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

Motion assessment of the thoracic aorta for flow numerical modeling

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Auxiliary GABAB Receptor Subunits Uncouple G Protein βγ Subunits from Effector Channels to Induce Desensitization

SummaryActivation of K+ channels by the G protein βγ subunits is an important signaling mechanism of G-protein-coupled receptors. Typically, receptor-activated K+ currents desensitize in the sustained presence of agonists to avoid excessive effects on cellular activity. The auxiliary GABAB receptor subunit KCTD12 induces fast and pronounced desensitization of the K+ current response. Using proteomic and electrophysiological approaches, we now show that KCTD12-induced desensitization results from a dual interaction with the G protein: constitutive binding stabilizes the heterotrimeric G protein at the receptor, whereas dynamic binding to the receptor-activated Gβγ subunits induces desensitization by uncoupling Gβγ from the effector K+ channel. While receptor-free KCTD12 desensitizes K+ currents activated by other GPCRs in vitro, native KCTD12 is exclusively associated with GABAB receptors. Accordingly, genetic ablation of KCTD12 specifically alters GABAB responses in the brain. Our results show that GABAB receptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts Gβγ signaling

Correlation between unfavorable TEVAR evolution and morphological parameters

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Volume Analysis to Predict the Long-Term Evolution of Residual Aortic Dissection after Type A Repair

International audienceBackground: The aim of this study was to evaluate the aortic diameter and volume during the first year after a type A repair to predict the long-term prognosis of a residual aortic dissection (RAD). Methods: All patients treated in our center for an acute type A dissection with a RAD and follow-up > 3 years were included. We defined two groups: group 1 with dissection-related events (defined as an aneurysmal evolution, distal reintervention, or aortic-related death) and group 2 without dissection-related events. The aortic diameters and volume analysis were evaluated on three postoperative CT scans: pre-discharge (T1), 3–6 months (T2) and 1 year (T3). Results: Between 2009 and 2016, 54 patients were included. Following a mean follow-up of 75.4 months (SD 31.5), the rate of dissection-related events was 62.9% (34/54). The total aortic diameters of the descending thoracic aorta were greater in group 1 at T1, T2 and T3, with greater diameters in the FL (p < 0.01). The aortic diameter evolution at 3 months was not predictive of long-term dissection-related events. The total thoracic aortic volume was significantly greater in group 1 at T1 (p < 0.01), T2 (p < 0.01), and T3 (p < 0.01). At 3 months, the increase in the FL volume was significantly greater in group 1 (p < 0.01) and was predictive for long-term dissection-related events. Conclusion: This study shows that an initial CT scan volume analysis coupled with another at 3 months is predictive for the long-term evolution in a RAD. Based on this finding, more aggressive treatment could be given at an earlier stage

Results of a prospective follow-up study after type A aortic dissection repair: a high rate of distal aneurysmal evolution and reinterventions

International audienceOBJECTIVES We investigated the anatomical evolution of residual aortic dissection after type A repair and factors associated with poor prognosis at a high-volume aortic centre. METHODS Between 2017 and 2019, all type A aortic dissections were included for prospective follow-up. Patients without follow-up computed tomography (CT) scan available for radiological analysis and patients without residual aortic dissection were excluded from this study. The primary end point was a composite end point defined as dissection-related events including aneurysmal evolution (increased diameter &gt; 5 mm/year), aortic reintervention for malperfusion syndrome, aortic diameter &gt;55 mm, rapid aortic growth &gt;10 mm/year or aortic rupture and death. The secondary end points were risk factors for dissection-related events and reintervention analysis. All immediate and last postoperative CT scans were analysed. RESULTS Among 104 patients, after a mean follow-up of 20.4 months (8–41), the risk of dissection-related events was 46.1% (48/104) and the risk of distal reintervention was 17.3% (18/104). Marfan syndrome (P &lt; 0.01), aortic bicuspid valve (P = 0.038), innominate artery debranching (P = 0.025), short aortic cross-clamp time (P = 0.011), initial aortic diameter &gt;40 mm (P &lt; 0.01) and absence of resection of the primary entry tear (P = 0.015) were associated with an increased risk of dissection-related events or reintervention during follow-up. CONCLUSIONS Residual aortic dissection is a serious disease requiring close follow-up at an expert centre. This study shows higher reintervention and aneurysmal development rates than currently published. To improve long-term outcomes, the early demographic and anatomic poor prognostic factors identified may be used for more aggressive treatment at an early phase

A 10-Year Aortic Center Experience with Hybrid Repair of Chronic “Residual” Aortic Dissection After Type A Repair

International audiencePurpose Hybrid aortic arch repair in patients with chronic residual aortic dissection (RAD) is a less invasive alternative to conventional surgical treatment. The aim of this study was to describe the short-term and long-term results of hybrid treatment for RAD after type A repair. Methods In this retrospective single-center cohort study, all patients treated for chronic RAD with hybrid aortic arch repair were included. Indications for treatment were rapid aortic growth, aortic diameter > 55 mm, or aortic rupture. Results Between 2009 and 2020, we performed 29 hybrid treatments for chronic RAD. Twenty-four patients were treated for complete supra-aortic debranching in zones 0 and 5 with left subclavian artery debranching alone in zone 2. There was 1 perioperative death (3.4%): The patient was treated for an aortic rupture. There was no spinal cord ischemia and 1 minor stroke (3.4%). After a median follow-up of 25.4 months (range 3-97 months), the long-term mortality was 10.3% (3/29) with no late aortic-related deaths. Twenty-seven patients (93.1%) developed FL thrombosis of the descending thoracic aorta; the rate of aneurysmal progression on thoraco-abdominal aorta was 41.4% (12/29), and the rate of aortic reintervention was 34.5% (10/29). Conclusion In a high-volume aortic center, hybrid repair of RAD is associated with good anatomical results and a low risk of perioperative morbidity and mortality, including that of patients treated in zone 0. A redo replacement of the ascending aortic segment is sometimes necessary to provide a safer proximal landing zone and reduce the risk of type 1 endoleak after TEVAR

tRNA 2'-O-methylation modulates small RNA silencing and life span in Drosophila

2'-O-methylation (Nm) represents one of the most common RNA modifications. Nm affects RNA structure and function with crucial roles in various RNA-mediated processes ranging from RNA silencing, translation, self versus non-self recognition to viral defense mechanisms. Here, we identify two novel Nm methyltransferases (Nm-MTases) in Drosophila melanogaster (CG7009 and CG5220) as functional orthologs of yeast TRM7 and human FTSJ1, respectively. Genetic knockout studies together with MALDI-TOF mass spectrometry and RiboMethSeq mapping revealed that CG7009 is responsible for methylating the wobble position in tRNA Phe , tRNA Trp and tRNA Leu , while subsequently, CG5220 methylates position C32 in the same tRNAs and targets also additional tRNAs. CG7009 or CG5220 mutant animals were viable and fertile but exhibited various phenotypes such as life span reduction, small RNA pathways dysfunction and increased sensitivity to RNA virus infections. Our results provide the first detailed characterization of two TRM7 family members in Drosophila and uncover a molecular link between enzymes catalysing Nm at specific tRNAs and small RNA-induced gene silencing pathways

tRNA 2′-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila

International audience2'-O-Methylation (Nm) represents one of the most common RNA modifications. Nm affects RNA structure and function with crucial roles in various RNA-mediated processes ranging from RNA silencing, translation, self versus non-self recognition to viral defense mechanisms. Here, we identify two Nm methyltransferases (Nm-MTases) in Drosophila melanogaster (CG7009 and CG5220) as functional orthologs of yeast TRM7 and human FTSJ1. Genetic knockout studies together with MALDI-TOF mass spectrometry and RiboMethSeq mapping revealed that CG7009 is responsible for methylating the wobble position in tRNAPhe, tRNATrp and tRNALeu, while CG5220 methylates position C32 in the same tRNAs and also targets additional tRNAs. CG7009 or CG5220 mutant animals were viable and fertile but exhibited various phenotypes such as lifespan reduction, small RNA pathways dysfunction and increased sensitivity to RNA virus infections. Our results provide the first detailed characterization of two TRM7 family members in Drosophila and uncover a molecular link between enzymes catalyzing Nm at specific tRNAs and small RNA-induced gene silencing pathways