanda S. , de Freitas Karoline S. , do Nascimento Samuel , Ribeiro Arthur B. , de A. e Silva Márcio L. , Cunha Wilson R. , Tavares Denise C.
Published: September 2021

Phytochemicals have been suggested as an effective strategy for cancer prevention. Within this context, triterpene betulinic acid (BA) exhibits several biological properties but its chemopreventive effect has not been fully demonstrated. The present study investigated the antigenotoxic potential of BA against doxorubicin (DXR)‐induced genotoxicity using the mouse peripheral blood micronucleus assay, as well as its anticarcinogenic activity against 1,2dimethylhydrazine (DMH)‐induced colorectal lesions in rats. Micronuclei (MN) assay and aberrant crypt foci assay were used to assess the antigenotoxic and the anticarcinogenic potential, respectively. The molecular mechanisms underlying the anticarcinogenic activity of BA were evaluated by assessing anti‐inflammatory (COX‐2) and antiproliferative (PCNA) pathways. The results demonstrated that BA at the dose of 0.5 mg/kg bodyweight exerted antigenotoxic effects against DXR, with a reduction of 70.2% in the frequencies of chromosomal damage. Animals treated with BA showed a 64% reduction in the number of preneoplastic lesions when compared to those treated with the carcinogen alone. The levels of COX‐2 and PCNA expression in the colon were significantly lower in animals treated with BA and DMH compared to those treated with the carcinogen alone. The chemopreventive effect of BA is related, at least in part, to its antiproliferative and anti‐inflammatory activity, indicating a promising potential of this triterpene in anticancer therapies, especially for colorectal cancer.
The PRMT5/HURP axis retards Golgi repositioning by stabilizing acetyl‐tubulin and Golgi apparatus during cell migration
Authors: Chiu Shao‐Chih , Huang Yun‐Ru Jaoying , Wei Tong‐You Wade , Chen Jo‐Mei Maureen , Kuo Yi‐Chun , Huang Yu‐Ting Jenny , Liao Yu‐Ting Amber , Yu Chang‐Tze Ricky
Published: September 2021

The Golgi apparatus (GA) translocates to the cell leading end during directional migration, thereby determining cell polarity and transporting essential factors to the migration apparatus. The study provides mechanistic insights into how GA repositioning (GR) is regulated. We show that the methyltransferase PRMT5 methylates the microtubule regulator HURP at R122. The HURP methylation mimicking mutant 122F impairs GR and cell migration. Mechanistic studies revealed that HURP 122F or endogenous methylated HURP, that is, HURP m122, interacts with acetyl‐tubulin. Overexpression of HURP 122F stabilizes the bundling pattern of acetyl‐tubulin by decreasing the sensitivity of the latter to a microtubule disrupting agent nocodazole. HURP 122F also rigidifies GA via desensitizing the organelle to several GA disrupting chemicals. Similarly, the acetyl‐tubulin mimicking mutant 40Q or tubulin acetyltransferase αTAT1 can rigidify GA, impair GR, and retard cell migration. Reversal of HURP 122F‐induced GA rigidification, by knocking down GA assembly factors such as GRASP65 or GM130, attenuates 122F‐triggered GR and cell migration. Remarkably, PRMT5 is found downregulated and the level of HURP m122 is decreased during the early hours of wound healing‐based cell migration, collectively implying that the PRMT5‐HURP‐acetyl‐tubulin axis plays the role of brake, preventing GR and cell migration before cells reach empty space.
Evaluation of Individualized Cefepime Dosing Strategy Using Population Pharmacokinetics
Authors: Mo Yoonsun , Shcherbakova Natalia , Inman Kelsey L. , Li Wai Kin , Kovalenko Kateryna , Rosenberg Joshua , Orsini Jose , Truong James
Published: September 2021

The use of population pharmacokinetics (PK) to optimize cefepime dosing could be an effective strategy, given the increasing prevalence of resistant gram‐negative organisms. The objective of this study is to retrospectively compare dosing using a PK approach (intervention) vs traditional dosing (control) for cefepime in patients with hospital‐acquired pneumonia (HAP) or ventilator‐associated pneumonia (VAP). Adult hospitalized patients with HAP or VAP receiving cefepime for ≥72 hours were screened first from August 2018 to January 2019 to be included in the intervention group, then screened during the preintervention period from August 2017 to July 2018 for the control group. Clinical improvement on day 7 of cefepime therapy was achieved in 72% of the patients in the intervention group and 70% of the patients in the control group (P = .8110). However, the clinical cure rate in the intervention group was higher than that of the control group (50% vs 36.5%; P = .0034). Cefepime dosing using population PK appears to be a novel, effective, and safe dosing strategy for patients with HAP or VAP.
An observational study of learning effects of peer‐assisted learning tests in COVID‐19 pandemic times
Authors: Holfert Jonathan , Kesting Marco R. , Buchbender Mayte
Published: September 2021

Purpose

This study aimed to determine whether peer‐assisted learning (PAL) is a more effective learning and test method in terms of oral‐ and maxillofacial surgery.

Material and methods

In July 2020, a total of 267 students took a PAL‐based exam on fictional patients with surgical issues, in which they had to evaluate two fellow students and were themselves evaluated by two fellow students. The students evaluated their experience with the PAL‐based exam through a questionnaire which consisted of five given statements (answer possibilities: agree, disagree, neutral) and two questions (answer possibilities: better, equal, worse) to rate.

Results

In the survey, 77.9% of the students rated PAL as a better learning method and 21% rated it as at least equally effective to the known multiple‐choice (MC) test. A total of 74.9% of the students indicated that they learned more content with PAL and 20.2% said they learned the same amount; 83.7% said that their “clinical thinking has improved” through PAL. In the comments, 73% of the students noted that they think PAL is a good learning method, and at least 22% rated it as useful but in need of improvements. Only 5% did not see PAL as an acceptable learning method. In contrast to this, 1.3% saw PAL as a “bad alternative to MC tests.”

Conclusion

PAL, especially peer assessment, might represent a better learning method as it might encourage students to deal more intensively with the learning content and to improve clinical thinking.
Nonsimultaneous stimulus presentations and their role in listener naming
Authors: Sivaraman Maithri , Barnes‐Holmes Dermot , Roeyers Herbert
Published: September 2021

Previous studies on naming have presented the object and its name simultaneously during both training and testing, and thus the training component may establish a transformation of function directly between the object and the name. Successful tests for listener naming may thus not require the emergence of a novel (entailed) transformation of function. The current study aimed to control for this possibility by presenting the object and the name sequentially and nonsimultaneously. Eight typically developing toddlers participated in the current study. During name training, objects and names were presented nonsimultaneously, and all participants failed to emit listener‐naming responses during the first test session. Subsequently, 4 participants received multiple exemplar training, which led to improvements in listener naming for all 4; and speaker naming for only 1 participant. As a control condition, the remaining 4 participants were tested repeatedly, without multiple exemplar training, and did not show any consistent improvements in their listener or speaker performances. Multiple exemplar training thus appeared to be effective in establishing generalized listener responses, which involved generating entailed transformation of functions. The strategy of using nonsimultaneous stimulus presentations could allow for greater precision in identifying the behavioral processes involved in listener‐naming.
Comparison of pulse‐dose and high‐dose corticosteroids with no corticosteroid treatment for COVID‐19 pneumonia in the intensive care unit
Authors: Yaqoob Hamid , Greenberg Daniel , Hwang Frank , Lee Curtis , Vernik David , Manglani Ravi , Wang Zhen , Murad M. Hassan , Chandy Dipak , Epelbaum Oleg
Published: September 2021

Corticosteroid dosing in the range of 0.5–2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID‐19 pneumonia based on positive results of randomized trials and a meta‐analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID‐19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID‐19 pneumonia, we compared patients treated with 0.5–2 mg/kg/day in methylprednisolone equivalents (high‐dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse‐dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU‐free days at Day 28, and complications potentially attributable to corticosteroids. Pulse‐dose corticosteroid therapy was associated with a significant increase in ICU‐free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05–2.02; p = 0.03) and compared with high‐dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high‐dose corticosteroids—but not of pulse‐dose corticosteroids—significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12–0.77; p = 0.01). High‐dose corticosteroids reduced mortality compared to pulse‐dose corticosteroids (p = 0.04). Pulse‐dose corticosteroids—but not high‐dose corticosteroids—significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27–9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse‐dose group when compared to the high‐dose group (p = 0.05 for the comparison). In this single‐center study, pulse‐dose corticosteroid therapy for COVID‐19 pneumonia in the ICU was associated with an increase in ICU‐free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high‐dose corticosteroids on mortality was favorable.
Using different machine learning models to classify patients into mild and severe cases of COVID‐19 based on multivariate blood testing
Authors: Zhang Rui‐kun , Xiao Qi , Zhu Sheng‐lang , Lin Hai‐yan , Tang Ming
Published: September 2021

COVID‐19 is a serious respiratory disease. The ever‐increasing number of cases is causing heavier loads on the health service system. Using 38 blood test indicators on the first day of admission for the 422 patients diagnosed with COVID‐19 (from January 2020 to June 2021) to construct different machine learning (ML) models to classify patients into either mild or severe cases of COVID‐19. All models show good performance in the classification between COVID‐19 patients into mild and severe disease. The area under the curve (AUC) of the random forest model is 0.89, the AUC of the naive Bayes model is 0.90, the AUC of the support vector machine model is 0.86, and the AUC of the KNN model is 0.78, the AUC of the Logistic regression model is 0.84, and the AUC of the artificial neural network model is 0.87, among which the naive Bayes model has the best performance. Different ML models can classify patients into mild and severe cases based on 38 blood test indicators taken on the first day of admission for patients diagnosed with COVID‐19.
Prognostic Indicators of Survival in Sinonasal Diffuse LargeB‐CellLymphoma: A National Cancer Database Analysis
Authors: Brown Hannah J. , Varelas Eleni A. , Ganti Ashwin , Papagiannopoulos Peter , Mark Michelle , Kuan Edward C. , Tajudeen Bobby A.
Published: September 2021

Objectives/Hypothesis

This study offers an update on the epidemiologic and prognostic factors and treatment‐specific outcomes in patients diagnosed with sinonasal diffuse large B‐cell lymphoma (DLBCL).

Study Design

Retrospective cohort study.

Methods

National Cancer Database was queried from 2004 to 2016 for patients with sinonasal DLBCL. Univariate Kaplan‐Meier and multivariate Cox‐regression analyses were performed to evaluate the association of suspected prognostic factors with overall survival (OS).

Results

A total of 2,222 patients with sinonasal DLBCL were analyzed. OS was 62% at 5 years and 42% at 10 years. Prognostic factors associated with increased survival included African‐American race (HR: 0.48, 95% CI: 0.33–0.70), chemotherapy (HR: 0.30, CI: 0.25–0.35), and radiation (HR: 0.80, CI: 0.69–0.93). Prognostic factors associated with decreased survival included patients with Charlson‐Deyo scores of 1 (HR: 1.51, CI: 1.25–1.84), 2 (HR: 2.25, CI: 1.67–3.03), and 3 (HR: 2.36, CI: 1.49–3.74) and patients with Lugano stage III (HR: 1.69, CI: 1.09–2.62) and IV (HR: 1.96, CI: 1.46–2.64) disease. Stage‐based split multivariate analysis was performed and revealed chemotherapy was independently associated with increased OS in patients with stage I (HR: 0.24, CI: 0.19–0.30), II (HR: 0.17, CI: 0.11–0.28), and IV (HR: 0.41, CI: 0.26–0.64) disease. Radiotherapy was independently associated with increased OS in patients with stage I disease only (HR: 0.67, CI: 0.55–0.83), while immunotherapy was an independent prognostic factor in patients with stage IV disease only (HR: 0.60, CI: 0.37–0.98).

Conclusion

This study is the largest to date to analyze the association of demographic features and treatment modalities with OS in patients with sinonasal DLBCL. It is the first to investigate the association of immunotherapy with OS in this population. A combination treatment of immunochemotherapy or radioimmunochemotherapy confers increased survival, particularly in patients with advanced disease.

Level of Evidence

4Laryngoscope, 132:1515–1522, 2022
Estimations of Laryngotracheal Stenosis After Mechanical Ventilation: A Cross‐Sectional Analysis
Authors: Johnson Romaine F. , Bradshaw Stanley , Jaffal Hussein , Chorney Stephen R.
Published: September 2021

Objectives/Hypothesis

To estimate the incidence of laryngotracheal stenosis among adults after intubation.

Study Design

Cross‐sectional analysis.

Methods

We used the Nationwide Readmission Database to examine adult patients readmitted within 45 days after admission for mechanical ventilation. Those with a diagnosis of laryngotracheal stenosis or tracheostomy dependence on their index admission were excluded. Patient demographics, associated comorbidities, and intubation lengths were compared among those with and without a diagnosis of airway stenosis at readmission.

Results

An estimated 624,918 patients met inclusion with a mean age of 59 years (standard error = 0.2). There were 1,230 patients readmitted within 45 days and diagnosed with laryngeal (N = 362) or tracheal stenosis (N = 920) estimating an incidence of 1.98 per 1,000 discharges. Compared with those without a diagnosis of airway stenosis, those with stenosis were younger (57 vs. 59 years, P < .001), more often female (62% vs. 45%, P < .001) and frequently intubated for >96 hours (47% vs. 32%, P < .001). Additionally, a history of respiratory failure, pneumonia, obesity, gastroesophageal reflux disease, and chronic steroid use were also more common among patients with stenosis. Multiple logistic regression analysis identified a decreased risk of stenosis with advancing age while an increased risk was associated strongest for females (odds ratio [OR]: 1.96, 95% confidence interval [CI]: 1.58–2.44, P < .001) and those with chronic steroid use (OR: 2.69, 95% CI: 1.80–4.02, P < .001).

Conclusion

The incidence of laryngotracheal stenosis after intubation in adults is rare but is associated with female gender and younger age.

Level of Evidence

NA Laryngoscope, 132:1723–1728, 2022
The use of embedded visual methods in unveiling consumers' values: A digital ethnography perspective
Authors: Pera Rebecca , Quinton Sarah , Baima Gabriele
Published: September 2021

This methodological paper investigates how visual methods contribute to the understanding of consumers' values. The study adopts a digital ethnography approach in which participant generated photographs and videos unearth complex and intangible consumer values associated with food consumption. The findings indicate that visual methods are powerful in moving beyond the representational and offer a transformative capability for participants in making abstract constructs more concrete. The research illustrates that embedded visual methods are compelling in giving “voice” to participants and as such they are more engaged with the research process. In addition, the study suggests that visual methods provide valuable and more complete insights into consumer research when text, sound, and image interplay.
Passive Integrated Transponder Tag Monitoring Reveals Complex Migration and Life History Patterns in Mountain Whitefish in Upper Columbia River Tributaries
Authors: Snow Charles G. , Goodman Benjamin J.
Published: September 2021

Mountain Whitefish Prosopium williamsoni is a native salmonid distributed throughout the Columbia River basin, but little is known about the life history traits of tributary-specific populations. We captured and tagged 129 Mountain Whitefish with passive integrated transponder (PIT) tags between 2010 and 2015 at a weir on the Twisp River, Washington, to assess migration patterns. Detection records suggested that two populations of Mountain Whitefish overlap in the Twisp River during spring: resident fish that spawn in the Twisp River (42% of fish) and migrant fish that spawn in the Okanogan River (58% of fish). The median entry day into the Twisp River was similar for resident (April 17) and migrant (April 16) populations, but median exit day was significantly earlier for migrant (July 2) than for resident fish (November 6). Migrant fish exited the Methow basin and traveled at 14.1 river kilometers per day, passing the lower Okanogan River PIT antenna with a median date of September 17. After spawning and overwintering in the Okanogan River with a median exit date of March 16, these fish returned to the Methow basin traveling at 22.1 river kilometers per day. These results improve our understanding of Mountain Whitefish life history and habitat use in tributaries upstream of Wells Dam, Washington.
Quantitative effects of off‐resonance related distortion on brain mechanical property estimation with magnetic resonance elastography
Authors: McIlvain Grace , McGarry Matthew D. J. , Johnson Curtis L.
Published: September 2021

Off‐resonance related geometric distortion can impact quantitative MRI techniques, such as magnetic resonance elastography (MRE), and result in errors to these otherwise sensitive metrics of brain health. MRE is a phase contrast technique to determine the mechanical properties of tissue by imaging shear wave displacements and estimating tissue stiffness through inverse solution of Navier's equation. In this study, we systematically examined the quantitative effects of distortion and corresponding correction approaches on MRE measurements through a series of simulations, phantom models, and in vivo brain experiments. We studied two different k‐space trajectories, echo‐planar imaging and spiral, and we determined that readout time, off‐resonance gradient strength, and the combination of readout direction and off‐resonance gradient direction, impact the estimated mechanical properties. Images were also processed through traditional distortion correction pipelines, and we found that each of the correction mechanisms works well for reducing stiffness errors, but are limited in cases of very large distortion. The ability of MRE to detect subtle changes to neural tissue health relies on accurate, artifact‐free imaging, and thus off‐resonance related geometric distortion must be considered when designing sequences and protocols by limiting readout time and applying correction where appropriate.
Pharmacologically induced N‐methyl‐D‐aspartate receptor hypofunction impairs goal‐directed food seeking in rats
Authors: Ozawa Takaaki , Itokazu Tatsumi , Ichitani Yukio , Yamada Kazuo
Published: September 2021

Aim

Acute N‐methyl‐D‐aspartate (NMDA) receptor antagonism is an important pharmacological animal model of schizophrenia. In previous studies, schizophrenia patients show impaired goal‐directed behavior in an outcome‐specific devaluation procedure. In this study, we investigated whether the rat model of the NMDA receptor blockade also showed altered goal‐directed behavior in a satiety‐induced outcome devaluation paradigm.

Methods

In experiments 1 and 2, we aimed to establish the satiety‐induced outcome devaluation test using sucrose and lipid rewards in operant conditioning and free consumption paradigms. In experiment 3, we tested the effect of MK‐801 (0.1 mg/kg, i.p.) on outcome‐specific devaluation.

Results

Experiments 1 and 2 demonstrated that 1‐h ad libitum food consumption is sufficient to induce outcome‐specific devaluation in both lever‐press and free consumption tests in rats. Experiment 3 showed that the administration of MK‐801 impaired satiety‐induced devaluation in the lever‐press test but not in the subsequent free consumption test.

Conclusions

Our results suggest that acute pharmacological NMDA receptor antagonism in rats is a useful animal model for impaired goal‐directed behavior in schizophrenia.
Effect of stacking sequence on multi‐point low‐velocity impact and compression after impact damage mechanisms of UHMWPE composites
Authors: Wu Jian An , Zhang Zhongwei , Dai Xiaoqing , Duan Liqun , Lin Yuan , Sun Minqian
Published: September 2021

Composite materials are susceptible to low velocity impact, which is a very common phenomenon. A large number of studies have been conducted on the single‐point impact on their mechanical properties, but there is a lack of in‐depth exploration on the actual situation of multi‐point impact with a certain angle distribution of impact points. In this paper, three impact points with a certain angle distribution were set to carry out low‐velocity impact (LVI) sequentially, followed by compression after impact (CAI). Digital image correlation system (DIC) and X‐ray micro‐computed tomography techniques (micro‐CT) were used to analyze the mechanical response and failure mechanisms of the specimens. Experimental results demonstrated that the distribution of impact points will directly affect the overall mechanical properties of the material, and the mechanical properties are also sensitive to the stacking sequence. More importantly, it was also found that the boundary conditions have a great influence on the overall mechanical response, which makes the surrounding damage worse.
Wetting behavior and stability of surface‐modified polyurethane materials
Authors: Bauer Maria G. , Reithmeir Rosa , Lutz Theresa M. , Lieleg Oliver
Published: September 2021

Even though polyurethanes (PU) constitute a class of highly versatile and customizable polymeric materials, being able to modify their surface properties, for example, their wettability, without altering the composition of the bulk material would often be desirable. However, PU‐based materials can be both rather diverse and resilient to chemical modification. Thus, in this study, three PU variants are subjected to three different treatments that aim at altering the wetting properties of the materials: We assess the feasibility of plasma treatment, dopamine incubation, and chemical etching, and evaluate the stability of the obtained surface modifications with regard to wet and dry storage, UV exposure, and application‐specific properties such as lubricity and colonization with eukaryotic cells. The results obtained here can be used to achieve an additional customization of PU surfaces to tailor their behavior for selected applications where dedicated surface properties are required.
Quantitative proteomics analysis reveals novel insights into mechanisms of action of disulfiram (DSF)
Authors: Zheng Peng , Liu Chenglinzi , Wu Yaoqin , Xu Ruifeng , Chen Ying , Hu Fan , Chen Zhuo , Zhang Tongcun
Published: September 2021

Purpose

Disulfiram (DSF) has been proven safe and shows the promising antitumor effect in preclinical studies. However, the precise mechanism of DSF on tumor is rarely reported. This study aims to fully understand the mechanism of action of DSF with a systems perspective in anticancer effects.

Experimental Design

SILAC‐based quantitative proteomics strategy was used to systematically identify differential expression proteins (DEPs) after DSF treatment in HeLa cells. Bioinformatical analysis (PANTHER, DAVID, and STRING) were performed to characterize biological functions of DEPs. Functional studies were performed to explore underlying mechanisms of DSF in cancer cells.

Results

In total, 201 proteins were dysregulated significantly after DSF exposure. Functional studies of hexokinase 2 (HK2), which catalyzed the first irreversible enzymatic step in glucose metabolism, revealed that various phenotypic effects observed after DSF treatment in cancer cells, at least partly, through the regulation of HK2 expression.

Conclusions and Clinical Relevance

By correlating the proteomics data with these functional studies, the current results provided novel insights into the mechanism underlying DSF function in cancer cells. Meanwhile, these provided theoretical basis for the new use of old drugs in clinical therapy.
Gradient‐based criteria for sequential experiment design
Authors: Erickson Collin B. , Ankenman Bruce E. , Plumlee Matthew , Sanchez Susan M.
Published: September 2021

Computer experiments are often used as inexpensive alternatives to real‐world experiments. Statistical metamodels of the computer model's input‐output behavior can be constructed to serve as approximations of the response surface of the real‐world system. The suitability of a metamodel depends in part on its intended use. While decision makers may want to understand the entire response surface, they may be particularly keen on finding interesting regions of the design space, such as where the gradient is steep. We present an adaptive, value‐enhanced batch sequential algorithm that samples more heavily in such areas while still providing an understanding of the entire surface. The design points within each batch can be run in parallel to leverage modern multi‐core computing assets. We illustrate our approach for deterministic computer models, but it has potential for stochastic simulation models as well.
Robust profile monitoring for phase II analysis via residuals
Authors: Nassar Sara H. , Abdel‐Salam Abdel‐Salam G.
Published: September 2021

Many studies were conducted for fitting models using parametric and non‐parametric techniques; in fact, their fits may be biased and have inflated the estimated variances when the model is misspecified, respectively. Thus, semi‐parametric techniques are used for fitting models as they combine the advantages of parametric and non‐parametric fits. In this study, we introduce model robust regression technique‐2 (MRR2) for Phase II profile monitoring, namely, the semi‐parametric approach, where it is a combination of the parametric fit with a portion of a non‐parametric residuals fit. Multivariate CUSUM (MCUSUM) chart unitized for monitoring the slope of the linear mixed models in Phase II based on the random‐effects. A comprehensive simulation study was performed to evaluate the proposed approach for correlated and uncorrelated profiles assuming different profile sizes, sample sizes, and several model misspecification levels. Average run length (ARL) and average time to signal (ATS) criteria were used for comparing the performances of the parametric, non‐parametric, and semi‐parametric MCUSUM charts. The results showed that the semi‐parametric chart had the best performance in detecting different shifts. Also, a real data application was conducted, where it showed that the semi‐parametric chart had the highest sensitivity for the out‐of‐control scenarios.
When is tinkering with safety net programs harmful to beneficiaries?
Authors: Clemens Jeffrey , Wither Michael
Published: September 2021

Interactions between redistributive policies can confront low‐income households with complicated choices. We study one such interaction, namely the relationship between Medicaid eligibility thresholds and the minimum wage. A minimum wage increase reduces the number of hours a low‐skilled individual can work while retaining Medicaid eligibility. We show that the empirical and welfare implications of this interaction can depend crucially on the relevance of labor market frictions. Absent frictions, affected workers may maintain Medicaid eligibility through small reductions in hours of work. With frictions, affected workers may lose Medicaid eligibility unless they leave their initial job. Empirically, we find that workers facing this scenario became less likely to participate in Medicaid, less likely to work, and more likely to spend time looking for new jobs, including search while employed. The observed outcomes suggest that low‐skilled workers face substantial labor market frictions. Because adjustment is costly, tinkering with safety net program parameters that determine the location of program eligibility notches can be harmful to beneficiaries.
High‐dimensional precision matrix estimation with a known graphical structure
Authors: Le Thien‐Minh , Zhong Ping‐Shou
Published: September 2021

A precision matrix is the inverse of a covariance matrix. In this paper, we study the problem of estimating the precision matrix with a known graphical structure under high‐dimensional settings. We propose a simple estimator of the precision matrix based on the connection between the known graphical structure and the precision matrix. We obtain the rates of convergence of the proposed estimators and derive the asymptotic normality of the proposed estimator in the high‐dimensional setting when the data dimension grows with the sample size. Numerical simulations are conducted to demonstrate the performance of the proposed method. We also show that the proposed method outperforms some existing methods that do not utilize the graphical structure information.
Treatment with TNF‐α inhibitors versus methotrexate and the association with dementia and Alzheimer's disease
Authors: Kern David M. , Lovestone Simon , Cepeda M. Soledad
Published: September 2021

Introduction

Peripheral inhibition of tumor necrosis factor (TNF)‐α, outside of the central nervous system, may result in clinical improvement of Alzheimer's disease (AD) outcomes. TNF‐α inhibitors (TNFIs) are effective treatments for various autoimmune conditions and may be effective for preventing and/or treating AD. The objective of this study was to compare the risk of dementia and AD in patients initiating methotrexate versus those initiating TNFIs.

Methods

Insurance claims data from databases of commercially insured and Medicare‐eligible patients were used to estimate the risk of dementia and AD within patients with rheumatoid arthritis (RA) initiating a TNFI versus initiation of methotrexate. A sensitivity analysis included all patients without the RA diagnosis requirement. The at‐risk period spanned from the index date until a diagnosis of the outcome, loss‐to‐follow‐up, or receipt of the comparator drug. Patients were matched 1‐to‐1 using propensity scores. A Cox proportional hazards model was used to estimate the hazard ratio (HR). Negative controls were used to calibrate the results.

Results

A total of 11,092 new TNFI patients and 44,023 new methotrexate patients were identified, and 8925 from each group were matched. The outcome of dementia occurred in 1.4% of patients in both groups. The calibrated results from the Cox regression found no difference between the two groups (commercially insured database: calibrated HR = 0.69, 95% confidence interval = 0.45 to 1.05; Medicare‐only database: 1.14, 0.66 to 1.96). Results were similar in all sensitivity analyses: outcome of AD and including patients without RA.

Discussion

No significant difference for the risk of dementia or AD was seen between patients initiating a TNFI versus methotrexate. Although this study cannot conclude whether use of TNFIs is protective against dementia and AD compared with receiving no treatment, there was no evidence that it is more protective than the active comparator methotrexate.
Diagrams in Essays: Exploring the Kinds of Diagrams Students Generate and How Well They Work
Authors: Manalo Emmanuel , Fukuda Mari
Published: September 2021

Using appropriate diagrams is generally considered efficacious in communication. However, although diagrams are extensively used in printed and digital media, people in general rarely construct diagrams to use in common everyday communication. Furthermore, instruction on diagram use for communicative purposes is uncommon in formal education and, when students are required to communicate what they have learned, the usual expectation is they will use words – not diagrams. Requiring diagram inclusion in essays, for example, would be almost unheard of. Consequently, current understanding about student capabilities in this area is very limited. The aim of this study therefore was to contribute to addressing this gap: it comprised a qualitative exploration of 12 undergraduate students’ diagram use in two essays (in which they were asked to include at least one diagram). Analysis focused on identifying the kinds of diagrams produced, and the effectiveness with which those diagrams were used. Useful functions that the diagrams served included clarification, summarization, integration of points, and provision of additional information and/or perspectives in visual form. However, there were also redundancies, as well as unclear, schematically erroneous, and overly complicated representations in some of the diagrams that the students constructed. These findings are discussed in terms of needs, opportunities, and challenges in instructional provision.
HPS meets AMPS: how soft hair dissolves the firewall
Authors: Pasterski Sabrina , Verlinde Herman
Published: September 2021

Abstract

We build on the observation by Hawking, Perry and Strominger that a global black hole space-time supports a large number of soft hair degrees of freedom to shed new light on the firewall argument by Almheiri, Marolf, Polchinski, and Sully. We propose that the soft hair Goldstone mode is encoded in a classical transition function that connects the asymptotic and near horizon region. The entropy carried by the soft hair is part of the black hole entropy and encoded in the outside geometry. We argue that the infalling observer automatically measures the classical value of the soft mode before reaching the horizon and that this measurement implements a code subspace projection that enables the reconstruction of interior operators. We use the soft hair dynamics to introduce an observer dependent notion of the firewall and show that for an infalling observer it recedes inwards into the black hole interior: the observer never encounters a firewall before reaching the singularity. Our results indicate that the HPS black hole soft hair plays an essential role in dissolving the AMPS firewall.
Radio line properties of axion dark matter conversion in neutron stars
Authors: Battye R. A. , Garbrecht B. , McDonald J. , Srinivasan S.
Published: September 2021

Abstract

Axions are well-motivated candidates for dark matter. Recently, much interest has focused on the detection of photons produced by the resonant conversion of axion dark matter in neutron star magnetospheres. Various groups have begun to obtain radio data to search for the signal, however, more work is needed to obtain a robust theory prediction for the corresponding radio lines. In this work we derive detailed properties for the signal, obtaining both the line shape and time-dependence. The principal physical effects are from refraction in the plasma as well as from gravitation which together lead to substantial lensing which varies over the pulse period. The time-dependence from the co-rotation of the plasma with the pulsar distorts the frequencies leading to a Doppler broadened signal whose width varies in time. For our predictions, we trace curvilinear rays to the line of sight using the full set of equations from Hamiltonian optics for a dispersive medium in curved spacetime. Thus, for the first time, we describe the detailed shape of the line signal as well as its time dependence, which is more pronounced compared to earlier results. Our prediction of the features of the signal will be essential for this kind of dark matter search.
The Case Against Smooth Null Infinity I: Heuristics and Counter-Examples
Authors: Kehrberger Leonhard M. A.
Published: September 2021

This paper initiates a series of works dedicated to the rigorous study of the precise structure of gravitational radiation near infinity. We begin with a brief review of an argument due to Christodoulou (in: The Ninth Marcel Grossmann Meeting, World Scientific Publishing Company, Singapore, 2002) stating that Penrose’s proposal of smooth conformal compactification of spacetime (or smooth null infinity) fails to accurately capture the structure of gravitational radiation emitted by N infalling masses coming from past timelike infinity $$i^-$$

i
-

. Modelling gravitational radiation by scalar radiation, we then take a first step towards a dynamical understanding of the non-smoothness of null infinity by constructing solutions to the spherically symmetric Einstein–Scalar field equations that arise from polynomially decaying boundary data, $$r\phi \sim t^{-1}$$

r
ϕ
∼

t

-
1

as $$t\rightarrow -\infty $$

t
→
-
∞

, on a timelike hypersurface (to be thought of as the surface of a star) and the no incoming radiation condition, $$r\partial _v\phi =0$$

r

∂
v

ϕ
=
0

, on past null infinity. We show that if the initial Hawking mass at $$i^-$$

i
-

is nonzero, then, in accordance with the non-smoothness of $${\mathcal {I}}^+$$

I

+

, the asymptotic expansion of $$\partial _v(r\phi )$$

∂
v

(
r
ϕ
)

near $${\mathcal {I}}^+$$

I

+

reads $$\partial _v(r\phi )=Cr^{-3}\log r+{\mathcal {O}}(r^{-3})$$

∂
v

(
r
ϕ
)

=
C

r

-
3

log
r
+
O

(

r

-
3

)

for some non-vanishing constant C. In fact, the same logarithmic terms appear already in the linear theory, i.e. when considering the spherically symmetric linear wave equation on a fixed Schwarzschild background. As a corollary, we can apply our results to the scattering problem on Schwarzschild: Putting compactly supported scattering data for the linear (or coupled) wave equation on $${\mathcal {I}}^-$$

I

-

and on $${\mathcal {H}}^-$$

H

-

, we find that the asymptotic expansion of $$\partial _v(r\phi )$$

∂
v

(
r
ϕ
)

near $${\mathcal {I}}^+$$

I

+

generically contains logarithmic terms at second order, i.e. at order $$r^{-4}\log r$$

r

-
4

log
r

.
Warming in Europe: Recent Trends in Annual and Seasonal temperatures
Authors: Twardosz Robert , Walanus Adam , Guzik Izabela
Published: September 2021

Contemporary climate warming is a key problem faced not only by scientists, but also all by humanity because, as is shown by the experience of recent years, it has multiple environmental, economic and biometeorological implications. In this paper, the authors identify the magnitude of annual and seasonal temperature changes in Europe and its immediate surroundings on the basis of data from 210 weather stations from 1951 to 2020. An analysis of temperatures in the 70-year period shows that air temperature has continued to grow linearly in Europe since 1985. The rate of temperature rise in three seasons of the year, namely winter, spring and summer, does not differ greatly. The highest growth over the 1985–2020 timespan was recorded in spring and the lowest in autumn—0.061 °C/year and 0.045 °C/year, respectively. In winter, the rise in temperature should be considered the least steady, as opposed to the summer when it displays the greatest stability. Overall, the warming intensifies towards the north-east of the continent. Such a strong gradient of change is especially perceivable in winter and spring, and is also marked in autumn. The opposite is true in summer, when it increases towards the south and south-west.
Assessment of Artificial Intelligence Automatic Multiple Sclerosis Lesion Delineation Tool for Clinical Use
Authors: Hindsholm Amalie Monberg , Cramer Stig Præstekjær , Simonsen Helle Juhl , Frederiksen Jette Lautrup , Andersen Flemming , Højgaard Liselotte , Ladefoged Claes Nøhr , Lindberg Ulrich
Published: September 2021

Purpose

To implement and validate an existing algorithm for automatic delineation of white matter lesions on magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) on a local single-center dataset.

Methods

We implemented a white matter hyperintensity segmentation model, based on a 2D convolutional neural network, using the conventional T2-weighted fluid attenuated inversion recovery (FLAIR) MRI sequence as input. The model was adapted for delineation of MS lesions by further training on a local dataset of 93 MS patients with a total of 3040 lesions. A quantitative evaluation was performed on ten test patients, in which model-generated masks were compared to manually delineated masks from two expert delineators. A subsequent qualitative evaluation of the implemented model was performed by two expert delineators, in which generated delineation masks on a clinical dataset of 53 patients were rated acceptable (< 10% errors) or unacceptable (> 10% errors) based on the total number of true lesions.

Results

The quantitative evaluation resulted in an average accuracy score (F1) of 0.71, recall of 0.77 and dice similarity coefficient of 0.62. Our implemented model obtained the highest scores in all three metrics, when compared to three out of the box lesion segmentation models. In the clinical evaluation an average of 94% of our 53 model-generated masks were rated acceptable.

Conclusion

After adaptation to our local dataset, the implemented segmentation model was able to delineate MS lesions with a high clinical value as rated by delineation experts while outperforming popular out of the box applications. This serves as a promising step towards implementation of automatic lesion delineation in our MS clinic.
Magnetic exchange coupling in Cu dimers studied with modern multireference methods and broken-symmetry coupled cluster theory
Authors: Singh Gurjot , Gamboa Stefani , Orio Maylis , Pantazis Dimitrios A. , Roemelt Michael
Published: September 2021

Spin-state energetics of exchange-coupled copper complexes pose a persistent challenge for applied quantum chemistry. Here, we provide a comprehensive comparison of all available theoretical approaches to the problem of exchange coupling in two antiferromagnetically coupled bis-μ-hydroxo Cu(II) dimers. The evaluated methods include multireference methods based on the density matrix renormalization group (DMRG), multireference methods that incorporate dynamic electron correlation either perturbatively, such as the N-electron valence state perturbation theory, or variationally, such as the difference-dedicated configuration interaction. In addition, we contrast the multireference results with those obtained using broken-symmetry approaches that utilize either density functional theory or, as demonstrated here for the first time in such systems, a local implementation of coupled cluster theory. The results show that the spin-state energetics of these copper dimers are dominated by dynamic electron correlation and represent an impossible challenge for multireference methods that rely on brute-force expansion of the active space to recover correlation energy. Therefore, DMRG-based methods even at the limit of their applicability cannot describe quantitatively the antiferromagnetic exchange coupling in these dimers, in contrast to dinuclear complexes of earlier transition metal ions. The convergence of the broken-symmetry coupled cluster approach is studied and shown to be a limiting factor for the practical application of the method. The advantages and disadvantages of all approaches are discussed, and recommendations are made for future developments.