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

The US Program in Ground-Based Gravitational Wave Science: Contribution from the LIGO Laboratory

Recent gravitational-wave observations from the LIGO and Virgo observatories have brought a sense of great excitement to scientists and citizens the world over. Since September 2015,10 binary black hole coalescences and one binary neutron star coalescence have been observed. They have provided remarkable, revolutionary insight into the "gravitational Universe" and have greatly extended the field of multi-messenger astronomy. At present, Advanced LIGO can see binary black hole coalescences out to redshift 0.6 and binary neutron star coalescences to redshift 0.05. This probes only a very small fraction of the volume of the observable Universe. However, current technologies can be extended to construct "3rd Generation" (3G) gravitational-wave observatories that would extend our reach to the very edge of the observable Universe. The event rates over such a large volume would be in the hundreds of thousands per year (i.e. tens per hour). Such 3G detectors would have a 10-fold improvement in strain sensitivity over the current generation of instruments, yielding signal-to-noise ratios of 1000 for events like those already seen. Several concepts are being studied for which engineering studies and reliable cost estimates will be developed in the next 5 years

Impact of implant depth on hydrodynamic function with the ACURATE neo transcatheter heart valve following valve-in-valve transcatheter aortic valve replacement in Mitroflow bioprosthetic valves: an ex vivo bench study

Aims: We aimed to assess the impact of implant depth on hydrodynamic function following valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) using the ACURATE neo transcatheter heart valve (THV) through an ex vivo bench study.Methods and results: Multiple implantation depths were tested at incremental depths of 2 mm using a small size ACURATE neo valve for VIV TAVR in 19 mm, 21 mm, 23 mm, and 25 mm Mitroflow bioprosthetic valves. Multimodality imaging and hydrodynamic evaluation was performed at each implantation depth. A low implantation was associated with higher transvalvular gradients. The highest transvalvular gradient was observed at -10 mm depth for 19 mm (40.00 +/- 0.5 mmHg), -8 mm for 21 mm (15.31 +/- 0.2 mmHg), -6 mm for 23 mm (14.7 +/- 02.3 mmHg) and -8 mm for 25 mm (8.41 +/- 0.2 mmHg) surgical valves. The lowest transvalvular gradient was observed at 0 mm depth for the 19 mm (14.91 +/- 0.2 mmHg)/21 mm (7.2 +/- 0.1 mmHg), and +2 mm depth for the 23 mm (5.7 +/- 0.1 mmHg)/25 mm (5.81-0.1 mmHg) surgical valves. At low implantation depth, there was worse leaflet pin-wheeling and also evidence of interaction of THV leaflets with those of the surgical valve that impaired leaflet coaptation, resulting in a high regurgitant fraction (42.5% in the 21 mm and 83.3% in the 23 mm surgical valve at -10 mm depths).Conclusions: A high implant is desirable to facilitate favourable hydrodynamic function when performing VIV TAVR using the ACURATE neo THV for Mitroflow aortic bioprostheses sized +/- 25 mm. In a 19 mm Mitroflow valve, positioning the upper crown of the ACURATE neo THV above the posts of the surgical valve is desirable to facilitate favourable transvalvular gradients. Low implantation results in higher transvalvular gradients and worse pin-wheeling, and THV leaflet dysfunction can be severe due to interaction with the surgical valve

Overexpansion of the SAPIEN 3 Transcatheter Heart Valve

International audienc

Valve-in-Valve Transcatheter Aortic Valve Replacement and Bioprosthetic Valve Fracture Comparing Different Transcatheter Heart Valve Designs: An Ex Vivo Bench Study

Objectives: The authors assessed the effect of valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) followed by bioprosthetic valve fracture (BVF), testing different transcatheter heart valve (THV) designs in an ex vivo bench study. Background: Bioprosthetic valve fracture can be performed to improve residual transvalvular gradients following VIV TAVR. Methods: The authors evaluated VIV TAVR and BVF with the SAPIEN 3 (S3) (Edwards Lifesciences, Irvine, California) and ACURATE neo (Boston Scientific Corporation, Natick, Massachusetts) THVs. A 20-mm and 23-mm S3 were deployed in a 19-mm and 21-mm Mitroflow (Sorin Group USA, Arvada, Colorado), respectively. A small ACURATE neo was deployed in both sizes of Mitroflow tested. VIV TAVR samples underwent multimodality imaging, and hydrodynamic evaluation before and after BVF. Results: A high implantation was required to enable full expansion of the upper crown of the ACURATE neo and allow optimal leaflet function. Marked underexpansion of the lower crown of the THV within the surgical valve was also observed. Before BVF, VIV TAVR in the 19-mm Mitroflow had high transvalvular gradients using either THV design (22.0 mm Hg S3, and 19.1 mm Hg ACURATE neo). After BVF, gradients improved and were similar for both THVs (14.2 mm Hg S3, and 13.8 mm Hg ACURATE neo). The effective orifice area increased with BVF from 1.2 to 1.6 cm with the S3 and from 1.4 to 1.6 cm with the ACURATE neo. Before BVF, VIV TAVR with the ACURATE neo in the 21-mm Mitroflow had lower gradients compared with S3 (11.3 mm Hg vs. 16 mm Hg). However, after BVF valve gradients were similar for both THVs (8.4 mm Hg ACURATE neo vs. 7.8 mm Hg S3). The effective orifice area increased from 1.5 to 2.1 cm with the S3 and from 1.8 to 2.2 cm with the ACURATE neo. Conclusions: BVF performed after VIV TAVR results in improved residual gradients. Following BVF, residual gradients were similar irrespective of THV design. Use of a small ACURATE neo for VIV TAVR in small (≤21 mm) surgical valves may be associated with challenges in achieving optimum THV position and expansion. BVF could be considered in selected clinical cases