bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 quantification across tumor types using the reverse phase protein microarray: implications for precision medicine
Authors: Baldelli Elisa , Hodge K Alex , Bellezza Guido , Shah Neil J , Gambara Guido , Sidoni Angelo , Mandarano Martina , Ruhunusiri Chamodya , Dunetz Bryant , Abu-Khalaf Maysa , Wulfkuhle Julia , Gallagher Rosa I , Liotta Lance , de Bono Johann , Mehra Niven , Riisnaes Ruth , Ravaggi Antonella , Odicino Franco , Sereni Maria Isabella , Blackburn Matthew , Zupa Angela , Improta Giuseppina , Demsko Perry , Crino' Lucio , Ludovini Vienna , Giaccone Giuseppe , Petricoin Emanuel F , Pierobon Mariaelena
Published: October 2021

Background

Anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-L1) agents are broadly used in first-line and second-line treatment across different tumor types. While immunohistochemistry-based assays are routinely used to assess PD-L1 expression, their clinical utility remains controversial due to the partial predictive value and lack of standardized cut-offs across antibody clones. Using a high throughput immunoassay, the reverse phase protein microarray (RPPA), coupled with a fluorescence-based detection system, this study compared the performance of six anti-PD-L1 antibody clones on 666 tumor samples.

Methods

PD-L1 expression was measured using five antibody clones (22C3, 28–8, CAL10, E1L3N and SP142) and the therapeutic antibody atezolizumab on 222 lung, 71 ovarian, 52 prostate and 267 breast cancers, and 54 metastatic lesions. To capture clinically relevant variables, our cohort included frozen and formalin-fixed paraffin-embedded samples, surgical specimens and core needle biopsies. Pure tumor epithelia were isolated using laser capture microdissection from 602 samples. Correlation coefficients were calculated to assess concordance between antibody clones. For two independent cohorts of patients with lung cancer treated with nivolumab, RPPA-based PD-L1 measurements were examined along with response to treatment.

Results

Median-center PD-L1 dynamic ranged from 0.01 to 39.37 across antibody clones. Correlation coefficients between the six antibody clones were heterogeneous (range: −0.48 to 0.95) and below 0.50 in 61% of the comparisons. In nivolumab-treated patients, RPPA-based measurement identified a subgroup of tumors, where low PD-L1 expression equated to lack of response.

Conclusions

Continuous RPPA-based measurements capture a broad dynamic range of PD-L1 expression in human specimens and heterogeneous concordance levels between antibody clones. This high throughput immunoassay can potentially identify subgroups of tumors in which low expression of PD-L1 equates to lack of response to treatment.
Apparent and standardized digestibility in broilers fed flaxseed meal with multi-carbohydrase and phytase at 35 days of age
Authors: Araujo Robert Guaracy Aparecido Cardoso , Gallardo Vela Connie , Roberto Sartori José , da Trindade Neto Messias Alves
Published: October 2021

The apparent total tract digestibility (ATTD; trial 1) and the apparent (AID) and standardized (SID) ileal digestibility of the amino acids (AA) (trial 2) in flaxseed meal (FM) were evaluated with the addition of exogenous multi-carbohydrase (MC) and phytase (Phy). A total of 80 28-d-old broilers were allotted in a completely randomized design to receive treatments up to 35 d of age. A 2 × 2 factorial design is used to determine the enzyme effects, on the ATTD of dry matter, nitrogen, calcium, phosphorus and fiber, energy use, and the AID and SID of AA, in five replicate cages. There was synergism between MC and Phy on the ATTD of nitrogen and energy. The isolated inclusion of MC or Phy increased the ATTD of dry matter, calcium, phosphorus and fiber of FM. The enzyme inclusion on the AID and SID of AA in FM, established by comparing the means, suggested a better response to the addition of MC + Phy. Supplementation with Phy or combination of MC and Phy was a viable alternative to increase the ATTD of nutrients and energy. The combination of MC + Phy resulted in higher apparent and standardized digestibility of AA from FM.
Stability of additive-quadratic 3D functional equation in modular spaces by direct method
Authors: Rassias John M. , Karthikeyan S.
Published: October 2021

This paper deals with the Ulam–Hyers stability of the following additive-quadratic mixed type functional equation: [Formula: see text] [Formula: see text] [Formula: see text] in modular spaces using the direct method.
The Supply Chain Diversification and India–South Korea Cooperation in a Contested East Asia in the Post-COVID-19 Era
Authors: KUMAR RAJIV
Published: October 2021

This paper analyzes the dynamics of supply chain diversification in a contested East Asia and their implications for India–South Korea cooperation in the post-COVID-19 era. Major powers have sought to restructure supply chain by designing a strategy to reduce their reliance on China-controlled supply chain. The United States–China trade and technological war, Asian regional powers’ escalating conflicts with a rising China, and pandemic-induced supply chain disruptions have played key roles in driving the restructuring process. India and South Korea, Asia’s two major economies, have also re-evaluated their supply chain strategies. As this paper explains, on the one hand, India has been striving to emerge as a supply chain hub for key industries by ending China’s control. On the other hand, South Korea has also been aiming to diversify its supply chain beyond China under the New Southern Policy. Against that backdrop, critical developments concerning supply chain cooperation have occurred between the two countries amid the COVID-19 crisis. The pandemic has not only facilitated the opening of high-level political exchanges on supply chain but also brought tangible outcomes, as Korean companies have become active participants in India’s quest to build an India-centric supply chain. I conclude this study by contending that the two countries are “natural partners” in reshaping the supply chain dynamics in East Asia in the post-COVID-19 era.
Computational Design of Planar Multistable Compliant Structures
Authors: Zhang Ran , Auzinger Thomas , Bickel Bernd
Published: October 2021

This article presents a method for designing planar multistable compliant structures. Given a sequence of desired stable states and the corresponding poses of the structure, we identify the topology and geometric realization of a mechanism—consisting of bars and joints—that is able to physically reproduce the desired multistable behavior. In order to solve this problem efficiently, we build on insights from minimally rigid graph theory to identify simple but effective topologies for the mechanism. We then optimize its geometric parameters, such as joint positions and bar lengths, to obtain correct transitions between the given poses. Simultaneously, we ensure adequate stability of each pose based on an effective approximate error metric related to the elastic energy Hessian of the bars in the mechanism. As demonstrated by our results, we obtain functional multistable mechanisms of manageable complexity that can be fabricated using 3D printing. Further, we evaluated the effectiveness of our method on a large number of examples in the simulation and fabricated several physical prototypes.
Building Personalized Trust: Discovering What Makes One Trust and Act on Facebook Posts
Authors: Zhou Michelle X. , Yang Huahai , Mark Gloria , Hu Mengdie , Mahumd Jalal , Pal Aditya
Published: October 2021

What makes one trust or distrust a post on Facebook? What makes one willing to take an action on the post, such as sharing it with friends, following its advice, or even making a donation for its cause? We hypothesize that personal factors in addition to the characteristics of a post would be associated with one's trust and willingness to take actions on the post. To test our hypothesis, we have examined the relationships between a wide variety of personal factors and how users perceived the credibility of a post on Facebook and their associated behavior—willingness to act on the post with the acceptance of potential risks. Our results from a study involving 400 participants reveal several new findings. Notably, beyond message properties, we have discovered that personal factors are significantly associated with how users perceived the credibility of Facebook posts. Not only do our findings extend prior work on studying the relationships between information properties and users' trust in Facebook posts, but they also indicate the potential of tailoring intended messages to an audience based on their personal factors for establishing desired trust. Moreover, we have found that a combination of personal factors is associated more with users' willingness to act on a post than their perceptions of credibility alone. This finding deepens the understanding of users' behavior on Facebook beyond learning their subjective perceptions. It also informs how to potentially tailor intended messages to an audience based on the audience's personal factors so that the audience can act on the messages beyond just perceiving the credibility of the messages. We also discuss the implications of our findings for building personalized trust between message authors and readers on Facebook and beyond.
A Survey on Concept Drift in Process Mining
Authors: Sato Denise Maria Vecino , De Freitas Sheila Cristiana , Barddal Jean Paul , Scalabrin Edson Emilio
Published: October 2021

Concept drift in process mining (PM) is a challenge as classical methods assume processes are in a steady-state, i.e., events share the same process version. We conducted a systematic literature review on the intersection of these areas, and thus, we review concept drift in PM and bring forward a taxonomy of existing techniques for drift detection and online PM for evolving environments. Existing works depict that (i) PM still primarily focuses on offline analysis, and (ii) the assessment of concept drift techniques in processes is cumbersome due to the lack of common evaluation protocol, datasets, and metrics.
A Survey on Data-driven Network Intrusion Detection
Authors: Chou Dylan , Jiang Meng
Published: October 2021

Data-driven network intrusion detection (NID) has a tendency towards minority attack classes compared to normal traffic. Many datasets are collected in simulated environments rather than real-world networks. These challenges undermine the performance of intrusion detection machine learning models by fitting machine learning models to unrepresentative “sandbox” datasets. This survey presents a taxonomy with eight main challenges and explores common datasets from 1999 to 2020. Trends are analyzed on the challenges in the past decade and future directions are proposed on expanding NID into cloud-based environments, devising scalable models for large network data, and creating labeled datasets collected in real-world networks.
Gotta CAPTCHA ’Em All: A Survey of 20 Years of the Human-or-computer Dilemma
Authors: Guerar Meriem , Verderame Luca , Migliardi Mauro , Palmieri Francesco , Merlo Alessio
Published: October 2021

A recent study has found that malicious bots generated nearly a quarter of overall website traffic in 2019 [102]. These malicious bots perform activities such as price and content scraping, account creation and takeover, credit card fraud, denial of service, and so on. Thus, they represent a serious threat to all businesses in general, but are especially troublesome for e-commerce, travel, and financial services. One of the most common defense mechanisms against bots abusing online services is the introduction of Completely Automated Public Turing test to tell Computers and Humans Apart (CAPTCHA), so it is extremely important to understand which CAPTCHA schemes have been designed and their actual effectiveness against the ever-evolving bots. To this end, this work provides an overview of the current state-of-the-art in the field of CAPTCHA schemes and defines a new classification that includes all the emerging schemes. In addition, for each identified CAPTCHA category, the most successful attack methods are summarized by also describing how CAPTCHA schemes evolved to resist bot attacks, and discussing the limitations of different CAPTCHA schemes from the security, usability, and compatibility point of view. Finally, an assessment of the open issues, challenges, and opportunities for further study is provided, paving the road toward the design of the next-generation secure and user-friendly CAPTCHA schemes.
Adversary Models for Mobile Device Authentication
Authors: Mayrhofer René , Sigg Stephan
Published: October 2021

Mobile device authentication has been a highly active research topic for over 10 years, with a vast range of methods proposed and analyzed. In related areas, such as secure channel protocols, remote authentication, or desktop user authentication, strong, systematic, and increasingly formal threat models have been established and are used to qualitatively compare different methods. However, the analysis of mobile device authentication is often based on weak adversary models, suggesting overly optimistic results on their respective security. In this article, we introduce a new classification of adversaries to better analyze and compare mobile device authentication methods. We apply this classification to a systematic literature survey. The survey shows that security is still an afterthought and that most proposed protocols lack a comprehensive security analysis. The proposed classification of adversaries provides a strong and practical adversary model that offers a comparable and transparent classification of security properties in mobile device authentication.
Mechanism and potential treatment of the “no reflow” phenomenon after acute myocardial infarction: role of pericytes and GPR39
Authors: Methner Carmen , Cao Zhiping , Mishra Anusha , Kaul Sanjiv
Published: October 2021

The mechanism of “no reflow” phenomenon, where the coronary artery is patent after treatment of acute myocardial infarction but tissue perfusion is not restored, is unknown. This condition is associated with worse outcome. Here, we show that GPR39-mediated pericyte contraction during reduced coronary perfusion pressure causes capillary constriction resulting in no reflow. Smaller no-reflow zones in GPR39-knockout animals and those treated with a GPR39 inhibitor are associated with smaller infarct size. These results could have important therapeutic implications.
Mountain Rainfall Estimation and BIM Technology Site Safety Management Based on Internet of Things
Authors: Liu Peng
Published: October 2021

Mountain rainfall estimation is a major source of information for determining the safety of a geographical (mountainous) area. It can be done easily by using a modeling and simulation application, BIM, which is a building information modeling tool. It helps in transforming the real-time scenarios into the construction and business models. Now, this whole process can be easily realized by the help of an evolving technology known as IoT (Internet of Things). Internet of Things is supposedly going to take over the world by the end of this decade. It will reshape the whole communication architecture. IoT is actually going to be a basis for D2D (Device to Device) communication. Here, the MTC (Machine Type Communications) are going to take place which have almost zero human involvement. Now, in order to overcome the problem that the traditional construction site safety management method is difficult to accurately estimate the rainfall, resulting in poor safety management effect, a mountain rainfall estimation and BIM technology site safety management methods based on Internet of things are proposed. Firstly, based on the Internet of Things data, the limit learning machine method is used to accurately estimate the mountain rainfall. Secondly, based on the rainfall estimation results and combined with BIM technology, the construction site safety and management model is constructed. In the end, experimental verification is carried out. The experimental results show that this method can precisely estimate the rainfall in mountainous areas, and the computational results of safety factor are basically consistent with the actual results, indicating that the safety management effect of this system is good. In this paper, I reveal the complications and drawbacks associated with the ongoing mechanisms used for mountain rainfall estimations and how to overcome them by using the new technology, i.e., Internet of Things.
A Novel Approach for Outlier Detection in Multivariate Data
Authors: Afzal Saima , Afzal Ayesha , Amin Muhammad , Saleem Sehar , Ali Nouman , Sajid Muhammad
Published: October 2021

Outlier detection is a challenging task especially when outliers are defined by rare combinations of multiple variables. In this paper, we develop and evaluate a new method for the detection of outliers in multivariate data that relies on Principal Components Analysis (PCA) and three-sigma limits. The proposed approach employs PCA to effectively perform dimension reduction by regenerating variables, i.e., fitted points from the original observations. The observations lying outside the three-sigma limits are identified as the outliers. This proposed method has been successfully employed to two real life and several artificially generated datasets. The performance of the proposed method is compared with some of the existing methods using different performance evaluation criteria including the percentage of correct classification, precision, recall, and F-measure. The supremacy of the proposed method is confirmed by abovementioned criteria and datasets. The F-measure for the first real life dataset is the highest, i.e., 0.6667 for the proposed method and 0.3333 and 0.4000 for the two existing approaches. Similarly, for the second real dataset, this measure is 0.8000 for the proposed approach and 0.5263 and 0.6315 for the two existing approaches. It is also observed by the simulation experiments that the performance of the proposed approach got better with increasing sample size.
Maxillary Dentigerous Cyst with Double Wolf Teeth in a 3-Year-Old Quarter Horse Mare
Authors: Gutzmer Constanze , Nijdam Pieter
Published: October 2021

Dentigerous cysts are characterised by the formation of cysts containing dental material with a variable level of development. They are the result of a distinct embryological phenomenon. Usually, they are of significant clinical relevance in horses, especially in tandem with ectopic tooth. Contrarily, supernumerary teeth or typical polyodontias usually have limited impact. In this case report, we describe the occurrence of a supernumerary first premolar (Triadan 105). Dissimilar to known scientific literature however was the formation of a cystic structure around the supernumerary tooth. Surgical removal of the dentigerous cyst is discussed, as are the possible causes for the formation of the cystic structure. Based on this case report, we suspect that the formation of a cystic structure may not be limited to atypical polyodontias, as they may also occur in supernumerary teeth.
Surgical Strategy for Huge Right Coronary Artery Aneurysm Combined with Left Ventricular Fistula
Authors: Terada Takafumi , Araki Yoshimori , Kobayashi Akihiro , Kawaguchi Osamu
Published: October 2021

Coronary artery aneurysms combined with left ventricular fistulas are rare; coronary revascularization strategy after coronary artery aneurysm resection is complex in such cases. We report the surgical repair of a giant right coronary artery aneurysm with a fistula in the left ventricle in a 79-year-old woman diagnosed with an aneurysm 50 mm in diameter. Surgical repair included resection of the coronary artery aneurysm, coronary artery bypass grafting to the posterior descending artery, and isolation of reconstructed right coronary circulation from the fistula. The postoperative course was uneventful; postoperative coronary angiography revealed a patent bypass graft unconnected to the left ventricle.
Understanding the Effects of Fare Discount Schemes to Metro Transit Ridership Based on Structural Change Analysis
Authors: Li Zhe , Li Weifeng , Yu Qing
Published: October 2021

Since fare discounts have been regarded as an effective economical measure to increase passenger flow, it is helpful for local governments and transit operators to understand its impact on ridership. Taking Xiamen, China, as an example, this study uses transaction data to analyze the changes of weekday daily metro ridership after the opening of Xiamen Metro Line 1. At the initial stage of operation of Xiamen Metro Line 1, there are three preferential schemes: discount per trip, money reduced per trip, and discount after reaching the accumulated fare. Therefore, the algorithm of the iterated cumulative sums of squares is introduced to identify structural change points of the time series of daily ridership, which varies according to the type of ticket. The effects of different fare discounts on total ridership and ridership varied by ticket types are analyzed by the regression discontinuity method. The results show that the dates of structural change points are well-matched with the start and end dates of preferential schemes. Each preferential scheme has its own benefited groups. During the fare discount period, the number of passengers gradually increased. But after the cancellation of the favorable preferential scheme, the number of passengers decreased sharply. By understanding the impact of fare discounts on ridership in Xiamen, China, several metro ticketing policy recommendations are put forward, including raising the focus on E-Tickets, formulating more attractive preferential measures to promote the mode conversion of private cars and vehicles to metro, paying attention to high-frequency passengers, and seeking common subsidies from the financial industry to achieve a win-win situation. In addition, the analytical framework proposed in this study can be used to evaluate the effectiveness of other transportation policies in the future.
The Type 2 Deiodinase Thr92Ala Polymorphism Is Associated with Higher Body Mass Index and Fasting Glucose Levels: A Systematic Review and Meta‐Analysis
Authors: Wang Xichang , Chen Kan , Zhang Chenyu , Wang Haoyu , Li Jiashu , Wang Chuyuan , Teng Weiping , Shan Zhongyan , Lai Yaxin
Published: October 2021

Background. Type 2 deiodinase (Dio2) is a selenoenzyme that is mainly expressed in the endoplasmic reticulum of the central nervous system, brown adipose tissue, and placenta and is responsible for outer ring deiodination of thyroxine (T4) to form biologically active triiodothyronine (T3). The Thr92Ala polymorphism of Dio2 has been found to be a potential risk factor for various diseases beyond the hypothalamus‐pituitary‐thyroid (HPT) axis. Methods. We searched the relevant studies in the PubMed, Embase, and Cochrane Library databases and Google Scholar. A systematic review and meta‐analysis of studies on the Thr92Ala polymorphism and metabolic parameters beyond the HPT axis (e.g., BMI, fasting glycemic traits, plasma lipid levels, and hypertension risk) were performed. Results. Six eligible studies that analyzed the relationship between the Thr92Ala polymorphism and metabolic parameters beyond the thyroid were identified. All selected studies excluded patients with thyroid dysfunction, and diabetic patients were also excluded when fasting glucose and fasting insulin levels were meta‐analyzed. The Thr92Ala polymorphism was found to be a significant risk factor for higher BMI (Std. mean difference 0.31 (0.01, 0.60), p = 0.04) and higher fasting glucose levels (Std. mean difference 1.18 (0.05, 2.31), p = 0.04). However, fasting insulin levels, plasma lipid levels, and hypertension risk showed a nonsignificant association with the Thr92Ala polymorphism. Conclusion. Compared with euthyroid noncarriers (Thr/Thr), euthyroid Ala92‐Dio2 carriers showed increased BMI levels, and Ala92‐Dio2 carriers also had higher fasting plasma glucose levels than matched euthyroid nondiabetic noncarriers.
The Mutational Signature Comprehensive Analysis Toolkit (musicatk) for the Discovery, Prediction, and Exploration of Mutational Signatures
Authors: Chevalier Aaron , Yang Shiyi , Khurshid Zainab , Sahelijo Nathan , Tong Tong , Huggins Jonathan H. , Yajima Masanao , Campbell Joshua D.
Published: October 2021

Mutational signatures are patterns of somatic alterations in the genome caused by carcinogenic exposures or aberrant cellular processes. To provide a comprehensive workflow for preprocessing, analysis, and visualization of mutational signatures, we created the Mutational Signature Comprehensive Analysis Toolkit (musicatk) package. musicatk enables users to select different schemas for counting mutation types and to easily combine count tables from different schemas. Multiple distinct methods are available to deconvolute signatures and exposures or to predict exposures in individual samples given a pre-existing set of signatures. Additional exploratory features include the ability to compare signatures to the Catalogue Of Somatic Mutations In Cancer (COSMIC) database, embed tumors in two dimensions with uniform manifold approximation and projection, cluster tumors into subgroups based on exposure frequencies, identify differentially active exposures between tumor subgroups, and plot exposure distributions across user-defined annotations such as tumor type. Overall, musicatk will enable users to gain novel insights into the patterns of mutational signatures observed in cancer cohorts.

Significance:

The musicatk package empowers researchers to characterize mutational signatures and tumor heterogeneity with a comprehensive set of preprocessing utilities, discovery and prediction tools, and multiple functions for downstream analysis and visualization.
Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer
Authors: Mandigo Amy C. , Shafi Ayesha A. , McCann Jennifer J. , Yuan Wei , Laufer Talya S. , Bogdan Denisa , Gallagher Lewis , Dylgjeri Emanuela , Semenova Galina , Vasilevskaya Irina A. , Schiewer Matthew J. , McNair Chris M. , de Bono Johann S. , Knudsen Karen E.
Published: October 2021

The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function.

Significance:

This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease.
A Benzenesulfonamide-Based Mitochondrial Uncoupler Induces Endoplasmic Reticulum Stress and Immunogenic Cell Death in Epithelial Ovarian Cancer
Authors: Bi Fangfang , Jiang Ziyan , Park Wonmin , Hartwich Tobias M.P. , Ge Zhiping , Chong Kay Y. , Yang Kevin , Morrison Madeline J. , Kim Dongin , Kim Jaeyeon , Zhang Wen , Kril Liliia M. , Watt David S. , Liu Chunming , Yang-Hartwich Yang
Published: October 2021

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOC metastasizes in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro-N-(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells in vitro. Y3 was well tolerated in vivo and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect patients with ovarian cancer against relapse.
Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study
Authors: Furniss C. Sloane , Yurgelun Matthew B. , Ukaegbu Chinedu , Constantinou Pamela E. , Lafferty Catherine C. , Talcove-Berko Eliana R. , Schwartz Alison N. , Stopfer Jill E. , Underhill-Blazey Meghan , Kenner Barbara , Nelson Scott H. , Okumura Sydney , Law Sherman , Zhou Alicia Y. , Coffin Tara B. , Rodriguez Nicolette J. , Uno Hajime , Ocean Allyson J. , McAllister Florencia , Lowy Andrew M. , Lippman Scott M. , Klein Alison P. , Madlensky Lisa , Petersen Gloria M. , Garber Judy E. , Goggins Michael G. , Maitra Anirban , Syngal Sapna
Published: October 2021

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches.

Prevention Relevance:

Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.
Paisagismo e Cerrado: jardins para celebrar savanas e campos brasileiros
Authors: Siqueira Mariana de Melo , Sampaio Alexandre , Robredo Amalia , Cortes Claudomiro de Almeida , Bringel Junior João Bernardo de A. , Pellizzaro Keiko Fueta , Schmidt Isabel Belloni
Published: October 2021

Este artigo apresenta o projeto Jardins de Cerrado e suas atividades iniciais. Desde 2015, fazemos expedições em busca de plantas (o chamado planthunting), cultivo de ervas e arbustos nativos, experimentos científicos e jardins experimentais. Testamos metodologias de projeto e implantação, baseadas nos jardins naturalistas contemporâneos. O objetivo do projeto é promover a criação de uma linguagem paisagística que expresse o Cerrado, a savana mais rica em biodiversidade e mais ameaçada do planeta, colocando em evidência as ervas e arbustos que compõem a base de suas formações vegetais. Consideramos que jardins são ferramentas estratégicas para a conservação da biodiversidade, ao contribuir para o aumento da percepção e da valorização da flora nativa pelo público em geral.
Gestão de áreas verdes e sustentabilidade: estudo de caso a partir dos indicadores de qualidade ambiental urbana
Authors: Almeida Juscidalva Rodrigues de
Published: October 2021

As Áreas Verdes Urbanas são estruturas ecológicas importantes para a sustentabilidade ambiental das cidades, sendo essenciais para amenizar os efeitos da urbanização, cuja falhas no planejamento interferem na preservação da vegetação. Nesse sentido, este estudo tem por objetivo identificar as Áreas Verdes Urbanas de Cacoal/Rondônia e, a partir dos indicadores ambientais, avaliar o status das respectivas áreas em relação ao número de habitantes e crescimento urbano. Os procedimentos envolveram: revisão bibliográfica, pesquisa de campo e elaboração de material cartográfico por meio de Sistemas de Informações Geográficas (SIGs). Utilizamos indicadores que possibilitam analisar os espaços em estudo de forma qualitativa (espacialização das AVPs, tipologia, condições ambientais e usos sociais das mesmas) e quantitativo (quantidade de AVPs e habitantes). Os resultados demonstram que, nos últimos 10 anos, foram criados 20 bairros novos, totalizando 39, possibilitando a criação de novas Áreas Verdes, somando 24 áreas (476.835,55 m2). No entanto, o PAV é estimado em 0,011% e o IAV em 6,73 m2 por habitantes, assim, Cacoal, com 69.780 habitantes na área urbana, apresenta um índice baixo em relação a valor mínimo de 15 m2 por habitante recomendado pela Associação Brasileira de Arborização Urbana. No que refere às condições ambientais, 64,34% das Áreas Verdes estão degradadas devido às ações antropogênicas.
Amyloid Deposits and Fibrosis on Left Ventricular Endomyocardial Biopsy Correlate With Extracellular Volume in Cardiac Amyloidosis
Authors: Pucci Angela , Aimo Alberto , Musetti Veronica , Barison Andrea , Vergaro Giuseppe , Genovesi Dario , Giorgetti Assuero , Masotti Silvia , Arzilli Chiara , Prontera Concetta , Pastormerlo Luigi Emilio , Coceani Michele Alessandro , Ciardetti Marco , Martini Nicola , Palmieri Cataldo , Passino Claudio , Rapezzi Claudio , Emdin Michele
Published: October 2021

Background

The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined.

Methods and Results

We included all patients diagnosed with amyloid light‐chain (AL) or transthyretin cardiac amyloidosis at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular endomyocardial biopsy. Patients (n=37) were more often men (92%), with a median age of 72 years (interquartile range, 68–81). Lambda‐positive AL was found in 14 of 19 AL cases (38%) and kappa‐positive AL in 5 of 19 (14%), while transthyretin was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10%–30%), without significant differences between AL and transthyretin amyloidosis. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10%–23%; range, 5%–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between transthyretin amyloidosis and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance, the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (
r
=0.661,
P
=0.001). The combined amyloid and fibrosis extent correlated with high‐sensitivity troponin T (
P
=0.035) and N‐terminal pro‐B‐type natriuretic peptide (
P
=0.002) serum levels.

Conclusions

Extracellular spaces in cardiac amyloidosis are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased extracellular volume at cardiac magnetic resonance and circulating biomarkers than amyloid extent alone.
Efficacy and Safety of Vorapaxar by Intensity of Background Lipid‐Lowering Therapy in Patients With Peripheral Artery Disease: Insights From the TRA2P‐TIMI 50 Trial
Authors: Gilchrist Ian C. , Morrow David A. , Creager Mark A. , Olin Jeffrey W. , Scirica Benjamin M. , Goodrich Erica L. , Bonaca Marc P.
Published: October 2021

Background

Patients with peripheral artery disease are at increased risk of both major adverse cardiovascular events (MACEs) and limb events. The pathobiology of limb events is likely multifactorial. Observational studies suggest a benefit of statin therapy for reducing the risk of limb ischemic events while randomized trials demonstrate a benefit with more potent antithrombotic therapies, particularly those targeting thrombin. Whether the effects of these therapeutic pathways are independent and complementary is not known.

Methods and Results

The TRA 2°P‐TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial demonstrated that vorapaxar significantly reduced MACEs and limb events. The purpose of the current analysis was to evaluate the association of statin use and intensity and the occurrence of MACEs and limb events in 5845 patients with symptomatic peripheral artery disease randomized in TRA 2°P‐TIMI 50 and then to understand whether statin use modified the benefits of vorapaxar for MACEs or limb ischemic events. We found that statin therapy was associated with significantly lower risk of MACEs (hazard ratio [HR], 0.77; 95% CI, 0.66–0.89;
P
<0.001) and limb ischemic events (HR, 0.73; 95% CI, 0.60–0.89;
P
=0.002). The benefit of vorapaxar for reducing MACEs and limb events was consistent regardless of background statin (
P
‐interaction=0.715 and 0.073, respectively). Event rates were lowest in patients receiving the combination of statin therapy and vorapaxar.

Conclusions

In conclusion, statin use and intensity is associated with significantly lower rates of MACEs and limb ischemic events. Thrombin inhibition with vorapaxar is effective regardless of background statin therapy. These results suggest that targeting both lipid and thrombotic risk in peripheral artery disease is necessary in order to optimize outcomes.
Large-Scale Multivariate Analysis to Interrogate an Animal Model of Stroke: Novel Insights Into Poststroke Pathology
Authors: Zhang Shenpeng R. , Kim Hyun Ah , Chu Hannah X. , Lee Seyoung , Evans Megan A. , Li Xia , Ma Henry , Drummond Grant R. , Sobey Christopher G. , Phan Thanh G.
Published: October 2021

Background and Purpose:

Preclinical stroke studies endeavor to model the pathophysiology of clinical stroke, assessing a range of parameters of injury and impairment. However, poststroke pathology is complex and variable, and associations between diverse parameters may be difficult to identify within the usual small study designs that focus on infarct size.

Methods:

We have performed a retrospective large-scale big data analysis of records from 631 C57BL/6 mice of either sex in which the middle cerebral artery was occluded by 1 of 5 surgeons either transiently for 1 hour followed by 23-hour reperfusion (transient middle cerebral artery occlusion [MCAO]; n=435) or permanently for 24 hours without reperfusion (permanent MCAO; n=196). Analyses included a multivariate linear mixed model with random intercept for different surgeons as a random effect to reduce type I and type II errors and a generalized ordinal regression model for ordinal data when random effects are low.

Results:

Analyses indicated that brain edema volume was associated with infarct volume at 24 hours (β, 0.52 [95% CI, 0.45–0.59]) and was higher after permanent MCAO than after transient MCAO (
P
<0.05). A more severe clinical score was associated with a greater infarct volume but not with the animal’s age or edema volume. Further, a more severe clinical score was observed for a given brain infarct volume after transient MCAO versus permanent MCAO. Remarkably the animal’s age, which corresponded with the period of young adulthood (6–40 weeks; equivalent to ≈18–35 years in humans), was positively associated with severity of lung infection (β, 0.65 [95% CI, 0.42–0.88]) and negatively with spleen weight (β, −0.36 [95% CI, −0.63 to −0.09]).

Conclusions:

Large-scale analysis of preclinical stroke data can provide researchers in our field with insight into relationships between variables not possible if individual studies are analyzed in isolation and has identified hypotheses for future study.
Using an Artificial Neural Network to improve operational wind prediction in a small unresolved valley
Authors: CHINYOKA SINCLAIR , STEENEVELD GERT-JAN , HEDDE THIERRY
Published: October 2021

This study improves surface wind predictions in an unresolved valley using an artificial neural network (ANN). Forecasting winds in complex terrain with a mesoscale model is challenging. This study assesses the quality of 3-km wind forecasts by the Weather Research and Forecasting (WRF) model and the potential of post-processing by an ANN within the 1-2 km wide Cadarache Valley in southeast France. Operational wind forecasts for 110m above ground level and the near-surface vertical potential temperature gradient with a lead time of 24-48h were used as ANN input. Observed horizontal wind components at 10m within the valley were used as targets during ANN training. We use the Directional ACCuracy (DACC45, wind direction error ≤ 45°) and mean absolute error to evaluate the WRF direct model output and the ANN results. By post-processing, the score for DACC45 improves from 56% in the WRF direct model output to 79% after applying the ANN. Furthermore, the ANN performed well during the day and night, but poorly during the morning and afternoon transitions. The ANN improves the DACC45 at 10m even for poor WRF forecasts (direction bias ≥ 45°) from 42% to 72%. A shorter lead time and finer grid spacing (1 km) showed negligible impact which suggests that a 3 km grid spacing and a 24-48h lead time is effective and relatively cheap to apply. We find that WRF performs well in near-neutral conditions and poorly in other atmospheric stability conditions. The ANN post-treatment consistently improves the wind forecast for all stability classes to a DACC45 of about 80%. The study demonstrates the ability to improve Cadarache valley wind forecasts using an ANN as post-processing for WRF daily forecasts.
Brexit and the stratified uses of national and European Union citizenship
Authors: Sredanovic Djordje , Della Puppa Francesco
Published: October 2021

In this article the authors explore how Brexit changes the social meanings and uses of formal national and EU citizenship and how these meanings and uses are stratified, including by migratory experience, class and age. They do so through in-depth interviews with Britons in Belgium, EU27 citizens ‘by birth’ residing in the UK, and Bangladeshis who naturalised in Italy before moving to the UK. The article highlights the differences both between the three groups and within the groups, along lines of class and age, in the expectations regarding rights linked to citizenship, in the salience of different rights (e.g. freedom of movement, access to welfare, voting), and in the availability of alternative resources to contain the impact of Brexit. The authors argue that the Brexit process not only highlights the value of citizenship as well as the added value of a citizenship of an EU member state, but that it also reveals how the value of citizenships is internally stratified.
Instructional Level and Engagement in Students With Behavioral Disorders
Authors: Carr Chelsea E. , Umbreit John , Hartzell Rebecca
Published: October 2021

This study examined the effects of adjusting the difficulty level of instructional materials on the on-task time and comprehension of four students with emotional and behavioral disorders. All participants previously exhibited low rates of on-task behavior during reading assignments. Students were presented with reading materials at their instructional, frustration, and independent levels to assess the effect on time on-task and comprehension. All four students demonstrated the highest percentage of on-task behavior when presented with reading materials at their instructional level. Comprehension scores were highest for all four students at the independent level and lowest at the frustration level.
Delirium Assessment and Management in Geriatric Psychiatry under Prevailing Indian Laws (MHCA 2017)
Authors: Sonal Akanksha , Kumar Prerak , Srivastava Shrikant
Published: October 2021

The Indian Mental Health Care Act of 2017 (the Act) focuses on the human rights of persons with mental illness. It is based on the individual’s dignity, autonomy, and independence with a client-centered approach. Delirium is frequently seen in the hospitalized geriatric population, more commonly in medical and surgical wards, and much less frequently in psychiatry wards. Delirium is covered under the Act as a “substantial disturbance of thinking, mood, perception, orientation or memory that grossly impairs judgment, behavior, (and) capacity to recognize reality or ability to meet the ordinary demands of life.” The Act provides provisions for capacity assessment, emergency treatment, supported admission, advance directive, and the role of nominated representative in such cases.
Percutaneous cholecystostomy for acute cholecystitis after stent insertion in patients with malignant biliary obstruction: clinical outcomes of 107 patients
Authors: Choi Woosun , Gwon Dong Il , Kim Jong Woo , Kim Jin Hyoung , Shin Ji Hoon , Ko Gi-Young , Hur Joonho
Published: October 2021

Background

The outcome of percutaneous cholecystostomy (PC) in malignant patients with acute cholecystitis (AC) after biliary stent insertion has not been investigated in a large group.

Purpose

To evaluate the clinical outcomes of PC for AC after stent insertion in patients with malignant biliary obstruction.

Material and Methods

From April 2007 to February 2019, 107 patients (57 men, 52 women; mean age = 67.5 years; age range = 27–93 years) who had undergone PC for AC after biliary stent insertion were retrospectively evaluated. Of the 107 patients, 86 underwent biliary stent insertion by the endoscopic approach and the remaining 21 patients by the percutaneous approach. All patients were classified into three groups: those with stent-induced AC; those with cancer-induced AC; and those with AC without mechanical cause (biliary stent, GB stone, or cancer invasion). The mean survival time, recurrence rate, symptom improvement, and cystic duct patency in each patient group were analyzed.

Results

Stent-induced AC (n = 40, 37.4%) developed with a mean onset time of six days (range = 0–14 days), AC without mechanical cause (n = 27, 25.2%), 87 days (range = 15–273 days), and cancer-induced AC (n = 40, 37.4%), 137 days (range = 15–447 days) after stent insertion. Symptom resolution and significant improvement in laboratory test values were achieved in 95 patients (88.8%) within four days after PC.

Conclusion

PC is a technically safe and effective method for the treatment of AC after biliary stent insertion in patients with malignant biliary obstruction.