Genotype-Guided Hydralazine Therapy

Background: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. Summary: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension

Using ecological and field survey data to establish a national list of the wild bee pollinators of crops

The importance of wild bees for crop pollination is well established, but less is known about which species contribute to service delivery to inform agricultural management, monitoring and conservation. Using sites in Great Britain as a case study, we use a novel qualitative approach combining ecological information and field survey data to establish a national list of crop pollinating bees for four economically important crops (apple, field bean, oilseed rape and strawberry). A traits data base was used to establish potential pollinators, and combined with field data to identify both dominant crop flower visiting bee species and other species that could be important crop pollinators, but which are not presently sampled in large numbers on crops flowers. Whilst we found evidence that a small number of common, generalist species make a disproportionate contribution to flower visits, many more species were identified as potential pollinators, including rare and specialist species. Furthermore, we found evidence of substantial variation in the bee communities of different crops. Establishing a national list of crop pollinators is important for practitioners and policy makers, allowing targeted management approaches for improved ecosystem services, conservation and species monitoring. Data can be used to make recommendations about how pollinator diversity could be promoted in agricultural landscapes. Our results suggest agri-environment schemes need to support a higher diversity of species than at present, notably of solitary bees. Management would also benefit from targeting specific species to enhance crop pollination services to particular crops. Whilst our study is focused upon Great Britain, our methodology can easily be applied to other countries, crops and groups of pollinating insects.LH was funded by NERC QMEE CDT. EJB was funded by a BBSRC Ph.D. studentship under grant BB/F016581/1. LB was was supported by the Scholarship Program of the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt, DBU, AZ 20014/302). AJC was funded by the BBSRC and Syngenta UK as part of a case award Ph.D. (grant no. 1518739). AE was funded by the Swiss National Science Foundation (grant number 405940-115642). DG and A-MK were funded by grant PCIN2014-145-C02-02 (MinECo; EcoFruit project BiodivERsA-FACCE2014-74). MG was supported by Establishing a UK Pollinator Monitoring and Research Partnership (PMRP) a collaborative project funded by Defra, the Welsh and Scottish Governments, JNCC and project partners’. GAdG was funded via research projects BO-11-011.01-051 and BO-43-011.06-007, commissioned by the Dutch Ministry of Agriculture, Nature and Food Quality. DK was funded by the Dutch Ministry of Economic Affairs (BO-11-011.01-011). AK-H was funded by the NKFIH project (FK123813), the Bolyai János Fellowship of the MTA, the ÚNKP-19-4-SZIE-3 New National Excellence Program of the Ministry for Innovation and Technology, and together with RF by the Hungarian Scientific Research Fund OTKA 101940. MM was funded by Waitrose & Partners, Fruition PO, and the University of Worcester. MM was funded by grant INIA-RTA2013-00139-C03-01 (MinECo and FEDER). BBP and RFS were funded by the UK Natural Environment Research Council as part of Wessex BESS (ref. NE/J014680/1). NJV was funded by the Walloon Region (Belgium) Direction générale opérationnelle de l’Agriculture, des Ressources naturelles et de l’Environnement (DGO3) for the "Modèle permaculturel" project on biodiversity in micro-farms, FNRS/FWO joint programme EOS — Excellence Of Science CliPS: Climate change and its impact on Pollination Services (project 30947854)". CW was funded by the Deutsche Forschungsgemeinschaft (DFG) (Project number 405945293). BW was funded by the Natural Environment Research Council (NERC) under research programme NE/N018125/1 ASSIST – Achieving Sustainable Agricultural Systems www.assist.ceh.ac.uk. TB and TO are supported by BBSRC, NERC, ESRC and the Scottish Government under the Global Food Security Programme (Grant BB/R00580X/1)

Internet of Things for Environmental Sustainability and Climate Change

Our world is vulnerable to climate change risks such as glacier retreat, rising temperatures, more variable and intense weather events (e.g., floods, droughts, and frosts), deteriorating mountain ecosystems, soil degradation, and increasing water scarcity. However, there are big gaps in our understanding of changes in regional climate and how these changes will impact human and natural systems, making it difficult to anticipate, plan, and adapt to the coming changes. The IoT paradigm in this area can enhance our understanding of regional climate by using technology solutions, while providing the dynamic climate elements based on integrated environmental sensing and communications that is necessary to support climate change impacts assessments in each of the related areas (e.g., environmental quality and monitoring, sustainable energy, agricultural systems, cultural preservation, and sustainable mining). In the IoT in Environmental Sustainability and Climate Change chapter, a framework for informed creation, interpretation and use of climate change projections and for continued innovations in climate and environmental science driven by key societal and economic stakeholders is presented. In addition, the IoT cyberinfrastructure to support the development of continued innovations in climate and environmental science is discussed

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

The effects of long-term total parenteral nutrition on gut mucosal immunity in children with short bowel syndrome: a systematic review

BACKGROUND: Short bowel syndrome (SBS) is defined as the malabsorptive state that often follows massive resection of the small intestine. Most cases originate in the newborn period and result from congenital anomalies. It is associated with a high morbidity, is potentially lethal and often requires months, sometimes years, in the hospital and home on total parenteral nutrition (TPN). Long-term survival without parenteral nutrition depends upon establishing enteral nutrition and the process of intestinal adaptation through which the remaining small bowel gradually increases its absorptive capacity. The purpose of this article is to perform a descriptive systematic review of the published articles on the effects of TPN on the intestinal immune system investigating whether long-term TPN induces bacterial translocation, decreases secretory immunoglobulin A (S-IgA), impairs intestinal immunity, and changes mucosal architecture in children with SBS. METHODS: The databases of OVID, such as MEDLINE and CINAHL, Cochran Library, and Evidence-Based Medicine were searched for articles published from 1990 to 2001. Search terms were total parenteral nutrition, children, bacterial translocation, small bowel syndrome, short gut syndrome, intestinal immunity, gut permeability, sepsis, hyperglycemia, immunonutrition, glutamine, enteral tube feeding, and systematic reviews. The goal was to include all clinical studies conducted in children directly addressing the effects of TPN on gut immunity. RESULTS: A total of 13 studies were identified. These 13 studies included a total of 414 infants and children between the ages approximately 4 months to 17 years old, and 16 healthy adults as controls; and they varied in design and were conducted in several disciplines. The results were integrated into common themes. Five themes were identified: 1) sepsis, 2) impaired immune functions: In vitro studies, 3) mortality, 4) villous atrophy, 5) duration of dependency on TPN after bowel resection. CONCLUSION: Based on this exhaustive literature review, there is no direct evidence suggesting that TPN promotes bacterial overgrowth, impairs neutrophil functions, inhibits blood's bactericidal effect, causes villous atrophy, or causes to death in human model. The hypothesis relating negative effects of TPN on gut immunity remains attractive, but unproven. Enteral nutrition is cheaper, but no safer than TPN. Based on the current evidence, TPN seems to be safe and a life saving solution

Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. // Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. // Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. // Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. // Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization. // Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). // Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed

Международный музыкальный конкурс в формировании имиджа страны проведения (на примере Евровидения 2017)

Аннотация выпускной квалификационной работы Орлов Никита Сергеевич «МЕЖДУНАРОДНЫЙ МУЗЫКАЛЬНЫЙ КОНКУРС В ФОРМИРОВАНИИ ИМИДЖА СТРАНЫ ПРОВЕДЕНИЯ (НА ПРИМЕРЕ ЕВРОВИДЕНИЯ-2017)» Н. рук. - Быкова Елена Владимировна, доктор филологических наук, доцент Кафедра связей с общественностью Очная форма обучения Актуальность: международный музыкальный конкурс Евровидение как самое масштабное регулярное высокотехнологичное телевизионное и медиа-событие, которое . Е ежегодно акцентирует внимание аудитории на национально-культурных особенностях страны-организатора конкурса, формирует значительные туристические потоки и тем самым способствует формированию имиджа территории. Более того, победа страны-участницы конкурса Евровидения зачастую отражает идеолого-политический вектор Европы и по сути дела выполняет функцию политического PR страны-победителя и страны-хозяйки мероприятия. Следовательно анализ используемых на мероприятии коммуникативных технологий является актуальным и востребованным для событийного и устроительного PR Объект исследования: коммуникационные активности международного музыкального конкурса (на примере Евровидения в Киеве в 2017 г.). Предмет исследования: функция статусного PR-мероприятия в формировании имиджа страны. Цель исследования: доказать, что международный музыкальный конкурс Евровидение способствует формированию имиджа страны проведения. Задачи исследования: разработать терминологический аппарат исследования на основе научной литературы по имиджмейкингу, брендингу и ивент-менеджменту; определить актуальные коммуникационные технологии, применяемые в рамках специальных событий для формирования имиджа страны; описать роль Европейского Вещательного Союза как организатора Евровидения в формировании имиджа страны проведения конкурса; оценить эффективность реализованных коммуникативных технологий формирования имиджа страны в рамках Евровидения; дать рекомендации по формированию имиджа страны с помощью Евровидения. Теоретическая база: научные труды Е. Быковой, Д. Гавры, А. Панкрухина, Б. Дженеса, Е. Кавериной, У. Хальцбаура, Дж. Голдблатта а также труды Д. Пассмана о музыкальном бизнесе, П. Джордана о продвижении имиджа стран с помощью Евровидения и др. Эмпирическая база: PR-документы, размещенные на сайте Евровидения и Европейского Вещательного Союза; более полутора миллиона статей об Украине в европейских СМИ, размещенные в базе проекта мониторинга международного имиджа Украины «Oko»; данные базы материалов СМИ и социальных медиа Factiva; данные Google.Analytics. Практическая значимость: исследование доказывает, что международный музыкальный конкурс Евровидение формирует имидж страны проведения независимо от успешности использования конкретных технологий формирования имиджа страны. Тезисы исследования были апробированы на международном научном форуме «Медиа в современном мире. 57-е Петербургские чтения», опубликованы в сборнике материалов статей форума и имеют статус научной статьи, размещенной в базе РИНЦ. Структура работы: Работа состоит из введения, 3 глав: «функция специального события в формировании имиджа страны», «Евровидение как специальное событие Европейского Вещательного Союза» и «коммуникационный потенциал Евровидения как площадки для формирования имиджа страны», заключения, списка использованной литературы из 67 позиций и 12 приложений. Общий объем 76 страниц.Abstract of graduating qualification thesis Mikita Arlou INTERNATIONAL MUSIC CONTEST IN HOST COUNTRY IMAGE FORMATION (ON THE EXAMPLE OF EUROVISION 2017) Supervisor associate professor Elena Bykova, doctor of philology Department of PR in business full-time study Relevance: the international music contest Eurovision as the most wide scale regular high tech TV and Media event which annually emphasizes audience attention on national cultural features of the host country, forms tourist flows which have huge influence on territorial image formation. Besides the win of a participating in the Eurovision country often shows the ideological and political European vector and in fact serves as political PR of the winning or host country. Consequently the analysis of applied communication technologies is relevant and in-demand for event PR. Research object: communication activities of international music contest (on the example of Eurovision in Kyiv in 2017). Research subject: function of status PR event in country image formation. The aim of research: to prove that international music contest Eurovision contributes host country image formation. The tasks of research: to develop research terminology based on scientific literature on image making, branding and event management; to define actual communication technologies applied in special PR events on country image formation; to describe European Broadcasting Union role in host country image formation; to appreciate effectiveness of applied communication technologies on host country image formation in Eurovision; to give recommendations for host country image formation with the help of Eurovision. Theoretical base: scientific works written by E. Bykova, D. Gavra, A. Pankrukhin, B. Jenes, E. Kaverina, U. Halcbaur, J. Goldblatt and D. Passman´s works on music business and P. Jordan on county image building with the help of Eurovision, etc. The empirical base: PR documents from official Eurovision and European Broadcasting Union websites; more than 1.5 million articles on Ukraine in European media stored in the base of international Ukrainian image monitoring project Oko; content of the mass media and social media base Factiva; Google.Analytics data. Practical significance: the research proves that international music contest Eurovision is relevant for the host country image formation independently of the success level of applied country image formation communication technologies. Approbation: General positions of current thesis were aprobated on international scientific forum Media in modern world and were published at the collection of articles of the forum and have the status of a scientific article posted in the RINC database. Thesis structure: Research consists of introduction, 3 chapters: Special event function in country image formation, Eurovision as EBU special event and communication potential of Eurovision as a platform for image formation; conclusion, literature list from 67 positions and 12 attachments. The total volume is 76 pages

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate