bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteplase for the treatment of acute ischaemic stroke: a single technology appraisal
Authors: Lloyd Jones M , Holmes M
Published: February 2021

This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of alteplase for the treatment of acute ischaemic stroke, in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included several randomised controlled trials indicating that, in highly selected patients, alteplase administered at a licensed dose within 3 hours of the onset of acute ischaemic stroke is associated with a statistically significant reduction in the risk of death or dependency at 3 months compared with placebo, despite a significantly increased risk of symptomatic intracranial haemorrhage within the first 7–10 days. Data from the National Institute of Neurological Disorders and Stroke (NINDS) trial suggest that the benefit of treatment is sustained at 6 and 12 months. However, data from observational studies suggest that few patients with acute ischaemic stroke will be eligible for alteplase therapy under the terms of the current licensing agreement. In particular, many patients will be excluded by virtue of their age, and many more by the restriction of therapy to patients in whom treatment can be initiated within 3 hours of symptom onset. The manufacturer’s submission included a state transition model evaluating the impact of treatment with alteplase within 3 hours of onset of stroke symptoms compared to standard treatment reporting that, in the base-case analysis, alteplase was both less costly and more effective than standard treatment. This increased to a maximum of approximately £4000 upon one-way sensitivity analysis of the parameters. The probabilistic sensitivity analysis presented within the submission suggests that the probability that alteplase has a cost-effectiveness ratio greater than £20,000 per quality-adjusted life-year (QALY) gained is close to 1 (0.99). The results of the short-term model demonstrate that alteplase is cost-effective over a 12-month period, with an incremental cost-effectiveness ratio of £14,026 per QALY gained. This increased to a maximum of £50,000 upon one-way sensitivity analysis of the parameters. At 12 months, the probabilistic sensitivity analysis presented within the submission suggests that the probability that alteplase has a cost-effectiveness ratio greater than £20,000 per QALY gained is approximately 0.7. The guidance issued by NICE in April 2007 as a result of the STA states that alteplase is recommended for the treatment of acute ischaemic stroke only when used by physicians trained and experienced in the management of acute stroke and in centres with the required facilities.
Infliximab for the treatment of acute exacerbations of ulcerative colitis
Authors: Bryan S , Andronis L , Hyde C , Connock M , Fry-Smith A , Wang D
Published: February 2021

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of infliximab for the treatment of acute exacerbations of ulcerative colitis, in accordance with the licensed indication, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included four randomised controlled trials (RCTs), two comparing infliximab with placebo in patients not responsive to initial treatment with intravenous corticosteroids and one comparing ciclosporin with placebo. A fourth RCT compared ciclosporin with intravenous corticosteroids as the initial treatment after hospitalisation. The manufacturer’s submission concluded that infliximab provides clinical benefit to patients with acute severe, steroid-refractory ulcerative colitis and is well tolerated; it also provides additional clinical benefits over ciclosporin, particularly avoidance of colectomy. A decision tree model was built to compare infliximab with strategies involving ciclosporin, standard care and surgery. After correcting a small number of errors in the model, the revised base-case incremental cost-effectiveness ratio (ICER) for infliximab compared with standard care was £20,000. However, sensitivity analyses revealed considerable uncertainty emanating from the weight of the patient, the timeframe considered and, most importantly, the colectomy rates used. When a more appropriate mix of trials were included in the estimation of colectomy rates, the ICER for infliximab rose to £48,000. The guidance issued by NICE on 31 October 2008 states that infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient; for people who do not meet this criterion, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials.
Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer
Authors: Brown T , Boland A , Bagust A , Oyee J , Hockenhull J , Dundar Y , Dickson R , Ramani VS , Proudlove C
Published: February 2021

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in accordance with the licensed indication, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence consisted of the IRESSA Pan-ASian Study (IPASS); a phase III open-label randomised controlled trial conducted in 87 centres in East Asia which compared the use of gefitinib with paclitaxel/carboplatin in 1217 chemotherapy (CTX)-naive patients with stage IIIB/IV pulmonary adenocarcinoma. The manufacturer’s submission focused on a subgroup of patients in IPASS who were epidermal growth factor receptor (EGFR) gene mutation-positive (M+) (n = 261; 21% of the total IPASS population). The primary clinical outcome was progression-free survival (PFS). Secondary outcomes included overall survival, clinically relevant improvement in quality of life and adverse events (AEs). Cost-effectiveness was measured in terms of incremental cost per quality-adjusted life-year (QALY). In the overall population, PFS was significantly longer in patients treated with gefitinib than in those treated with paclitaxel/carboplatin (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85; p < 0.0001). The manufacturer reported an incremental cost-effectiveness ratio (ICER) of £20,744 per QALY gained for the target population. The probabilistic sensitivity analysis illustrated that for patients who are EGFR M+, gefitinib compared with doublet CTX was not likely to be cost-effective at what would usually be considered standard levels of willingness to pay for an additional QALY; the mean ICER for gefitinib EGFR M+ versus doublet CTX EGFR M+ was reported as £35,700 per QALY. Additional analysis by the ERG included amendments to the base-case analysis, including an alternative approach to projecting survival, inclusion of two important additional comparators, sensitivity to EGFR M+ prevalence, and AE costs and disutilities. The manufacturer’s submission provides clinical evidence to support the use of gefitinib in EGFR M+ patients with adenocarcinoma histology only. Before patients can be offered first-line treatment with gefitinib they must undergo EGFR mutation status testing which is currently not routinely available in the NHS. At the time of writing, the guidance document issued by NICE on 28 July 2010 states that ‘Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the manufacturer provides gefitinib at the fixed price agreed under the patient access scheme’.
MATHEMATICS EDUCATION: SOME ASPECTS CONNECTED TO ITS CONTENT
Authors: Bussotti Paolo
Published: February 2021

The literature concerning the various methods by means of which the teaching of mathematics can be developed is simply huge and is increasing more and more. Several aspects are dealt with: the use of new technologies, especially as far as new computer programs or web sources are concerned; new techniques to develop calculations; researches concerning the possible relations between the everyday life of the pupils/students and the mathematical concepts; the best way to frame a lesson (frontal lessons, interactive lessons, discussions), and so on. This literature covers the entire school-life of a young boy/girl: from the elementary school to the university.
PREDICTING A FAST-TRACK MARITIME CAREER: CHARACTERISTICS OF SUCCESSFUL OFFICERS DURING TEENAGE YEARS
Authors: Fernández González Manuel Joaquín , Semjonovs Dmitrijs , Narica Irma , Strautmane Diāna , Ozola Sandra
Published: February 2021

Fast-track maritime career is a topical question worldwide due to the shortage of seafarers in maritime industry. Assuming that the fast-track career officers’ relevant common characteristics in adolescence could predict future maritime career speed, the research questions of this research are: What were the common characteristics of fast-track career officers when they were 16-18? Were there any statistically significant differences between the fast-track career groups and the officers with a slower career at that age?
A questionnaire survey involving 175 maritime officers was conducted in Latvia in January – October 2016, regarding officers’ family context, school achievement, involvement in sports, and personality traits when they were 16-18.
Fast-track career officers perceived themselves as more conscientious, calm and more leadership oriented than the whole group in adolescence. Statistically significant differences among career-speed groups were found regarding family socioeconomic status, family atmosphere and family career support at that age.
Based on those communalities among maritime officers with a fast-track carrier when they were 16-18, maritime education and training institutions could better find and give appropriate career guidance to prospective maritime officers. Even if maritime career speed is a very individualized phenomenon, family characteristics could be studied further as a potential good predictor of fast-track maritime career.
Keywords: career success predictors, fast-track career, maritime career, maritime officers.
Crucial role of hematopoietic JAK2 V617F in the development of aortic aneurysms
Authors: Yokokawa Tetsuro , Misaka Tomofumi , Kimishima Yusuke , Wada Kento , Minakawa Keiji , Sugimoto Koichi , Ishida Takafumi , Morishita Soji , Komatsu Norio , Ikeda Kazuhiko , Takeishi Yasuchika
Published: February 2021

JAK2V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPNs) and is associated with vascular complications. However, the impact of hematopoietic JAK2V617F on the aortic aneurysms (AAs) remains unknown. Our cross-sectional study indicated that 9 (23%) out of 39 MPN patients with JAK2V617F exhibited the presence of AAs. Next, to clarify whether the hematopoietic JAK2V617F contributes to the AAs, we applied a bone marrow transplantation (BMT) with the donor cells from Jak2V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2V617F in the abdominal aorta was confirmed by use of reporter GFP-transgene. BM-derived macrophages carrying JAK2V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AAs in MPNs with JAK2V617F.
Economic aspects of efficient milk production in Ukraine
Authors: Svynous I. , Mykytyuk D. , Semysal A.
Published: February 2021

The article considers the issues of increasing the efficiency of dairy production in agricultural enterprises and households. The main stages and their features in dairy farming development of the country and their impact on the efficiency of milk production in agricultural enterprises and households were highlighted. The reasons which cause decrease of cow livestock in both agricultural enterprises and households were identified. The inhibitory factors in the development of dairy cattle breeding were identified and the directions of its revival were outlined.
It was substantiated that considering the current state and trends of dairy farming in Ukraine, its efficiency, government support measures should be aimed at increasing production mainly in farms of the corporate sector of the agricultural economy, which in the nearest future will become major producers of raw milk.
It was determined that without the introduction of an effective system of government support for milk producers, which firstly will include the restoration of the special VAT regime, financing of dairy breeding revival at the state and regional level, it is impossible to have positive changes in increasing cows amount and increasing production efficiency, in addition the population of cows will continue to fall in the households.
It is proved that today the system of breeding service, which was previously in Ukraine and allowed to conduct breeding at the appropriate level, is destroyed and does not work. It was concluded that further productivity growth and reproduction of animal’s livestock is extremely problematic due to the lack of a modern selection system in animal husbandry.
It was established that the current level of profitability allows to ensure only simple reproduction in independent agricultural enterprises, mostly small and medium.It is true that in this situation, most farms in the corporate sector of the agricultural economy are trying to become part of vertically integrated structures of preserving and expanding their production activities on a qualitatively new material and technical base in the future.It was proved that the innovative type of dairy cattle breeding development will ensure the profitability of production and, accordingly, the growth of the income level of rural residents who are the employees of an agricultural enterprise.
Measures of state and regional support of milk production in Ukraine were offered.
Key words: dairy cattle breeding, agricultural enterprises, households, government support, milk processing plant.
Experience of healthcare workers in combatting COVID-19 in Indonesia: A descriptive qualitative study
Authors: Tosepu Ramadhan , Gunawan Joko , Effendy Devi Savitri , Rustam HN Muhammad , Muchtar Febriana , Sakka Ambo , Indriastuti Diah
Published: February 2021

Background: The number of COVID-19 cases in Indonesia continues to rise. The roles and responsibilities of healthcare workers are crucial in the battle of the COVID-19.

Objective: This study aimed to explore the experience of healthcare workers in combatting COVID-19 in some parts of Indonesia.

Methods: This study employed a descriptive qualitative study design. Online semi-structured interviews were conducted in April 2020 among thirteen participants who were purposively selected. Data were analyzed using thematic analysis.

Results: Eight themes emerged from data, including lack of personal protective equipment, lack of referral hospitals and limited facilities, dealing with patients with unknown status, feeling worried about getting infected or being a source of viral transmission, being creative, too long shift and fatigue, being surrender to God, and government issues.

Conclusion: Findings of this study could be used as the input for the government, healthcare workers, and the general population in combatting COVID-19.
Activation of adenosine A3 receptors potentiates stimulatory effects of IL-3, SCF, and GM-CSF on mouse granulocyte-macrophage hematopoietic progenitor cells
Authors: Hofer M , Vacek A , Pospíšil M , Holá J , Štreitová D , Znojil V
Published: February 2021

Adenosine A3 receptor agonist N6-(3-iodobenzyl)adenosine-5’-Nmethyluronamide (IB-MECA) has been tested from the point of view of potentiating the effects of hematopoietic growth factors interleukin-3 (IL-3), stem cell factor (SCF), granulocytemacrophage colony-stimulating factor (GM-CSF), and granulocyte
colony-stimulating factor (G-CSF) on the growth of hematopoietic
progenitor cells for granulocytes and macrophages (GM-CFC) in
suspension of normal mouse bone marrow cells in vitro. IB-MECA
alone induced no GM-CFC growth. Significant elevation of
numbers of GM-CFC evoked by the combinations of IB-MECA with
IL-3, SCF, or GM-CSF as compared with these growth factors
alone has been noted. Combination of IB-MECA with G-CSF did
not induce significantly higher numbers of GM-CFC in comparison
with G-CSF alone. Joint action of three drugs, namely of IB-MECA
+ IL-3 + GM-CSF, produced significantly higher numbers of
GM-CFC in comparison with the combinations of IB-MECA + IL-3,
IB-MECA + GM-CSF, or IL-3 + GM-CSF. These results give
evidence of a significant role of selective activation of adenosine
A3 receptors in stimulation of the growth of granulocyte/
macrophage hematopoietic progenitor cells.
Natriuretic peptides – physiology, pathophysiology and clinical use in heart failure
Authors: Krupička J , Janota T , Kasalová Z , Hradec J
Published: February 2021

The natriuretic peptides – atrial, brain and C-type – were
discovered during the last twenty years. Their effects on
cardiovascular, renal, cerebral and other tissues through guanylyl
cyclase were uncovered. Over the past decade natriuretic
peptides (NPs) became a very useful tool in the management of
heart failure patients. Results of many clinical trials have shown
that BNP and NT-proBNP are helpful for diagnosis of heart
failure. They are also independent markers of prognosis not only
in heart failure patients but also in patients with other
cardiovascular diseases. Recently published data document the
utility of NPs in guiding treatment of heart failure patients. In this
article, we focus on basic biochemical and physiological
characteristics of NPs as well as on their significance in
management of heart failure patients. Some limitations and
pitfalls of NPs levels interpretation in diagnosing heart failure are
also discussed.
Parvalbumin and TRPV1 receptor expression in dorsal root ganglion neurons after acute peripheral inflammation
Authors: Zachařová G , Paleček J
Published: February 2021

Expression of parvalbumin (PV) and transient receptor potential
vanilloid (TRPV1) receptors in the lumbar dorsal root ganglion
neurons (DRG) was evaluated in control animals and in rats after
acute carageenan-induced knee joint inflammation. PV is a
calcium binding protein that acts as a calcium buffer, affects
intracellular calcium homeostasis and may thus influence signal
transduction and synaptic transmission. TRPV1 receptors are
viewed as molecular integrators of nociceptive stimuli and
modulate spinal cord synaptic transmission beside their function
in the peripheral nerve endings. In naive rats, 13 % of the L4
DRG neurons had PV immunopositivity (PV+) and 36 %
expressed TRPV1 receptors (TRPV1+). The soma of the PV+
neurons was of medium to large size, while the TRPV1 receptors
were expressed in small diameter neurons. The co-localization of
the PV and TRPV1 immunoreactivity was minimal (0.2 %). There
was no significant change in the PV+ (11 %), TRPV1+ (42 %)
and PV+TRPV1+ (0.25 %) expression, or shift in the neuronal
size distribution 28 h after the unilateral peripheral inflammation,
both when compared to controls and when ipsilateral to
contralateral sides were evaluated. Thus under the given
experimental conditions, no change in somatic TRPV1 receptors
and PV expression in L4 DRG neurons was found.
El modelo sistémico de aprendizaje y enseñanza, como apoyo en la inserción laboral
Authors: Corcino-Barrueta Fernando E. , Chamoli-Falcon Andy W. , Otalora-Martinez Claudia R. , Melgarejo-Figueroa Maria Del Pilar
Published: February 2021

La investigación tuvo como objetivo principal buscar cómo influye el proceso sistémico con el enfoque de enseñanza y aprendizaje, en la inclusión laboral de los egresados de la Facultad de Derecho de la Universidad Nacional Hermilio Valdizán. Para lograrlo, se desarrolló el estudio en base a tipo descriptivo explicativo, bajo un diseño no experimental, correlacional  y de tipo transversal, para lo cual se trabajó con una población de 121 egresados y la muestra estuvo constituida por 37 egresados de los años 2016 y 2017, siendo del tipo no probabilístico, los cuales se construyeron dos cuestionarios, un cuestionario para medir la variable proceso sistemático de enseñanza-aprendizaje, otro cuestionario para medir la variable oportunidad de inserción laboral, todo ello para calificar el nivel de influencia. Para evaluar la hipótesis se aplicó la prueba Ro de Sperman. A raíz de ello nuestros resultados confirmaron la hipótesis de estudio, demostrando que el proceso sistémico de enseñanza-aprendizaje muestra una relación significativa con la inserción laboral y que existe influencia positiva entre ambas variables. Llegando a la conclusión que ejercer un proceso sistémico en la enseñanza y aprendizaje genera oportunidad en la inclusión laboral.
La litografía: elemento manipulador propicio para la compraventa mercantil del siglo XIX del Perú
Authors: Delgado Del Aguila Jesús M.
Published: February 2021

Este artículo se enfoca en el análisis social acerca de las conciencias consumidoras del país durante el periodo finisecular del siglo XIX. Se toma como referencia la revista El Perú Ilustrado (1887-1892), dirigida por Bacigalupi y Matto de Turner, para demostrar la funcionalidad de la prensa al promocionar y reorientar la cultura hacia un enfoque materialista. Por un lado, mediante la semiótica tensiva que desarrolla Jacques Fontanille, se originan significaciones relevantes desde los campos de la expresión y el contenido, imprescindibles de indagar para comprender la finalidad de las imágenes publicitarias. Asimismo, a través de los regímenes de sentido de Landowski (manipulación y programación), se evidencia cómo se instaura una moda en los consumidores por su pretensión de adquirir los productos que se someten a la compraventa del mercado.
Розвиток законодавства України про кримінальні правопорушення у сфері господарської діяльності: проблеми і тенденції
Authors: Дудоров O.O. , Мовчан P.O.
Published: February 2021

Статтю присвячено з’ясуванню тенденцій розвитку законодавства України про відповідальніст ь за господарські кримінальні правопорушення протягом останніх п՚яти років. Указані тенденції визначаються за результатами аналізу законодавчих новел, пов’язаних із криміналізацією контрабанди деревини, легалізацією грального бізнесу і зменшенням тиску на бізнес.Установлено, що законодавець, як і раніше, безпідставно надає перевагу спеціальним (казуїстичним) кримінально-правовим заборонам, а також гіперболізує роль репресивного впливу цих заборон як фактору, що погіршує бізнес-клімат і заважає нормальному розвитку економічних відносин.
The sources of forensic recommendations for collection, examination and use of evidence in criminal proceedings
Authors: Коваленко А.В.
Published: February 2021

The article is devoted to identifying the main sources of forensic recommendations for the collection, examination and use of evidence in criminal proceedings. The author emphasizes that the relevance, sufficiency, practicality and methodological literacy of these recommendations should be ensured by the use of appropriate scientifically sound sources for their formation. The sources of formation of such recommendations are: the most relevant provisions of forensic science; provisions of the legislation of Ukraine on criminal liability and provisions of the science of criminal law; provisions of the criminal procedural legislation of Ukraine and achievements of science of criminal procedure; legal positions formulated by the European Court of Human Rights; the practice of detection, investigation and trial of criminal offenses; scientific provisions of other (non-legal) sciences, which are integrated by forensic science and implemented in law enforcement practice.
Проблеми адміністративної відповідальності за порушення правил щодо карантину людей
Authors: Мотиль В. І. , Дякін Я. О.
Published: February 2021

У статті досліджуються актуальні проблеми адміністративної відповідальності за порушення правил карантину людей, пов’язані насамперед з бланкетною диспозицією ст. 44-3 КУпАП, спільними рисами форм об’єктивної сторони адміністративного правопорушення, передбаченого ст. 44-3 КУпАП, та злочину, передбаченого ст. 325 КК України, а також обмеженням гарантованих Конституцією прав та свобод людини й громадянина через запровадження на території України окремих правил карантину у зв՚язку зі стрімким поширенням гострої респіраторної хвороби COVID-19, спричиненої коронавірусом SARS-CoV-2. Розроблено пропозиції щодо вирішення зазначених проблем, зокрема шляхом диференціації адміністративної відповідальності за вказані діяння, створення чіткого переліку нормативно-правових актів порушення яких може мати наслідком притягнення до адміністративної відповідальності за певні діяння, а також запровадження відповідних заборон у суворій згідності з Конституцією України, зокрема після введення надзвичайного стану або внесення відповідних змін до Основного закону української держави.
Which Are the Main Surface Disinfection Approaches at the Time of SARS-CoV-2?
Authors: Ghedini Elena , Pizzolato Marco , Longo Lilia , Menegazzo Federica , Zanardo Danny , Signoretto Michela
Published: February 2021

Among many guidelines issued by the World Health Organization to prevent contagion from novel coronavirus (SARS-CoV-2), disinfection of animate and inanimate surfaces has emerged as a key issue. One effective approach to prevent its propagation can be achieved by disinfecting air, skin, or surfaces. A thorough and rational application of an Environmental Protection Agent for disinfection of surfaces, as well as a good personal hygiene, including cleaning hands with appropriate products (e.g., 60–90% alcohol-based product) should minimize transmission of viral respiratory pathogens such as SARS-CoV-2. Critical issues, associated with the potential health hazard of chemical disinfectants and the ineffective duration of most of the treatments, have fostered the introduction of innovative and alternative disinfection approaches. The present review aims to provide an outline of methods currently used for inanimate surface disinfection with a look to the future and a focus on the development of innovative and effective disinfection approaches (e.g., metal nanoparticles, photocatalysis, self-cleaning, and self-disinfection) with particular focus on SARS-CoV-2. The research reviews are, usually, focused on a specific category of disinfection methods, and therefore they are limited. On the contrary, a panoramic review with a wider focus, as the one here proposed, can be an added value for operators in the sector and generally for the scientific community.
Monitoring Systems for Checking Websites on Accessibility
Authors: Burkard Andreas , Zimmermann Gottfried , Schwarzer Bettina
Published: February 2021

Web accessibility monitoring systems support users in checking entire websites for accessibility issues. Although these tools can only check the compliance with some of the many success criteria of the Web Content Accessibility Guidelines, they can assist quality assurance personnel, web administrators and web authors to discover hotspots of barriers and overlooked accessibility issues in a continuous manner. These tools should be effective in identifying accessibility issues. Furthermore, they should motivate users, as this promotes employee productivity and increases interest in accessibility in general. In a comparative study, we applied four commercial monitoring systems on two of the Stuttgart Media University’s websites. The tools are: 1) The Accessibility module of Siteimprove from Siteimprove, 2) Pope Tech from Pope Tech, 3) WorldSpace Comply (now called axe Monitor) from Deque, and 4) ARC Monitoring from The Paciello Group. The criteria catalogue consists of functional criteria that we gleaned from literature and user experience criteria based on the User Experience Questionnaire. Based on a focus group consisting of experts of Stuttgart Media University, we derived individual weights for the criteria. The functional evaluation criteria are: Coverage of the website and the guidelines, completeness, correctness, support in locating errors, support for manual checks, degree of implementing gamification patterns, support for various input and report formats, and methodological support for the Website Accessibility Conformance Evaluation Methodology 1.0 and for the German procurement law for public authorities Barrierefreie Informationstechnik-Verordnung 2.0. For determination of the user experience criteria, we conducted exploratory think-aloud user tests (n = 15) using a coaching approach. Every participant tested all tools for 15 min (within-subject design). The participants completed post-test questionnaires, including the User Experience Questionnaire. According to our results, Siteimprove turned out to be the best tool for our purposes.
Comprehensive Analysis of Tumor Microenvironment Identified Prognostic Immune-Related Gene Signature in Ovarian Cancer
Authors: Li Na , Li Biao , Zhan Xianquan
Published: February 2021

Background

Accumulating evidence demonstrated that tumor microenvironmental cells played important roles in predicting clinical outcomes and therapeutic efficacy. We aimed to develop a reliable immune-related gene signature for predicting the prognosis of ovarian cancer (OC).

Methods

Single sample gene-set enrichment analysis (ssGSEA) of immune gene-sets was used to quantify the relative abundance of immune cell infiltration and develop high- and low-abundance immune subtypes of 308 OC samples. The presence of infiltrating stromal/immune cells in OC tissues was calculated as an estimate score. We estimated the correlation coefficients among the immune subtype, clinicopathological feature, immune score, distribution of immune cells, and tumor mutation burden (TMB). The differentially expressed immune-related genes between high- and low-abundance immune subtypes were further used to construct a gene signature of a prognostic model in OC with lasso regression analysis.

Results

The ssGSEA analysis divided OC samples into high- and low-abundance immune subtypes based on the abundance of immune cell infiltration, which was significantly related to the estimate score and clinical characteristics. The distribution of immune cells was also significantly different between high- and low-abundance immune subtypes. The correlation analysis showed the close relationship between TMB and the estimate score. The differentially expressed immune-related genes between high- and low-abundance immune subtypes were enriched in multiple immune-related pathways. Some immune checkpoints (PDL1, PD1, and CTLA-4) were overexpressed in the high-abundance immune subtype. Furthermore, the five-immune-related-gene-signature prognostic model (CCL18, CXCL13, HLA-DOB, HLA-DPB2, and TNFRSF17)-based high-risk and low-risk groups were significantly related to OC overall survival.

Conclusion

Immune-related genes were the promising predictors of prognosis and survival, and the comprehensive landscape of tumor microenvironmental cells of OC has potential for therapeutic schedule monitoring.
m6A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma
Authors: Wang Hongbo , Zhao Xiangxuan , Lu Zaiming
Published: February 2021

N6-methyladenosine [m(6)A/m6A] methylation is one of the most common RNA modifications in eukaryotic cell mRNA and plays an important regulatory role in mRNA metabolism, splicing, translocation, stability, and translation. Previous studies have demonstrated that the m6A modification is highly associated with tumor cell proliferation, migration, and invasion. In the present study, five m6A regulatory factors have been revealed, namely heterogeneous nuclear ribonucleoprotein A2/B1(HNRNPA2B1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), Vir like m6A methyltransferase associated protein (KIAA1429/VIRMA), RNA binding motif protein 15 (RBM15) and methyltransferase like 3 (METTL3), which are closely related to the overall survival (OS) of patients with lung adenocarcinoma (LUAD). These five m6A regulatory factors exhibited potential prognostic value for the 1, 3, and 5-years survival outcomes of LUAD patients. Our findings revealed that several signaling pathways, such as cell cycle, DNA replication, RNA degradation, RNA polymerase, nucleotide excision repair and basal transcription factors, are activated in the high-risk group of LUAD patients.
CFH I62V as a Putative Genetic Marker for Posner-Schlossman Syndrome
Authors: Yang Ming Ming , Sun Hong Yan , Meng Ting , Qiu Shan Hu , Zeng Qi Qiao , Ng Tsz Kin , Jiang Li , Deng Ting Ming , Zeng Ai Neng , Wang Jun , Luo Xiao Ling
Published: February 2021

Objective: Posner-Schlossman syndrome (PSS), also known as glaucomatocyclitic crisis, is an ocular condition characterized by recurrent attacks of anterior uveitis and raised intraocular pressure. Previous studies by our team and others have identified the genetic association of complement pathway genes with uveitis and glaucoma. This study aimed to investigate the complement genes in PSS patients with the view of elucidating the genetic background of the disease.

Methods: A total of 331 subjects (56 PSS patients and 275 controls) were recruited for this study. We selected 27 variants in six complement pathway genes (SERPING1, C2, CFB, CFH, C3, and C5) and detected them using TaqMan single nucleotide polymorphism (SNP) Genotyping Assays. Univariate SNP association analysis, haplotype-based association analysis, gene-gene interaction analysis among complement genes, and genotype-phenotype correlation analysis were performed.

Results: Among the 27 variants of six complement pathway genes, the functional variant I62V (rs800292) at the CFH gene was found to be significantly associated with PSS; there was a significant increase in the frequency of A allele and AA homozygosity in PSS patients than in controls (P = 1.79 × 10−4; odds ratio (OR) 2.18, 95% CI: 1.44–3.29; P = 4.65 × 10−4; OR 3.66, 95% CI: 1.70–7.85, respectively). The additive effect of CFH-rs800292 and SERPING1-rs3824988 was identified with an OR of 12.50 (95% CI: 2.16–72.28). Genotype-phenotype analysis indicated that the rs800292 AA genotype was associated with a higher intraocular pressure and higher frequency of recurrence. Unlike a high proportion of human leukocyte antigen (HLA)-B27 positivity in anterior uveitis, only 3 in 56 (5.36%) PSS patients were HLA-B27 positive. In addition, one haplotype block (GC) in the SERPING1 gene showed a nominal association with PSS with an increased risk of 2.04 (P = 0.01; 95% CI: 1.18–3.53), but the P-value could not withstand the Bonferroni correction (Pcorr > 0.05).

Conclusion: This study revealed a genetic association of a CFH variant with PSS as well as its clinical parameters, implying that the alternative complement pathway might play an important role in the pathogenesis of PSS. Further studies to enrich the understanding of the genetic background of PSS and the role of the complement system in ocular inflammation are warranted.
Insights Into the Antiviral Pathways of the Silkworm Bombyx mori
Authors: Jiang Liang
Published: February 2021

The lepidopteran model silkworm, Bombyx mori, is an important economic insect. Viruses cause serious economic losses in sericulture; thus, the economic importance of these viruses heightens the need to understand the antiviral pathways of silkworm to develop antiviral strategies. Insect innate immunity pathways play a critical role in the outcome of infection. The RNA interference (RNAi), NF-kB-mediated, immune deficiency (Imd), and stimulator of interferon gene (STING) pathways, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway are the major antiviral defense mechanisms, and these have been shown to play important roles in the antiviral immunity of silkworms. In contrast, viruses can modulate the prophenol oxidase (PPO), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and the extracellular signal-regulated kinase (ERK) signaling pathways of the host to elevate their proliferation in silkworms. In this review, we present an overview of the current understanding of the main immune pathways in response to viruses and the signaling pathways modulated by viruses in silkworms. Elucidation of these pathways involved in the antiviral mechanism of silkworms furnishes a theoretical basis for the enhancement of virus resistance in economic insects, such as upregulating antiviral immune pathways through transgenic overexpression, RNAi of virus genes, and targeting these virus-modulated pathways by gene editing or inhibitors.
Phylogeographic Analysis Suggests a Recent Population Bottleneck in the Rare Red Sea Tridacna squamosina
Authors: Lim Kah Kheng , Rossbach Susann , Geraldi Nathan R. , Serrão Ester A. , Duarte Carlos M.
Published: February 2021

Giant clams are an important ecological component of coral reefs in the Red Sea, as they enhance the reef’s productivity and provide habitat that can increase diversity. Three species of giant clams, namely Tridacna maxima, T. squamosa, and T. squamosina have been described within the Red Sea. However, due to its scarcity, information about the distribution and ecology of T. squamosina in the Saudi Arabian Red Sea is still lacking. This study used DNA barcoding to confirm the identity of the rare T. squamosina in the Farasan Banks. Six mtCOI fragments (500 bp) of T. squamosina were successfully amplified using the SQUA-primers for the first time. We used our data along with 18 reference sequences (16S) from the online database to assess the genetic diversity and population structure of T. squamosina. Low genetic diversity among the T. squamosina populations inferred from the 16S sequences implies a recent bottleneck for this species, which is supported by their historically higher diversity based on the coalescent-based estimator. Given the small population abundance and limited genetic variation of T. squamosina, it may warrant immediate local protections such as biobanking and fertility preservation programs as well as effective integrated coastal zone management plans.
Climate and Human-Driven Variability of Summer Hypoxia on a Large River-Dominated Shelf as Revealed by a Hypoxia Index
Authors: Wang Kui , Cai Wei-Jun , Chen Jianfang , Kirchman David , Wang Bin , Fan Wei , Huang Daji
Published: February 2021

Coastal hypoxia has become common especially in large river dominated coastal ecosystems. To better quantify the severity of hypoxia and the contribution of hypoxia drivers, we applied principal component analysis (PCA) on observable properties from eight summer hypoxia events in the East China Sea and defined the first principal component as the hypoxia index (HI). Multiple linear regression showed that the HI significantly correlated with three direct hypoxia drivers including water column stratification, subsurface water residence time, and respiration rates, which accounted for 5.7, 55.3, and 34.5%, respectively, of the total variance of PCA derived HI. We further reconstructed the HI over the past 60 years using available long-term data of stratification, model-derived residence times and respiration rates. The results show that summer hypoxia has become more severe since the 1960s. ENSO and global warming may have exacerbated hypoxia by affecting the river discharge, resulting in freshening in the plume-impacted shelf area, while anthropogenic activities may have exacerbated hypoxia by elevating fluvial nutrient concentrations, resulting in higher respiration rates. In addition, warming of the bottom water from the Kuroshio Current accounts for an additional increasing rate for HI, which made hypoxia more severe by means of decreasing oxygen solubility. Overall, our results indicate that stratification, water residence and oxygen solubility resulting from climate change can explain about 80% while higher respiration resulting from higher nutrient inputs can explain about 20% of the variation in the severity of hypoxia during the past half century.
Predominance of Non-carbapenemase Producing Carbapenem-Resistant Enterobacterales in South Texas
Authors: Black Cody A. , So Wonhee , Dallas Steven S. , Gawrys Gerard , Benavides Raymond , Aguilar Samantha , Chen Chang-Jui , Shurko James F. , Lee Grace C.
Published: February 2021

Background

Carbapenem-resistant Enterobacterales (CRE) pose a significant global public health threat. Resistance among CRE is particularly complex, owing to numerous possible resistance mechanisms and broad definitions. We aimed to characterize the clinical and molecular profiles of CRE in the South Texas region.

Materials and methods

We compared the clinical, genotypic, and phenotypic profiles of carbapenemase producing Enterobacterales (CPE) with those of non-carbapenemase producers (NCPE) isolated from South Texas, United States between 2011 and 2019. Molecular characteristics and resistance mechanisms were analyzed using whole-genome sequences.

Results

The majority (59%) of the CRE isolates were NCPE while 41% of isolates harbored carbapenemases, predmonantly blaKPC-type. The most common CPE was Klebsiella pneumoniae while majority of Enterobacter cloacae and Escherichia coli were NCPE Among K. pneumoniae, the clonal group 307 has emerged as a predmoninant group and was associated with as many CRE infections as the previous common clonal group 258. Patients with NCPE compared to CPE infections were associated with higher antimicrobial exposure prior to culture collection (days of therapy, 795 vs. 242; p < 0.001) and emergency department visits within past 90 days (22% vs. 4%; p = 0.011). The all cause 30-day mortality was 21%.

Conclusions

This study highlights the diversity of resistance mechanisms underlying CRE in South Texas, with 59% not harboring a carbapenemase. Individuals with NCPE infections were more likely to have had prior antimicrobial therapy and emergency department visits compared to those with CPE. Identification and distinction of these mechanisms by rapid identification of species and carbapenemase would allow for optimal treatment and infection control efforts.
A Phenome-Wide Association Study of the Effects of Fusarium graminearum Transcription Factors on Fusarium Graminearum Virus 1 Infection
Authors: Yu Jisuk , Kim Kook-Hyung
Published: February 2021

The Fusarium graminearum virus 1 (FgV1) causes noticeable phenotypic changes such as reduced mycelial growth, increase pigmentation, and reduced pathogenicity in its host fungi,Fusarium graminearum. Previous study showed that the numerousF. graminearumgenes including regulatory factors were differentially expressed upon FgV1 infection, however, we have limited knowledge on the effect(s) of specific transcription factor (TF) during FgV1 infection in host fungus. Using gene-deletion mutant library of 657 putative TFs inF. graminearum, we transferred FgV1 by hyphal anastomosis to screen transcription factors that might be associated with viral replication or symptom induction. FgV1-infected TF deletion mutants were divided into three groups according to the mycelial growth phenotype compare to the FgV1-infected wild-type strain (WT-VI). The FgV1-infected TF deletion mutants in Group 1 exhibited slow or weak mycelial growth compare to that of WT-VI on complete medium at 5 dpi. In contrast, Group 3 consists of virus-infected TF deletion mutants showing faster mycelial growth and mild symptom compared to that of WT-VI. The hyphal growth of FgV1-infected TF deletion mutants in Group 2 was not significantly different from that of WT-VI. We speculated that differences of mycelial growth among the FgV1-infected TF deletion mutant groups might be related with the level of FgV1 RNA accumulations in infected host fungi. By conducting real-time quantitative reverse transcription polymerase chain reaction, we observed close association between FgV1 RNA accumulation and phenotypic differences of FgV1-infected TF deletion mutants in each group, i.e., increased and decreased dsRNA accumulation in Group 1 and Group 3, respectively. Taken together, our analysis provides an opportunity to identify host’s regulator(s) of FgV1-triggered signaling and antiviral responses and helps to understand complex regulatory networks between FgV1 andF. graminearuminteraction.
DWV Infection in vitro Using Honey Bee Pupal Tissue
Authors: Wu Yunfei , Yuan Xuye , Li Jing , Kadowaki Tatsuhiko
Published: February 2021

The deformed wing virus (DWV) has been best characterized among honey bee viruses; however, very little is known regarding the mechanisms of viral infection and replication due to the lack of immortalized honey bee cell lines. To solve this problem, we established an in vitro system using honey bee pupal tissue to reconstruct DWV binding and entry into the host cell, followed by translation of the RNA genome and polyprotein processing using RNA-dependent RNA polymerase (RdRP) as a marker. Using this system, the P-domain of the virion subunit VP1 was found to be essential for DWV infection, but not for binding and entry into the cell. DWV efficiently infected the head tissue derived from early but not late pupa, suggesting that undifferentiated cells are targeted for viral infection. Furthermore, we found that inhibitors of mammalian picornavirus 3C-protease, rupintrivir and quercetin suppressed RdRP synthesis, indicating that this in vitro system is also useful for screening a compound to control viral infection. Our in vitro system may help to understand the mechanism of DWV infection in host cells.