bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a Ubiquitous Child Emergency App – Ideas to Simplify and Ensure the Machine-2-Machine Communication
Authors: Schmucker Michael , Haag Martin
Published: May 2021

Medical emergencies involving children are rare events. The experience of emergency physicians is therefore low and the results are correspondingly poor. Assistance services to help in emergencies are regularly requested. The use case is thus very complicated, a complex system consisting of multiple devices is necessary to provide the most efficient and effective service. This short paper presents prototypically tested ideas on how such a ubiquitous approach can be designed and how communication between devices can be simplified and ensured.
Engaging Social Media Users with Health Education and Physical Activity Promotion
Authors: Gabarron Elia , Larbi Dillys , Årsand Eirik , Wynn Rolf
Published: May 2021

Health-dedicated groups on social media provide different contents and social support to their peers. Our objective is to analyze users’ engagement with health education and physical activity promotion posts according to the expressed social support and social media. All health education and physical activity promotion posts on Facebook, Twitter, and Instagram during 2017–2019 by a diabetes association were extracted. We identified the type of social support within these posts; and analysed the users’ engagement with these posts according to the type of social support and social media channel. A total of 260 posts dealing with health education (n=200) and physical activity promotion (n=60) were published. Posts promoting physical activity received 54% more likes than posts on health education (p<0.05), but they were 69% less likely to receive comments and be shared (both p<0.01). Posts expressing tangible assistance received 6 times more likes (p<0.001), and the ones indicating network support almost 11 times more shares (p<0.05). Posts expressing two or more types of social support were the most engaging (3 times more likes, 2 times more comments, and over 6 times more shares, all p<0.001). Health-dedicated social media groups can be effective channels for providing health education and for promoting physical activity among individuals with diabetes. Our findings suggest that engagement with health education and physical activity promotion posts can be increased by providing tangible assistance, network support, or expressing two or more types of social support; and by posting on Facebook and Instagram.
Designing Shift Handoff Software: Clinical Learners and Design Students Collaborate Using the “Design Thinking” Process
Authors: Lesselroth Blake , Park Hannah , Monkman Helen , Duncan Ashten , Thompson Gabriel , Yarnall Ryan
Published: May 2021

Handoffs in patient care responsibilities between practitioners are common in the hospital setting. Because inadequate communication can lead to patient harm, professional organizations have published recommendations and practical guides to support standardized workflow. However, currently available electronic medical record (EMR) tools rarely provide the requisite functionality to support work and often suffer from major usability flaws. Our internal medicine residency program sponsored a quality improvement initiative to improve the design of handoff tools. To support this initiative, our medical informatics program collaborated with a school of architecture and design to identify requirements and ideate interface prototypes. In this article, we describe how we used Design Thinking principles and methods to inform our product design lifecycle, create novel designs, and teach inter-professional students health systems science concepts.
Health Informatics Learning Objectives on an Interoperable, Collaborative Platform
Authors: Spreckelsen Cord , Schemmann Ulrike , Phan-Vogtmann Lo An , Scherag André , Winter Alfred , Schneider Birgit
Published: May 2021

Catalogues of learning objectives for Biomedical and Health Informatics are relevant prerequisites for systematic and effective qualification. Catalogue management needs to integrate different catalogues and support collaborative revisioning. The Health Informatics Learning Objectives Navigator (HI-LONa) offers an open, interoperable platform based on Semantic Web Technology. At present HI-LONa contains 983 learning objectives of three relevant catalogues. HI-LONa successfully supported a multiprofessional consensus process.
Evaluating Medical Lexical Simplification: Rule-Based vs. BERT
Authors: Tran Linh , Velazquez Erick , Sips Robert-Jan , de Boer Victor
Published: May 2021

Lexical simplification (LS) can decrease the communication gap between medical experts and laypeople by replacing medical terms with layperson counterparts. In this paper, we present: 1) a rule-based approach to LS using a consumer health vocabulary, and 2) an unsupervised approach using BERT to generate word candidates. Human evaluation shows that the unsupervised model performed better for simplicity and grammaticality, while the rule-based method was better at meaning preservation.
Using Business Process Management Notation to Model Therapeutic Prescription Protocols: The PrescIT Approach
Authors: Natsiavas Pantelis , Stavropoulos Thanos G. , Pliatsios Antonios , Karanikas Haralampos , Gavriilidis George I. , Dimitriadis Vlasios K. , Nikolaidis George , Nikolopoulos Spiros , Skapinakis Petros , Thireos Eleytherios , Kompatsiaris Ioannis
Published: May 2021

Clinical Decision Support Systems (CDSS) could play a prominent role in preventing Adverse Drug Reactions (ADRs) especially when integrated in larger healthcare systems (e.g. Electronic Health Record – EHR systems, Hospital Management Systems – HMS, e-Prescription systems etc.). This poster presents an approach to model Therapeutic Prescription Protocols (TPPs) via the Business Process Management Notation (BPMN), as part of the e-Prescription CDSS developed in the context of the PrescIT project.
FhirExtinguisher: A FHIR Resource Flattening Tool Using FHIRPath
Authors: Oehm Johannes , Storck Michael , Fechner Maximilian , Brix Tobias J. , Yildirim Kemal , Dugas Martin
Published: May 2021

Data analysis with popular statistical toolchains like R usually needs to be performed on “flat tables” (so-called dataframes). However, data exchange is often done with FHIR, a format that is based on a hierarchical data model. In this paper, we want to present our tool FhirExtinguisher, which tackles the problems of loading FHIR data into statistical tools by extending the FHIRSearch API with an additional projection layer using FHIRPath. This projection layer can be used to select the data elements of interest and create a CSV file, which can be easily read as dataframe by almost any statistical toolchain.
УПРАВЛІННЯ ОБОРОТНИМИ АКТИВАМИ ПІДПРИЄМСТВА ТА ЇХ ВИДАМИ
Authors: Перевозова Ірина , Павлова Галина
Published: May 2021

В статті зазначено, що управлiння oбoрoтними активами cтанoвить найбiльш велику чаcтину фiнанcoвoгo менеджменту у cиcтемi управлiння активами підприємcтва. На основі аналізу літературних джерел нами було розроблено загальний алгоритм управління оборотними активами підприємства, який складається з шести етапів та включає аналіз використання оборотного капіталу в попередньому періоді, визначення підходів до формування оборотних активів, їх оптимізацію, забезпечення необхідної ліквідності та збільшення рентабельності оборотних активів. Запропоновано практичний варіант покращення управління оборотними активами на прикладі запасів фермерського господарства. Вказана пропозиція, а саме збільшення суми партії придбаних виробничих запасів зменшить не тільки суму транспортно-заготівельних витрат, але і вплине на вартість самої партії.
Application of Correction Procedures for Some Systematic Measurement Errors to Rainfall Intensity Data of a Rain Gauge in Budapest
Authors: Rácz Tibor
Published: May 2021

The rainfall intensity measurement has a 150 years long history. In the first period of data recordings, the siphoned recording precipitation gauge (pluviographs), or siphoned rainfall writers (SRW), later, the tipping bucket gauges (TBG) were widely used. The systematic errors of these instruments resulted in lower intensity values for long periods. These errors were compensated sporadically. Most of the inaccurate data can be found in the high rainfall intensity range. Some of these data can be found in extracted, aggregated versions only, and the original measurement data is no longer available. These kinds of inherited systematic errors can be corrected. The fixing of siphoning error of SRWs and the supplementary correction of long sampling period data of TBG devices can be a suitable method for the elimination of these issues. In this paper, the application of these two methods is shown in a case study to point out the magnitude and effect of these errors on the IDF curves. The case study on the use of the before-mentioned correction procedures is performed on the rainfall data of the Budapest-Belterület (Budapest City) rainfall station, using data series spanning 105 years. These corrections show that the earlier IDF curves can show 5–10% lower intensities, mainly in the short and low return frequency rainfalls. The result of these kinds of corrections can be significant for the climate change investigations or in the re-evaluation of the elder IDF curves.
Russia’s Young Army: Raising New Generations into Militarized Patriots
Authors: Alava Jonna
Published: May 2021

This chapter addresses military-patriotic education in Russia. The Russian state pays increasing attention to the military-patriotic upbringing of children to elevate patriotic spirit in society and to get a larger number of motivated young men join the armed forces. In 2015, Ûnarmiâ was founded to unite the country’s fragmented military-patriotic youth organisations. The movement aims to operate in all schools in Russia. By deconstructing the hegemonic discourse of military-patriotic education, I analyse the linguistic modes in which the legitimization of Ûnarmiâ is constructed. Discourses of heroism, masculinity, a beneficial and fun hobby, being citizen-soldiers, and military traditionalism include key strategies of legitimization processes for influencing audiences. Discourses suggest that rather than preparing young people for immediate war, Ûnarmiâ's purpose is to raise patriotic citizens who support the prevailing regime and contribute to solving the demographic crisis by repeating ‘traditional’ gender roles.
Wirtschaftsstandort Österreich
Authors: Kolm Barbara , Kammel Armin J
Published: May 2021

Kritischer Diskurs, Lösungsansätze und Handlungsanleitungen zum Wirtschaftsstandort Österreich Seit Jahrzehnten wird in Österreich eine ambivalente Diskussion über die Attraktivität des Wirtschaftsstandorts geführt, die in unterschiedlichen Phasen, Schattierungen und Schwerpunktsetzungen auftritt. Auslöser dafür sind partikular artikulierte Interessen oder Bedenken von Industriezweigen oder Branchen. Auch die offizielle wirtschaftspolitische Ausrichtung der letzten Jahrzehnte ist nicht von Konsistenz geprägt. Insbesondere vor dem Hintergrund der durch COVID-19 ausgelösten Wirtschaftskrise 2020 präsentiert dieser Sammelband einen holistischen, kritischen und lösungsorientierten, interdisziplinären Ansatz, mit dem Ziel, den Wirtschaftsstandort Österreich zu stärken und zukunftsfit zu machen. Führende Wirtschaftspolitikerinnen und -politiker des Landes legen zu Kernthemen der österreichischen Wirtschaft ihre Positionen dar.
ГОТОВНІСТЬ ДО САМООСВІТНЬОЇ ДІЯЛЬНОСТІ МАЙБУТНІХ ВЧИТЕЛІВ ПОЧАТКОВИХ КЛАСІВ: ЕМПІРИЧНЕ ДОСЛІДЖЕННЯ
Authors: Потапчук Т. В.
Published: May 2021

У статті зосереджено увагу на проблемі готовності до самоосвітньої діяльності майбутніх вчителів початкових класів. Зазначено, що самоосвіта виступає складовою професійної підготовки і розуміється в її межах як процес, який забезпечує безперервність підвищення освітнього рівня та розширення інформаційного поля фахівців, покращення якості та підняття рівня їхньої компетентності та професіоналізму, що пов’язаний з розвитком особистості та бере участь у формуванні загальної та педагогічної культури, слугує становленню світогляду, оскільки саме студент є суб’єктом управління власною навчальною діяльністю під час фахової підготовки.

Для визначення ставлення майбутніх вчителів до процесу самоосвіти та їх оцінки значущості володіння самоосвітньою компетентністю у сфері майбутньої професійної діяльності студентам пропонувалося відповісти на питання анкети з метою виявлення рівня сформованості самоосвітньої компетентності. Подано результати констатувального експерименту, які вказують на те, що студенти здібні до самоосвіти та саморозвитку, проте система професійної підготовки недостатньою мірою сприяє формуванню самоосвітньої компетентності, яка є ключовою для безперервної освіти майбутніх вчителів. Тому актуальним є здійснення цілеспрямованої підготовки до самоосвіти майбутніх вчителів початкових класів із врахуванням передового педагогічного досвіду.

Розроблено робочу програму спецкурсу «Самоосвіта у вищій школі», яка орієнтована для студентів спеціальності 013 «Початкова освіта» другого (магістерського) рівня вищої освіти. Мета курсу полягає у підготовці до самоосвіти; спрямуванні діяльності майбутніх вчителів початкових класів на саморозвитку і самовдосконаленні професійних компетентностей через самоосвіту. Зазначено, що однією з ключових завдань спецкурсу є формування самоосвітньої компетентності майбутніх вчителів початкових класів.
МЕТОДИКА ВИКЛАДАННЯ НАВЧАЛЬНОЇ ДИСЦИПЛІНИ «СТАРТ-АП-ТЕХНОЛОГІЇ» МАЙБУТНІМ ОФІЦЕРАМ-ПРИКОРДОННИКАМ
Authors: Тушко К. , Торічний В. , Топольницька Г. , Совва С.
Published: May 2021

У статті висвітлено специфіку методики викладання навчальної дисципліни «Старт-ап-технології» майбутнім офіцерам-прикордонникам. Автори торкнулись проблем якості вищої освіти в Україні і, зокрема, вищої військової освіти. Проаналізовано низку наукових праць з проблеми дослідження: і публікації, і монографії, і дисертації. Сутність методики викладання «Старт-ап-технологій» автори розкрили на прикладі спеціальності «Телекомунікації та радіотехніка» у прикордонній академії. Основними особливостями методики є: побудова робочої програми згаданої навчальної дисципліни із врахуванням змісту професійної діяльності офіцерів-прикордонників; розподіл аудиторних годин було здійснено таким чином, щоб більша їх частка забезпечувала практичну підготовку майбутніх офіцерів-прикордонників. Приблизно 26 навчальних годин з 46 аудиторних – це практичні заняття, решта лекційні та семінарські; під час проведення практичних та семінарських занять з майбутніми офіцерами-прикордонниками використовувався широкий спектр педагогічних технологій: від інтерактивних бесід до колабораційних технологій; забезпечення міждисциплінарного зв’язку, оскільки «Старт-ап-технології» пов’язані із дисциплінами «Філософія», «Політичні та економічні системи», «Управління проектами» та іншими; використання управлінського потенціалу навчальної дисципліни, з метою формування здатності до прийняття рішень та усвідомлення відповідальності за ці рішення; формування нового стилю мислення, що демонструють власники старт-апів всього світу; розширення світогляду курсантів-прикордонників; забезпечення виховання майбутніх офіцерів-прикордонників, зокрема таких якостей, як толерантність, стриманість тощо. Методика викладання сучасної навчальної дисципліни «Старт-ап-технології» вимагає врахування специфіки організації освітнього процесу у навчальному закладі, змісту професійної діяльності майбутніх офіцерів-прикордонників та оптимального рівня підготовленості до її викладання науково-педагогічних працівників.
КОНЦЕПЦІЇ ТА МОДЕЛІ НАВЧАННЯ ПЕДАГОГІКИ: ТРАДИЦІЇ ТА ІННОВАЦІЇ
Authors: Бутенко Л. Л.
Published: May 2021

Визначено актуальність дослідження концепцій та моделей навчання педагогіки як теоретичного фундаменту професійного та особистісного становлення майбутніх учителів. На основі аналізу наукової літератури представлено моделі навчання педагогіки – емпірична, навчальна (теорія – … – практика), практико зорієнтована, антропосоціальна, квазіпрофесійна, евристична, рефлексивна, особистісно практична, самоосвітня, їхнє співвіднесення з різними видами діяльності студентів.

Схарактеризовано особливості концентрованого навчання педагогіки (В. Безрукова), що забезпечує «занурення» майбутніх учителів у проблемне поле педагогічної теорії та практики, формування цілісного уявлення про педагогіку. Розкрито основні положення генеративного навчання педагогіки (І. Циркун, В. Пунчик) з опорою на самостійну пізнавальну діяльність студентів, орієнтацією на формування компетентностей самоосвіти та саморозвитку.

Визначено особливості оновлення та удосконалення змісту курсу «Педагогіка» згідно наукових позицій О. Дубасенюк (системний підхід до аналізу педагогічних явищ, професіографічний підхід до конструювання змісту навчання педагогіки). Представлено основні концептуальні положення експериментально-аналітичного навчання педагогіки (Л. Косолапова), зокрема ідея доповнювальності пізнавальної й професійно-педагогічної діяльності, взаємоперехід теорії та практики, аналітичний розгляд компонентів освітньої системи.
Australia’s notifiable disease status, 2016: Annual report of the National Notifiable Diseases Surveillance System
Authors:   NNDSS Annual Report Working Group
Published: May 2021

In 2016, a total of 67 diseases and conditions were nationally notifiable in Australia. The states and territories reported 330,387 notifications of communicable diseases to the National Notifiable Diseases Surveillance System. Notifications have remained stable between 2015 and 2016. In 2016, the most frequently notified diseases were vaccine preventable diseases (139,687 notifications, 42% of total notifications); sexually transmissible infections (112,714 notifications, 34% of total notifications); and gastrointestinal diseases (49,885 notifications, 15% of total notifications). Additionally, there were 18,595 notifications of bloodborne diseases; 6,760 notifications of vectorborne diseases; 2,020 notifications of other bacterial infections; 725 notifications of zoonoses and one notification of a quarantinable disease.
Representasi Gender Inequality dalam Film Kim Ji-Young, Born 1982 (Analisis Wacana Kritis Sara Mills)
Authors: Amalia Ghina Fadhilah , Kaestiningtyas Ira , Safitri Anaziah
Published: May 2021

ABSTRACTGender inequality refers to unequal treatment or perceptions of individuals based on their gender. This situation occurs more common in countries that still uphold of patriarchal system in their social structure where men hold the highest position in daily and it was considered appropriate to discriminate women as they dominate them. As it seems in “Kim Ji-young, Born 1982”, a film that tried to speak up about gender issue that has been happened in South Korea. The method used in this research is descriptive qualitative to analyze how they portrayed gender inequality through research method with the approach of critical discourse analysis by Sara Mills. The conclusion of this article is as mass media, film has roles to entertain, to inform, to persuade, and to educate people. And yet in this case also to reveal the reality about how women are treated as weaklings in society and it is inevitable for women to face gender inequality.Keywords: gender inequality, gender, film, critical discourse analysis, Sara MillsABSTRAKKetidaksetaraan Gender merupakan suatu kondisi dimana terjadi ketidakadilan atau perbedaan antara laki-laki dan perempuan hingga muncul diskriminatif. Keadaan ini lebih banyak terjadi di negara yang memegang teguh struktur sosial patriarkhi, dimana laki-laki mempunyai kedudukan tertinggi pada seluruh kehidupan dan dianggap patut untuk mendominasi dan mendeskriditkan kaum perempuan. Seperti halnya dalam film Kim Ji-young, Born 1982 yang mencoba mengangkat isu gender yang terjadi di Korea Selatan. Menggunakan meode deskriptif kualitatif penelitian ini mengupas nilai-nilai ketidaksetaraan gender melalui pendekatan teori analisis wacana kritis cetusan Sara Mills. Simpulan dari tulisan ini yaitu film sebagai media massa memperlihatkan realitas bagaimana perempuan dalam konstruk sosial diperlakukan sebagai sosok yang lemah dan tidak terelakkan dari ketimpangan akibat dari ketidakadilan gender yang membudaya di masyarakat.Kata Kunci: ketidaksetaraan gender, gender, film, analisis wacana kritis, Sara Mills
Теоретические основы организации ликвидации последствий применения противником средств поражения: специальные принципы и терминологический аппарат организации
Authors: Bordak Sergey S. , Karpilenya Nikolay V. , Subbotin Mikhail N.
Published: May 2021

Цель. Обосновать специальные принципы организации ликвидации последствий применения противником средств поражения силами гражданских формирований гражданской обороны, а также внести уточнения в терминологический аппарат данной предметной области.

Методы. В качестве теоретической базы использовались метод аналогии, а также общенаучные методы индукции, дедукции, анализа и синтеза.

Результаты. На основе общих законов развития, известных законов (закономерностей) войны (вооруженной борьбы) и с учетом общих законов и принципов управления установлена диалектическая связь с принципами военного управления и конкретизирован механизм их проявления относительно особенностей управления гражданской обороной. Разработаны специальные принципы организации ликвидации последствий применения противником средств поражения силами гражданских формирований гражданской обороны, а также внесены уточнения в терминологический аппарат.

Область применения исследований. Результаты исследования могут быть использованы в научных исследованиях, связанных с аспектами подготовки и ведения гражданской обороны, а также в практической деятельности начальников и штабов гражданской обороны.
Greater muscle strength is associated with reduced autonomic reactivity
Authors: Souto Filho José Morais , Sousa Caio Victor de , Rosa Thiago dos Santos , Simões Herbert Gustavo
Published: May 2021

We aimed to investigate the autonomic responses to cold pressor test (CPT) in individual with different levels of muscle strength. 57 male subjects participated in the study. Volunteers were divided in tertiles according to their level of relative handgrip strength as Low (LS), Medium (MS) and High (HS). For the CPT the volunteers remained seated in resting for 15 minutes and inserted the right hand in cold water for two minutes. Blood pressure (BP) measurements were taken at rest, during CPT and during recovery. HRV was continuously recorded during the entire protocol. All three groups had similar BP variation, with the values of systolic blood pressure (SBP) increasing during CPT and diminishing during recovery until the third minute. At the first CPT minute LS group showed a substantial increase in low-frequency (LF) activity and a diminished high frequency (HF). LS also presented higher and lower values of LF and HF, respectively, than MS group at the first CPT minute. HS showed an increased vagal activity during recovery. In conclusion, individuals from LS presented similar BP responses to CPT than MS and HS groups but with higher sympathetic activation. HS individuals presented an elevated vagal activity during recovery.
Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis
Authors: Folick Andrew , Koliwad Suneil K. , Valdearcos Martin
Published: May 2021

In mammals, myeloid cells help maintain the homeostasis of peripheral metabolic tissues, and their immunologic dysregulation contributes to the progression of obesity and associated metabolic disease. There is accumulating evidence that innate immune cells also serve as functional regulators within the mediobasal hypothalamus (MBH), a critical brain region controlling both energy and glucose homeostasis. Specifically, microglia, the resident parenchymal myeloid cells of the CNS, play important roles in brain physiology and pathology. Recent studies have revealed an expanding array of microglial functions beyond their established roles as immune sentinels, including roles in brain development, circuit refinement, and synaptic organization. We showed that microglia modulate MBH function by transmitting information resulting from excess nutrient consumption. For instance, microglia can sense the excessive consumption of saturated fats and instruct neurons within the MBH accordingly, leading to responsive alterations in energy balance. Interestingly, the recent emergence of high-resolution single-cell techniques has enabled specific microglial populations and phenotypes to be profiled in unprecedented detail. Such techniques have highlighted specific subsets of microglia notable for their capacity to regulate the expression of lipid metabolic genes, including lipoprotein lipase (LPL), apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The discovery of this transcriptional signature highlights microglial lipid metabolism as a determinant of brain health and disease pathogenesis, with intriguing implications for the treatment of brain disorders and potentially metabolic disease. Here we review our current understanding of how changes in microglial lipid metabolism could influence the hypothalamic control of systemic metabolism.
Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice
Authors: Kim Jieun , Park Jin-Hee , Park Seon Kyeong , Hoe Hyang-Sook
Published: May 2021

Sorafenib is FDA-approved for the treatment of primary kidney or liver cancer, but its ability to inhibit many types of kinases suggests it may have potential for treating other diseases. Here, the effects of sorafenib on neuroinflammatory responses in vitro and in vivo and the underlying mechanisms were assessed. Sorafenib reduced the induction of mRNA levels of the proinflammatory cytokines COX-2 and IL-1β by LPS in BV2 microglial cells, but in primary astrocytes, only COX-2 mRNA levels were altered by sorafenib. Interestingly, sorafenib altered the LPS-mediated neuroinflammatory response in BV2 microglial cells by modulating AKT/P38-linked STAT3/NF-kB signaling pathways. In LPS-stimulated wild-type mice, sorafenib administration suppressed microglial/astroglial kinetics and morphological changes and COX-2 mRNA levels by decreasing AKT phosphorylation in the brain. In 5xFAD mice (an Alzheimer’s disease model), sorafenib treatment daily for 3 days significantly reduced astrogliosis but not microgliosis. Thus, sorafenib may have therapeutic potential for suppressing neuroinflammatory responses in the brain.
Immunodominance of Epitopes and Protective Efficacy of HI Antigen Are Differentially Altered Using Different Adjuvants in a Mouse Model of Staphylococcus aureus Bacteremia
Authors: Chen Zhifu , Gou Qiang , Xiong Qingshan , Duan Lianli , Yuan Yue , Zhu Jiang , Zou Jintao , Chen Longlong , Jing Haiming , Zhang Xiaoli , Luo Ping , Zeng Hao , Zou Quanming , Zhao Zhuo , Zhang Jinyong
Published: May 2021

HI, a fusion protein that consists of the alpha-toxin (Hla) and the N2 domain of iron surface determinant B (IsdB), is one of the antigens in the previously reported S. aureus vaccine rFSAV and has already entered phase II clinical trials. Previous studies revealed that HI is highly immunogenic in both mice and healthy volunteers, and the humoral immune response plays key roles in HI-mediated protection. In this study, we further investigated the protective efficacy of immunization with HI plus four different adjuvants in a mouse bacteremia model. Results showed that HI-mediated protection was altered in response to different adjuvants. Using antisera from immunized mice, we identified seven B-cell immunodominant epitopes on Hla and IsdB, including 6 novel epitopes (Hla1-18, Hla84-101, Hla186-203, IsdB342-359, IsdB366-383, and IsdB384-401). The immunodominance of B-cell epitopes, total IgG titers and the levels of IFN-γ and IL-17A from mice immunized with HI plus different adjuvants were different from each other, which may explain the difference in protective immunity observed in each immunized group. Thus, our results indicate that adjuvants largely affected the immunodominance of epitopes and the protective efficacy of HI, which may guide further adjuvant screening for vaccine development and optimization.
The SOX9-MMS22L Axis Promotes Oxaliplatin Resistance in Colorectal Cancer
Authors: Liu Yiqiang , Wu Hong , Luo Tao , Luo Qiyu , Meng Ziyu , Shi Ying , Li Feifei , Liu Mingxin , Peng Xinhao , Liu Junjie , Xu Chuan , Tang Weizhong
Published: May 2021

Background

Colorectal cancer (CRC) is estimated to be one of the most common cancers and the leading cause of cancer-related death worldwide. SOX9 is commonly overexpressed in CRC and participates in drug resistance. In addition, DNA damage repair confers resistance to anticancer drugs. However, the correlation between DNA damage repair and high SOX9 expression is still unclear. In this study, we aimed to investigate the function and the specific underlying mechanism of the SOX9-dependent DNA damage repair pathway in CRC.

Methods

The expression levels of SOX9 and MMS22L in CRC were examined by immunohistochemistry (IHC) and TCGA analysis. RNA sequencing was conducted in RKO SOX9-deficient cells and RKO shControl cells. Mechanistic studies were performed in CRC cells by modulating SOX9 and MMS22L expression, and we evaluated drug sensitivity and DNA damage repair signaling events. In addition, we investigated the effect of oxaliplatin in tumors with SOX9 overexpression and low expression of MMS22L in vivo.

Results

Our study showed that SOX9 has a higher expression level in CRC tissues than in normal tissues and predicts poor prognosis in CRC patients. Overexpression and knockdown of SOX9 were associated with the efficacy of oxaliplatin. In addition, SOX9 activity was enriched in the DNA damage repair pathway via regulation of MMS22L expression and participation in DNA double-strand break repair. SOX9 was upregulated and formed a complex with MMS22L, which promoted the nuclear translocation of MMS22L upon oxaliplatin treatment. Moreover, the xenograft assay results showed that oxaliplatin abrogated tumor growth from cells with MMS22L downregulation in mice.

Conclusions

In CRC, activation of the SOX9-MMS22L-dependent DNA damage pathway is a core pathway regulating oxaliplatin sensitivity. Targeting this pathway in oxaliplatin-resistant CRC cells is a promising therapeutic option.
Eriodictyol Attenuates MCAO-Induced Brain Injury and Neurological Deficits via Reversing the Autophagy Dysfunction
Authors: Wang Chuanxiang , Ma Zhequan , Wang Zuqiang , Ming Shuping , Ding Yanbing , Zhou Sufang , Qian Hongyu
Published: May 2021

The present study was designed to investigate the protective effect of eriodictyol on MCAO-induced brain injury and its regulation of neural function and to explore the mechanism of its regulation of autophagy in rats. Brain injury was induced by middle cerebral artery occlusion (MCAO) in adult rats and pretreated with eriodictyol (low dose: 20 mg/kg; medium dose: 40 mg/kg; high dose: 80 mg/kg) or saline. Rats in the treatment group had a smaller volume of infarction and improved neurological outcome and reduced the latency to the platform, increased the time spent in the correct quadrant compared to MCAO rats pretreated with saline. ELISA kits results confirmed that eriodictyol reduced the inflammatory response induced by MCAO. The results of apoptosis and proliferation by Nissl staining and immunofluorescence detection indicated that eriodictyol could inhibit apoptosis and promote the proliferation in MCAO rats. The expressions of LC3, ATG5, p62, and Beclin1 were used to evaluate the autophagy, as well as the reversal of the autophagy activator (rapamycin) on the neuroprotective effect of eriodictyol, which suggested that the protective effect of eriodictyol on brain injury may be related to the inhibition of autophagy. In summary, we, therefore, suggested that eriodictyol could reduce the inflammation response of brain injury and inhibit neuroapoptosis, directly affecting autophagy to alleviate brain injury. It will provide theoretical support for eriodictyol in the treatment of ischemic stroke.
Absolute Lymphocyte Count Predicts Immune-Related Adverse Events in Patients With Non-Small-Cell Lung Cancer Treated With Nivolumab Monotherapy: A Multicenter Retrospective Study
Authors: Egami Saeka , Kawazoe Hitoshi , Hashimoto Hironobu , Uozumi Ryuji , Arami Toko , Sakiyama Naomi , Ohe Yuichiro , Nakada Hideo , Aomori Tohru , Ikemura Shinnosuke , Fukunaga Koichi , Yamaguchi Masakazu , Nakamura Tomonori
Published: May 2021

Background

Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting.

Materials and Methods

This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed.

Results

Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation.

Conclusions

The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.
Uncontrolled Confounders May Lead to False or Overvalued Radiomics Signature: A Proof of Concept Using Survival Analysis in a Multicenter Cohort of Kidney Cancer
Authors: Lu Lin , Ahmed Firas S. , Akin Oguz , Luk Lyndon , Guo Xiaotao , Yang Hao , Yoon Jin , Hakimi A. Aari , Schwartz Lawrence H. , Zhao Binsheng
Published: May 2021

Purpose

We aimed to explore potential confounders of prognostic radiomics signature predicting survival outcomes in clear cell renal cell carcinoma (ccRCC) patients and demonstrate how to control for them.

Materials and Methods

Preoperative contrast enhanced abdominal CT scan of ccRCC patients along with pathological grade/stage, gene mutation status, and survival outcomes were retrieved from The Cancer Imaging Archive (TCIA)/The Cancer Genome Atlas—Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database, a publicly available dataset. A semi-automatic segmentation method was applied to segment ccRCC tumors, and 1,160 radiomics features were extracted from each segmented tumor on the CT images. Non-parametric principal component decomposition (PCD) and unsupervised hierarchical clustering were applied to build the radiomics signature models. The factors confounding the radiomics signature were investigated and controlled sequentially. Kaplan–Meier curves and Cox regression analyses were performed to test the association between radiomics signatures and survival outcomes.

Results

183 patients of TCGA-KIRC cohort with available imaging, pathological, and clinical outcomes were included in this study. All 1,160 radiomics features were included in the first radiomics signature. Three additional radiomics signatures were then modelled in successive steps removing redundant radiomics features first, removing radiomics features biased by CT slice thickness second, and removing radiomics features dependent on tumor size third. The final radiomics signature model was the most parsimonious, unbiased by CT slice thickness, and independent of tumor size. This final radiomics signature stratified the cohort into radiomics phenotypes that are different by cancer-specific and recurrence-free survival; HR (95% CI) = 3.0 (1.5–5.7), p <0.05 and HR (95% CI) = 6.6 (3.1–14.1), p <0.05, respectively.

Conclusion

Radiomics signature can be confounded by multiple factors, including feature redundancy, image acquisition parameters like slice thickness, and tumor size. Attention to and proper control for these potential confounders are necessary for a reliable and clinically valuable radiomics signature.
Risk Factors for Noninvasive Ventilation Failure in Children Post-Hematopoietic Cell Transplant
Authors: Rowan Courtney M. , Fitzgerald Julie C. , Agulnik Asya , Zinter Matt S. , Sharron Matthew P. , Slaven James E. , Kreml Erin M. , Bajwa Rajinder P.S. , Mahadeo Kris M. , Moffet Jerelyn , Tarquinio Keiko M. , Steiner Marie E.
Published: May 2021

Rationale

Little is known on the use of noninvasive ventilation (NIPPV) in pediatric hematopoietic cell transplant (HCT) patients.

Objective

We sought to describe the landscape of NIPPV use and to identify risk factors for failure to inform future investigation or quality improvement.

Methods

This is a multicenter, retrospective observational cohort of 153 consecutive children post-HCT requiring NIPPV from 2010-2016.

Results

97 (63%) failed NIPPV. Factors associated with failure on univariate analysis included: longer oxygen use prior to NIPPV (p=0.04), vasoactive agent use (p<0.001), and higher respiratory rate at multiple hours of NIPPV use (1hr p=0.02, 2hr p=0.04, 4hr p=0.008, 8hr p=0.002). Using respiratory rate at 4 hours a multivariable model was constructed. This model demonstrated high ability to discriminate NIPPV failure (AUC=0.794) with the following results: respiratory rate >40 at 4 hours [aOR=6.3 9(95% CI: 2.4, 16.4), p<0.001] and vasoactive use [aOR=4.9 (95% CI: 1.9, 13.1), p=0.001]. Of note, 11 patients had a cardiac arrest during intubation (11%) and 3 others arrested prior to intubation. These 14 patients were closer to HCT [14 days (IQR:4, 73) vs 54 (IQR:21,117), p<0.01] and there was a trend toward beginning NIPPV outside of the PICU and arrest during/prior to intubation (p=0.056).

Conclusions

In this cohort respiratory rate at 4 hours and vasoactive use are independent risk factors of NIPPV failure. An objective model to predict which children may benefit from a trial of NIPPV, may also inform the timing of both NIPPV initiation and uncomplicated intubation.
Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model
Authors: Yang Liu , Zhang Houyu , Yang Xue , Lu Ting , Ma Shihui , Cheng Hui , Yen Kuangyu , Cheng Tao
Published: May 2021

Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML.
Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)
Authors: Yang Shaojie , Pang Liwei , Dai Wanlin , Wu Shuodong , Ren Tengqi , Duan Yunlong , Zheng Yuting , Bi Shiyuan , Zhang Xiaolin , Kong Jing
Published: May 2021

Hepatocellular carcinoma (HCC), the most common type of malignant tumor of the digestive system, is associated with high morbidity and mortality. The main treatment for HCC is surgical resection. Advanced disease, recurrence, and metastasis are the main factors affecting prognosis. Chemotherapy and radiotherapy are not sufficiently efficacious for the treatment of primary and metastatic HCC; therefore, optimizing targeted therapy is essential for improving outcomes. Forkhead box O (FOXO) proteins are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals, thereby inducing the specific expression of downstream signal factors and regulation of the cell cycle, senescence, apoptosis, oxidative stress, HCC development, and chemotherapy sensitivity. Accordingly, FOXO proteins are considered multifunctional targets of cancer treatment. The current review discusses the roles of FOXO proteins, particularly FOXO1, FOXO3, FOXO4, and FOXO6, in HCC and establishes a theoretical basis for the potential targeted therapy of HCC.
IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment
Authors: Clark Amanda M. , Heusey Haley L. , Griffith Linda G. , Lauffenburger Douglas. A. , Wells Alan
Published: May 2021

Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.
Additive Value of Preoperative Sarcopenia and Lymphopenia for Prognosis Prediction in Localized Pancreatic Ductal Adenocarcinoma
Authors: d’Engremont Christelle , Grillot Julienne , Raillat Julie , Vernerey Dewi , Vuitton Lucine , Koch Stéphane , Turco Célia , Heyd Bruno , Mouillet Guillaume , Jacquinot Quentin , Borg Christophe , Vienot Angélique
Published: May 2021

Background

Surgical resection with adjuvant chemotherapy is the only treatment that can provide long term survival in localized pancreatic ductal adenocarcinoma (LPDAC). Notwithstanding, recurrence occurs in the vast majority of patients and a better stratification of preoperative therapies is required. This study aimed to investigate preoperative immunological and nutritional factors to predict relapse-free survival (RFS) in patients with LPDAC.

Methods

Analyses were derived from all consecutive LPDAC patients treated with surgical resection at Besancon University Hospital, France, between January 2006 and December 2014 (n=146). Biological and nutritional parameters were recorded before and after surgery. The association of 24 baseline parameters with RFS was evaluated using univariate and multivariate Cox analyses. Based on the final model, a prognostic score was developed.

Results

Lymphocyte count and body composition were available for 94 patients. In multivariate analysis, preoperative lymphopenia and sarcopenia (or a low muscle mass) were identified as independent prognostic factors for RFS. The score determined three groups with a median RFS of 5.6 months (95% confidence interval [CI] = 4.3 to 9.6 months) for high-risk group, corresponding to patients with lymphopenia; 11.5 months (95%CI = 9.8 to 13.9 months), and 21.2 months (95%CI = 9.9 to 55.3 months), for intermediate-(patient with sarcopenia without lymphopenia), and low-risk groups (no risk factor), respectively (p <0.001). Preoperative sarcopenia predicts the occurrence of postoperative lymphopenia in patients with a preoperative lymphocyte count above 1,000/mm3 (p = 0.0029).

Conclusions

Preoperative lymphopenia and sarcopenia are pejorative prognostic factors in LPDAC and should be considered in the preoperative evaluation to stratify death risk in patients with LPDAC.
Rearrangements of Blood and Tissue Fatty Acid Profile in Colorectal Cancer - Molecular Mechanism and Diagnostic Potential
Authors: Mika Adriana , Duzowska Katarzyna , Halinski Lukasz P. , Pakiet Alicja , Czumaj Aleksandra , Rostkowska Olga , Dobrzycka Malgorzata , Kobiela Jaroslaw , Sledzinski Tomasz
Published: May 2021

Colorectal cancer (CRC) is often diagnosed at an advanced stage due to the invasiveness of colonoscopy; thus, non-invasive CRC diagnostics are desirable. CRC is associated with lipid alterations. We aimed to verify whether fatty acid (FA) profiles in CRC patients may serve as a potential diagnostic tool for CRC diagnosis. FA profiles were assayed by GC-MS in cancer tissue, paired normal mucosa and serum from CRC patients and healthy controls. The levels of very long FAs – VLCFAs (26:0, 28:0 and 26:1) were the most highly increased FAs in cancer tissue compared to normal colon mucosa. Moreover, these FA were present in serum of CRC patients, they were absent in the serum of healthy subjects, or present in only trace amounts. To verify if cancer cells are the source of small amounts of these VLCFAs in the serum of patients we performed experiment in HT-29 CRC cells, which proved that CRC cells can produce and release VLCFAs into the blood. Most importantly, we defined a panel of FAs that may be assayed in a single analysis that definitely distinguishes CRC patients and healthy subjects, which was confirmed by PLS-DA and multivariate ROC analysis (AUC = 0.985). This study shows that selected FA panel may serve as a diagnostic marker for CRC.
Erratum: Palma-Bautista et al. Resistance Mechanisms to 2,4-D in Six Different Dicotyledonous Weeds Around the World. Agronomy 2020, 10, 566
Authors: Palma-Bautista Candelario , Rojano-Delgado Antonia M. , Dellaferrera Ignacio , Rosario Jesús M. , Vigna Mario R. , Torra Joel , de Prado Rafael
Published: May 2021

The authors would like to make the following correction to the published paper [...]