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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Étude du protéome des cellules souches embryonnaires et des cellules germinales embryonnaires chez la souris à la recherche de nouveaux marqueurs de pluripotence

Les cellules souches (ES) et germinales embryonnaires (EG) sont les 2 principales sources de cellules pluripotentes connues chez les mammifères, et sont un modèle d étude intéressant pour une meilleure compréhension des mécanismes de la pluripotence. Leurs propriétés particulières en font des candidats attractifs pour leur utilisation en thérapie de remplacement cellulaire. Afin d étudier les voies de signalisation impliquées dans la pluripotence, une étude protéomique a été réalisée à partir des cellules ES et EG de souris. Une stratégie de soustraction des protéines contaminantes de l environnement de culture a été appliquée pour l étude du protéome spécifique de ces cellules. Cette approche a permis l identification de deux isoformes (acétylée et non-acétylée) d un marqueur de pluripotence connu, nommé DPPA5. Enfin, cette stratégie de soustraction couplée à un sous-fractionnement nucléaire a permis l identification de PRMT7, un nouveau marqueur potentiel de la pluripotence.Embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are the major pluripotent mammalian cells currently known and provide exciting models for understanding the underlying mechanisms that make a cell pluripotent. Furthermore, their particular properties make ESCs and EGCs very attractive candidates for cell replacement therapy. In order to investigate signaling pathways potentially involved in pluripotency, proteomic analyses have been performed on mouse ESC and EGC proteins. A subtractive strategy (subtracting culture environment contaminating proteins) was applied for the study of the specific proteome of these cells. This approach led to the identification of two isoforms (with and without N-terminal acetylation) of a known pluripotency marker, namely DPPA5. Furthermore, we demonstrated the efficiency of our subtracting strategy, in association with a nuclear subfractionation by the identification of a new protein (PRMT7) behaving as proteins involved in pluripotency.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Proteome analysis of the culture environment supporting undifferentiated mouse embryonic stem and germ cell growth.

The therapeutical interest of pluripotent cells and ethical issues related to the establishment of human embryonic stem cell (ESC) or embryonic germ cell (EGC) lines raise the understanding of the mechanism underlying pluripotency to a fundamental issue. Establishing a protein pluripotency signature for these cells can be complicated by the presence of unrelated proteins produced by the culture environment. Here, we have analyzed the environment supporting ESC and EGC growth, and established 2-D reference maps for each constituent present in this culture environment: mouse embryonic fibroblast feeder cells, culture medium (CM) and gelatin. The establishment of these reference maps is essential prior to the study of ESC and EGC specific proteomes. Indeed, these maps can be subtracted from ESC or EGC maps to allow focusing on spots specific for ESCs or EGCs. Our study led to the identification of 110 unique proteins from fibroblast feeder cells and 23 unique proteins from the CM, which represent major contaminants of ESC and EGC proteomes. For gelatin, no collagen-specific proteins were identified, most likely due to difficulties in resolution and low quantities. Furthermore, no differences were observed between naive and conditioned CM. Finally, we compared these reference maps to ESC 2-D gels and isolated 17 ESC specific spots. Among these spots, proteins that had already been identified in previous human and mouse ESC proteomes were identified but no apparent ESC-specific pluripotency marker could be identified. This work represents an essential step in furthering the knowledge of environmental factors supporting ESC and EGC growth

Nuclear proteome analysis of undifferentiated mouse embryonic stem and germ cells.

International audienceEmbryonic stem cells (ESCs) and embryonic germ cells (EGCs) provide exciting models for understanding the underlying mechanisms that make a cell pluripotent. Indeed, such understanding would enable dedifferentiation and reprogrammation of any cell type from a patient needing a cell therapy treatment. Proteome analysis has emerged as an important technology for deciphering these biological processes and thereby ESC and EGC proteomes are increasingly studied. Nevertheless, their nuclear proteomes have only been poorly investigated up to now. In order to investigate signaling pathways potentially involved in pluripotency, proteomic analyses have been performed on mouse ESC and EGC nuclear proteins. Nuclei from ESCs and EGCs at undifferentiated stage were purified by subcellular fractionation. After 2-D separation, a subtractive strategy (subtracting culture environment contaminating spots) was applied and a comparison of ESC, (8.5 day post co?m (dpc))-EGC and (11.5 dpc)-EGC specific nuclear proteomes was performed. A total of 33 ESC, 53 (8.5 dpc)-EGC, and 36 (11.5 dpc)-EGC spots were identified by MALDI-TOF-MS and/or nano-LC-MS/MS. This approach led to the identification of two isoforms (with and without N-terminal acetylation) of a known pluripotency marker, namely developmental pluripotency associated 5 (DPPA5), which has never been identified before in 2-D gel-MS studies of ESCs and EGCs. Furthermore, we demonstrated the efficiency of our subtracting strategy, in association with a nuclear subfractionation by the identification of a new protein (protein arginine N-methyltransferase 7; PRMT7) behaving as proteins involved in pluripotency

d-Alanylation of Lipoteichoic Acids in Streptococcus suis Reduces Association With Leukocytes in Porcine Blood

Streptococcus suis (S. suis) is a common swine pathogen but also poses a threat to human health in causing meningitis and severe cases of streptococcal toxic shock-like syndrome (STSLS). Therefore, it is crucial to understand how S. suis interacts with the host immune system during bacteremia. As S. suis has the ability to introduce d-alanine into its lipoteichoic acids (LTAs), we investigated the working hypothesis that cell wall modification by LTA d-alanylation influences the interaction of S. suis with porcine blood immune cells. We created an isogenic mutant of S. suis strain 10 by in-frame deletion of the d-alanine d-alanyl carrier ligase (DltA). d-alanylation of LTAs was associated with reduced phagocytosis of S. suis by porcine granulocytes, reduced deposition of complement factor C3 on the bacterial surface, increased hydrophobicity of streptococci, and increased resistance to cationic antimicrobial peptides (CAMPs). At the same time, survival of S. suis was not significantly increased by LTA d-alanylation in whole blood of conventional piglets with specific IgG. However, we found a distinct cytokine pattern as IL-1β but not tumor necrosis factor (TNF)-α levels were significantly reduced in blood infected with the ΔdltA mutant. In contrast to TNF-α, activation and secretion of IL-1β are inflammasome-dependent, suggesting a possible influence of LTA d-alanylation on inflammasome regulation. Especially in the absence of specific antibodies, the association of S. suis with porcine monocytes was reduced by d-alanylation of its LTAs. This dltA-dependent phenotype was also observed with a non-encapsulated dltA double mutant indicating that it is independent of capsular polysaccharides. High antibody levels caused high levels of S. suis—monocyte—association followed by inflammatory cell death and strong production of both IL-1β and TNF-α, while the influence of LTA d-alanylation of the streptococci became less visible. In summary, the results of this study expand previous findings on d-alanylation of LTAs in S. suis and suggest that this pathogen specifically modulates association with blood leukocytes through this modification of its surface

Initial Framework for Resilience Assessment

This report is targeting a framingof what SmartResilience actually wants to measure –“resilience”–,taking relevant research results and existing guidelinesand standardsinto account. This is especially challenging due to the vast variety of understandings, definitions, concepts, and applications of the term, including usages in different research areas or fields of application. In addition, for thereasonof this variety, a huge number of articlesand reportsdiscussing the term, its understandings and usages on a theoretical basis have been developed. Even several comprehensive reviews on the term, including qualitative and quantitative literature analyses as well as expert interviews, have already been conducted. SmartResilience starts with an initial concept of (critical infrastructure) resilience, which was already defined in the proposal phase of the project. Up-to-date comprehensive reviews on definitions and concepts of resilience, including critical infrastructure resilience, have been available from recent results prepared in the framework of projects that answer to the call topic EU H2020 DRS-07-2014 “Crises and disaster resilience –operationalizing resilience concepts”. The resulting reportshave been reviewed, identifying results that seem useful for the SmartResilience resilience definition and concept. Reviewing approaches and identifying aspects that seem useful for SmartResilience from selected additionalsources (international and US organisations, industry, standards) complemented the basis for framing the (still initial) SmartResilience resilience definition and concept. The initial definition has only slightly been changed, resulting in: Resilience of an infrastructure is the ability to understand risks, anticipate, prepare for, and adapt to changing conditions and withstand, respond to, and recover rapidly from disruption. However, the concept of resilience in a broader sense (including further framing questions such as resilience “of what” is in focus, what is the relation to vulnerability or risk management, how should the different levels and components of resilience be categorised) has been complemented, and slightly changed. Several aspects that were concluded based onthe reviews, are described in this report as issues to be considered and decided on when workingon the actual methodology (WP3), and/ or its application to specific SCI’s(WP2, WP5).This includes questions such asif a “transformative” character should be included as a main componentof resilience, or if “ability” and“capacity” should be distinguished, but also what to consider when identifyingrelevantissues for the resilience of specific SCI’s. Asfurther instrument forcreating and maintaining a common understanding, a first version of a glossary of terms that are relevant for SmartResilience has been developed, is online accessible,and will be continuously updated throughout the project

Scenarier för hållbart samhällsbyggande bortom BNP-tillväxt

QC 20210614Bortom BNP-tillväx

Preoperative calcitonin testing improves the diagnosis of medullary thyroid carcinoma in female and male patients

Weber T, Powlawski A, Vorlander C, et al. Preoperative calcitonin testing improves the diagnosis of medullary thyroid carcinoma in female and male patients. European Journal of Endocrinology. 2021: EJE-21-1015.R1.Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements.; METHODS: All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between 03/2017 and 09/2020 were included. Cutoff levels for Ctn were determined with ROC analyses to assess the preoperative diagnosis of MTC in subgroups for females and males.; FINDINGS: In 29.590 of 39.679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females, 130 males) histopathology confirmed MTC with a mean tumor size of 14.7 mm (± 12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/ml were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/ml. Cutoff levels for the diagnosis of MTC were 7.9 pg/ml for females and 15 pg/ml for males (p 7.9 pg/ml and males >15 pg/ml without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing, or ultrasound detects suspicious thyroid lesions