Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan

Introduction Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. Discussion The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.Peer reviewe

The Safety Attitudes Questionnaire: psychometric properties, benchmarking data, and emerging research

BACKGROUND: There is widespread interest in measuring healthcare provider attitudes about issues relevant to patient safety (often called safety climate or safety culture). Here we report the psychometric properties, establish benchmarking data, and discuss emerging areas of research with the University of Texas Safety Attitudes Questionnaire. METHODS: Six cross-sectional surveys of health care providers (n = 10,843) in 203 clinical areas (including critical care units, operating rooms, inpatient settings, and ambulatory clinics) in three countries (USA, UK, New Zealand). Multilevel factor analyses yielded results at the clinical area level and the respondent nested within clinical area level. We report scale reliability, floor/ceiling effects, item factor loadings, inter-factor correlations, and percentage of respondents who agree with each item and scale. RESULTS: A six factor model of provider attitudes fit to the data at both the clinical area and respondent nested within clinical area levels. The factors were: Teamwork Climate, Safety Climate, Perceptions of Management, Job Satisfaction, Working Conditions, and Stress Recognition. Scale reliability was 0.9. Provider attitudes varied greatly both within and among organizations. Results are presented to allow benchmarking among organizations and emerging research is discussed. CONCLUSION: The Safety Attitudes Questionnaire demonstrated good psychometric properties. Healthcare organizations can use the survey to measure caregiver attitudes about six patient safety-related domains, to compare themselves with other organizations, to prompt interventions to improve safety attitudes and to measure the effectiveness of these interventions

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care(1) or hospitalization(2-4) after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease. © 2022, The Author(s)

Worldwide clinical intensive care registries response to the pandemic : An international survey

Funding Information: Dr. Kumar is partially supported by Wellcome Trust grant (WT-215522) for his role as National Coordinator, IRIS. Funding Information: Dr. Martin Sigurdsson is supported by Landspitali Science Fund for COVID19 related projects. Funding Information: Drs. Salluh and Soares are supported in part by individual research grants from CNPq and FAPERJ.Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

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

Ethnic differences in SARS-CoV-2 infection and COVID-19-related hospitalisation, intensive care unit admission, and death in 17 million adults in England: an observational cohort study using the OpenSAFELY platform.

BACKGROUND: COVID-19 has disproportionately affected minority ethnic populations in the UK. Our aim was to quantify ethnic differences in SARS-CoV-2 infection and COVID-19 outcomes during the first and second waves of the COVID-19 pandemic in England. METHODS: We conducted an observational cohort study of adults (aged ≥18 years) registered with primary care practices in England for whom electronic health records were available through the OpenSAFELY platform, and who had at least 1 year of continuous registration at the start of each study period (Feb 1 to Aug 3, 2020 [wave 1], and Sept 1 to Dec 31, 2020 [wave 2]). Individual-level primary care data were linked to data from other sources on the outcomes of interest: SARS-CoV-2 testing and positive test results and COVID-19-related hospital admissions, intensive care unit (ICU) admissions, and death. The exposure was self-reported ethnicity as captured on the primary care record, grouped into five high-level census categories (White, South Asian, Black, other, and mixed) and 16 subcategories across these five categories, as well as an unknown ethnicity category. We used multivariable Cox regression to examine ethnic differences in the outcomes of interest. Models were adjusted for age, sex, deprivation, clinical factors and comorbidities, and household size, with stratification by geographical region. FINDINGS: Of 17 288 532 adults included in the study (excluding care home residents), 10 877 978 (62·9%) were White, 1 025 319 (5·9%) were South Asian, 340 912 (2·0%) were Black, 170 484 (1·0%) were of mixed ethnicity, 320 788 (1·9%) were of other ethnicity, and 4 553 051 (26·3%) were of unknown ethnicity. In wave 1, the likelihood of being tested for SARS-CoV-2 infection was slightly higher in the South Asian group (adjusted hazard ratio 1·08 [95% CI 1·07-1·09]), Black group (1·08 [1·06-1·09]), and mixed ethnicity group (1·04 [1·02-1·05]) and was decreased in the other ethnicity group (0·77 [0·76-0·78]) relative to the White group. The risk of testing positive for SARS-CoV-2 infection was higher in the South Asian group (1·99 [1·94-2·04]), Black group (1·69 [1·62-1·77]), mixed ethnicity group (1·49 [1·39-1·59]), and other ethnicity group (1·20 [1·14-1·28]). Compared with the White group, the four remaining high-level ethnic groups had an increased risk of COVID-19-related hospitalisation (South Asian group 1·48 [1·41-1·55], Black group 1·78 [1·67-1·90], mixed ethnicity group 1·63 [1·45-1·83], other ethnicity group 1·54 [1·41-1·69]), COVID-19-related ICU admission (2·18 [1·92-2·48], 3·12 [2·65-3·67], 2·96 [2·26-3·87], 3·18 [2·58-3·93]), and death (1·26 [1·15-1·37], 1·51 [1·31-1·71], 1·41 [1·11-1·81], 1·22 [1·00-1·48]). In wave 2, the risks of hospitalisation, ICU admission, and death relative to the White group were increased in the South Asian group but attenuated for the Black group compared with these risks in wave 1. Disaggregation into 16 ethnicity groups showed important heterogeneity within the five broader categories. INTERPRETATION: Some minority ethnic populations in England have excess risks of testing positive for SARS-CoV-2 and of adverse COVID-19 outcomes compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Causes are likely to be multifactorial, and delineating the exact mechanisms is crucial. Tackling ethnic inequalities will require action across many fronts, including reducing structural inequalities, addressing barriers to equitable care, and improving uptake of testing and vaccination. FUNDING: Medical Research Council

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707