Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

D rug-eluting stents (DES) have dramatically reduced the long-term rate of reintervention and improved clinical outcomes among patients undergoing percutaneous coronary interventions.1 However, DES use still carries a small but critically important cumulative risk of late stent thrombosis. Human pathology studies suggest that delayed healing leads to incomplete strut coverage, which has been associated with late thrombotic events.2 Moreover, early DES platforms elicited enhanced platelet adhesion 3 and endothelial dysfunction. 4 Most DES technologies now embody thinner metallic platforms containing minimal amounts of polymeric drug formulations while maintaining drug concentrations and release profiles. 5,6 Although a slight decline in the overall stent thrombosis rate has been observed with the use of latest generation of DES platforms, these potentially lethal events still occur. Despite their efficacy in preventing restenosis, the antiproliferative effect of drugs used in commercially available DES appear to delay stent endothelialization. Technological approaches have been used to enhance stent endothelialization by modifying the stent surface with antibodies to selectively bind circulating endothelial progenitor cells. 7 An alternate strategy to encourage reendothelialization is to modify the stent surface to increase the natural rate of endothelial cell migration from adjacent arterial areas of intact healthy endothelium. Previous studies in our laboratory have shown that parallel microgrooves applied to the surface of different metals 8,9 increase the rate of human aortic endothelial cell migration by >2-fold compared with smooth coupons. More importantly, when this pattern was applied to the luminal surface of stents in an early pilot study, the endothelialization rate on these grooved stents was double compared with Background-Stent luminal surface characteristics influence surface endothelialization. We hypothesize that luminal stent microgrooves created in the direction of coronary flow accelerate endothelial cell migration, resulting in lower levels of neointimal formation. Methods and Results-Surface coverage efficiency was evaluated in vitro by allowing human aortic endothelial cells (HAEC) to migrate onto microgrooved (G) or smooth (NG) surfaces. HAEC functionality was assessed by proliferation rate, apoptosis rate, nitric oxide production, and inflammatory markers TNF-α and VCAM-1 expression. Early endothelialization and restenosis studies were performed using the porcine coronary injury model. Stainless steel stents of identical design with (GS) and without (NGS) luminal microgrooves were used. The commercially available Multi-Link Vision (MLVS) stent of identical design was used as a control. The degree of GS and NGS surface endothelialization was compared at 3 days. Biocompatibility and tissue response outcomes were evaluated at 28 days. The in vitro study demonstrated that at 7 days the presence of surface microgrooves increased HAEC migration distance >2-fold. Cell proliferation rate and nit...

Primary hyperaldosteronism is a rare (<1%) and underdiagnosed cause of secondary hypertension. We present a case of aortic dissection in a patient with primary hyperaldosteronism. To our knowledge, there are six other reported cases of aortic dissection in patients with primary hyperaldosteronism. Our case strengthens the hypothesis that primary hyperaldosteronism is a potential independent risk factor for aortic dissection.

Calcium channel blocker overdoses are often fatal despite standard treatment. Methylene blue is a novel adjunct that should be considered in refractory cases. Currently accepted therapeutic modalities include intravenous fl uids, calcium, vasopressors and high-dose insulin euglycemic therapy, however shock may persist despite these treatment options. [1] Methylene blue has been utilized in sepsis, shock after cardiac surgery and other non-poisoning causes of shock. However, there are only ten human case reports and one animal study regarding its utility. The case reports describe its use in shock caused by quetiapine, valsartan and dihydropyridine calcium channel blockers, and measure the outcomes of hemodynamics and mortality. The animal study used a rat-model with thirty subjects treated with a lethal dose of amlodipine, followed by methylene blue or normal saline. Results revealed an increase in heart rate, mean arterial pressure (MAP) and median survival time in those treated with methylene blue. [2] E x pe r t c o n s e n s u s r e c o m m e n d a t i o n s f o r t h e management of calcium channel blocker poisoning in adults were recently assembled and did not recommend the use of methylene blue as first-line treatment, given that the experience was limited to a small number of case reports. [1] However, with additional case reports attesting to its effi cacy, there may be a role for methylene blue in the treatment of drug-induced vasodilatory shock. We present a case where methylene blue was administered to a patient suffering from refractory vasodilatory shock following toxic ingestion of amlodipine, resulting in subsequent hemodynamic improvement.

Diastolic performance is regulated by net myocardial stiffness, which is determined by the mechanosensitive protein network comprised of extracellular proteins such as collagen, intracellular sarcomeric proteins, and cell surface integrins. Mechanical force and its regulation are sensed and propagated by each of these components in a concerted fashion. 1 During diastole, titin filaments serve as tensiometers and passive force generators. This is accomplished by modulation via directional signaling of multiple linkages between different regions within the titin molecule and the cellular contractile apparatus. An intricate network of signaling molecules coordinates the extracellular and intracellular components in the contraction of a sarcomere. In this issue of Circulation Research, Hidalgo et al present an elegant set of experiments that reveal a novel mechanism whereby altering the phosphorylation state of titin modulates myocardial passive stiffness. 2 Specifically, they demonstrated that titin, in addition to being a protein kinase (PK)A and PKG substrate, is also a PKC␣ substrate. They further identified the PEVK region of titin as the prominent site of PKC␣ phosphorylation, and showed that phosphorylation at this site increased passive tension.Titin is an approximately 3000-kDa molecular-mass sarcomeric protein that spans the Z disk to the M line of the sarcomere. 3 Originally thought to only provide structural scaffolding to link the many regulatory, contractile, and structural proteins within the sarcomere, titin is now recognized to be a major regulator of intracellular myocyte stiffness. Titin determines the passive tension of the intracellular component of cardiomyocytes, which, together with collagen, determines the total myocardial passive stiffness. Although the immunoglobulin-like domain and fibronectin type III repeats make up 90% of the titin molecule, titin also includes a unique I-band region that is flexible and specifically serves as a molecular spring to determine passive stiffness. The I-band region contains 3 motifs: (1) serially linked immunoglobulin-like domains; (2) the N2B element; and (3) the PEVK region. Titin has direct and indirect links with many signaling molecules and has multiple phosphorylation sites in the Z-disk, M-band, and I-band segments, which establishes titin as a major regulator of myocyte signaling. 1 For example, the N2B element has previously been shown to be phosphorylated by PKA and PKG to decrease stiffness. 4,5 This study extends these observations to demonstrate that the PEVK region can be phosphorylated by PKC␣.There are 3 titin isoforms, including a fetal form and 2 adult forms (N2B and N2BA), that all arise from differential splicing of one gene to result in proteins of different length I bands. The adult N2B is the shortest form and results in the highest stiffness; the N2BA is longer and provides a medium level of stiffness; and the N2BA fetal form is the longest and most compliant. The difference in sizes among the isoforms is attributable to increased i...