Potent Omicron-neutralizing antibodies isolated from a patient vaccinated 6 months before Omicron emergence.

Therapeutic antibodies are an important tool in the arsenal against coronavirus infection. However, most antibodies developed early in the pandemic have lost most or all efficacy against newly emergent strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly those of the Omicron lineage. Here, we report the identification of a panel of vaccinee-derived antibodies that have broad-spectrum neutralization activity. Structural and biochemical characterization of the three broadest-spectrum antibodies reveal complementary footprints and differing requirements for avidity to overcome variant-associated mutations in their binding footprints. In the K18 mouse model of infection, these three antibodies exhibit protective efficacy against BA.1 and BA.2 infection. This study highlights the resilience and vulnerabilities of SARS-CoV-2 antibodies and provides road maps for further development of broad-spectrum therapeutics.

Mechanical Circulatory Support in Patients With COVID-19 Presenting With Myocardial Infarction.

ST-segment elevation myocardial infarction (STEMI) complicating COVID-19 is associated with an increased risk of cardiogenic shock and mortality. However, little is known about the frequency of use and clinical impact of mechanical circulatory support (MCS) in these patients. We sought to define patterns of MCS utilization, patient characteristics, and outcomes in patients with COVID-19 with STEMI. The NACMI (North American COVID-19 Myocardial Infarction) is an ongoing prospective, observational registry of patients with COVID-19 positive (COVID-19+) with STEMI with a contemporary control group of persons under investigation who subsequently tested negative for COVID-19 (COVID-19-). We compared the baseline characteristics and in-hospital outcomes of COVID-19+ and patients with COVID-19- according to the use of MCS. The primary outcome was a composite of in-hospital mortality, stroke, recurrent MI, and repeat unplanned revascularization. A total of 1,379 patients (586 COVID-19+ and 793 COVID-19-) enrolled in the NACMI registry between January 2020 and November 2021 were included in this analysis; overall, MCS use was 12.3% (12.1% [n = 71] COVID-19+/MCS positive [MCS+] vs 12.4% [n = 98] COVID-19-/MCS+). Baseline characteristics were similar between the 2 groups. The use of percutaneous coronary intervention was similar between the groups (84% vs 78%; p = 0.404). Intra-aortic balloon pump was the most frequently used MCS device in both groups (53% in COVID-19+/MCS+ and 75% in COVID-19-/MCS+). The primary outcome was significantly higher in COVID-19+/MCS+ patients (60% vs 30%; p = 0.001) because of very high in-hospital mortality (59% vs 28%; p = 0.001). In conclusion, patients with COVID-19+ with STEMI requiring MCS have very high in-hospital mortality, likely related to the significantly higher pulmonary involvement compared with patients with COVID-19- with STEMI requiring MCS.

Cellular mRNA triggers structural transformation of Ebola virus matrix protein VP40 to its essential regulatory form.

The Ebola virus matrix protein VP40 forms distinct structures linked to distinct functions in the virus life cycle. Dimeric VP40 is a structural protein associated with virus assembly, while octameric, ring-shaped VP40 is associated with transcriptional control. In this study, we show that suitable nucleic acid is sufficient to trigger a dynamic transformation of VP40 dimer into the octameric ring. Deep sequencing reveals a binding preference of the VP40 ring for the 3' untranslated region of cellular mRNA and a guanine- and adenine-rich binding motif. Complementary analyses of the nucleic-acid-induced VP40 ring by native mass spectrometry, electron microscopy, and X-ray crystal structures at 1.8 and 1.4 Å resolution reveal the stoichiometry of RNA binding, as well as an interface involving a key guanine nucleotide. The host factor-induced structural transformation of protein structure in response to specific RNA triggers in the Ebola virus life cycle presents unique opportunities for therapeutic inhibition.

One-year outcomes of supersaturated oxygen therapy in acute anterior myocardial infarction: The IC-HOT study.

BACKGROUND: Supersaturated oxygen (SSO2 ) has recently been approved by the U.S. Food and Drug Administration for administration after primary percutaneous coronary intervention (pPCI) in patients with anterior ST-segment elevation myocardial infarction (STEMI) based on its demonstration of infarct size reduction in the IC-HOT study. OBJECTIVES: To describe the 1-year clinical outcomes of intracoronary SSO2 treatment after pPCI in patients with anterior STEMI. METHODS: IC-HOT was a prospective, open-label, single-arm study in which 100 patients without cardiogenic shock undergoing successful pPCI of an occluded left anterior descending coronary artery were treated with a 60-min SSO2 infusion. One-year clinical outcomes were compared with a propensity-matched control group of similar patients with anterior STEMI enrolled in the INFUSE-AMI trial. RESULTS: Baseline and postprocedural characteristics were similar in the two groups except for pre-PCI thrombolysis in myocardial infarction 3 flow, which was less prevalent in patients treated with SSO2 (9.6% vs. 22.9%, p = .02). Treatment with SSO2 was associated with a lower 1-year rate of the composite endpoint of all-cause death or new-onset heart failure (HF) or hospitalization for HF (0.0% vs. 12.3%, p = .001). All-cause mortality, driven by cardiovascular mortality, and new-onset HF or HF hospitalization were each individually lower in SSO2 -treated patients. There were no significant differences between groups in the 1-year rates of reinfarction or clinically driven target vessel revascularization. CONCLUSIONS: Infusion of SSO2 following pPCI in patients with anterior STEMI was associated with improved 1-year clinical outcomes including lower rates of death and new-onset HF or HF hospitalizations.

Evaluation of intracoronary hyperoxemic oxygen therapy in acute anterior myocardial infarction: The IC-HOT study.

BACKGROUND: In the randomized AMIHOT-II trial, supersaturated oxygen [SSO2 ] delivered into the left anterior descending (LAD) artery via an indwelling intracoronary infusion catheter following primary percutaneous coronary intervention (PCI) significantly reduced infarct size in patients with anterior ST-segment elevation myocardial infarction (STEMI) but resulted in a numerically higher incidence of safety events. OBJECTIVES: The IC-HOT study evaluated the safety of SSO2 therapy selectively delivered to the left main coronary artery (LMCA) for 60 minutes after PCI in patients with anterior STEMI. METHODS: SSO2 therapy was administered to the LMCA after stent implantation in 100 patients with anterior STEMI and proximal or mid-LAD occlusion presenting within 6 hours of symptom onset. The primary endpoint was the 30-day composite rate of net adverse clinical events (NACE) (death, reinfarction, clinically driven target vessel revascularization, stent thrombosis, severe heart failure, or TIMI major/minor bleeding) compared against an objective performance goal of 10.7%. Cardiac magnetic resonance imaging was performed at 4 and 30 days to assess infarct size. RESULTS: SSO2 delivery was successful in 98% of patients. NACE at 30 days occurred 7.1% of patients (meeting the primary safety endpoint of the study); there were no deaths, only one stent thrombosis and one case of severe heart failure. Median [interquartile range] infarct size was 24.1% [14.4%, 31.6%] at 4 days and 19.4% [8.8%, 28.9%] at 30 days. CONCLUSION: Following primary PCI in acute anterior STEMI, infusion of SSO2 via the LMCA was feasible and was associated with a favorable early safety profile.

Filovirus Structural Biology: The Molecules in the Machine.

In this chapter, we describe what is known thus far about the structures and functions of the handful of proteins encoded by filovirus genomes. Amongst the fascinating findings of the last decade is the plurality of functions and structures that these polypeptides can adopt. Many of the encoded proteins can play multiple, distinct roles in the virus life cycle, although the mechanisms by which these functions are determined and controlled remain mostly veiled. Further, some filovirus proteins are multistructural: adopting different oligomeric assemblies and sometimes, different tertiary structures to achieve their separate, and equally essential functions. Structures, and the functions they dictate, are described for components of the nucleocapsid, the matrix, and the surface and secreted glycoproteins.

More than Meets the Eye: Hidden Structures in the Proteome.

A central dogma of molecular biology is that the sequence of a protein dictates its particular fold and the fold dictates its function. Indeed, the sequence → structure → function hypothesis has been a guiding principle by which scientists approach molecular biology. Every student knows that the genome encodes information for the progression from primary sequence to secondary, tertiary, and ultimately quaternary structure. Yet with a growing number of proteins, a fifth level has been identified: rearrangement of existing structures into distinct forms. Recent observations indicate that replication of Ebola virus depends on this fifth level. We believe other viruses with compact genomes and rapid evolution under selective pressure will be a rich source of examples of polypeptides that rearrange to gain added functions. In this review, we describe mechanisms by which viral, prokaryotic, and eukaryotic polypeptides have adopted alternate structures to control or gain function.

Prevalence and consequences of vitamin D insufficiency in women with takotsubo cardiomyopathy.

OBJECTIVE: The purpose of this study was to identify the prevalence and clinical consequences of vitamin D insufficiency in patients with takotsubo cardiomyopathy. BACKGROUND: Takotsubo cardiomyopathy is a syndrome of acute, transient left ventricular dysfunction seen predominantly in postmenopausal women after acute emotional or physical stress. Postmenopausal women have a high prevalence of bone and musculoskeletal consequences related to hypovitaminosis D. Although rickets is known to cause a reversible dilated cardiomyopathy in children, the importance of vitamin D for adult cardiovascular health is less understood. METHODS: We prospectively identified patients diagnosed with takotsubo cardiomyopathy at Danbury Hospital from April 2009 through January 2011, collected demographic, clinical, laboratory, and angiographic data, and performed serum 25 hydroxyvitamin D levels during the index hospitalization. Vitamin D insufficiency was defined as serum 25-hydroxy-vitamin D less than 30 ng/mL. We compared parameters of myocardial damage and heart failure between patients with and without vitamin D insufficiency. A χ² test and a Student's t test were used for categorical and continuous variables, respectively. Statistical significance was set at P < .05 (2 tailed). RESULTS: Twenty-seven women were diagnosed with takotsubo cardiomyopathy during the study period. The mean age was 67.4 years (SD 10.4). The serum 25-hydroxyvitamin D levels were performed on 25 patients, and 17 of these had hypovitaminosis D (68%). A comparison of laboratory and imaging parameters between the 2 groups revealed that patients with hypovitaminosis D had a slightly higher mean left ventricular end-diastolic pressure and lower mean left ventricular ejection fraction (P < .05), suggestive of slightly worse heart failure. CONCLUSIONS: Women diagnosed with takotsubo cardiomyopathy have a high prevalence of vitamin D insufficiency. In our prospective study of 25 women with takotsubo cardiomyopathy, this was associated with worse hemodynamic parameters.

Pretreatment with low-dose ß-adrenergic antagonist therapy does not affect severity of Takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy is a syndrome of transient left ventricular dysfunction following acute emotional or physical stress without obstructive coronary artery disease. The leading hypothesis for the etiology is stress-induced catecholamine surge. HYPOTHESIS: People taking outpatient ß-adrenergic receptor antagonist therapy have less-severe presentation and clinical course of Takotsubo cardiomyopathy. METHODS: We identified patients diagnosed with Takotsubo cardiomyopathy from October 2005 to January 2011 by analyzing our cardiac-catheterization database. Clinical records and angiograms were reviewed by 2 experienced observers independently to confirm the diagnosis. We collected clinical, demographic, laboratory, and angiographic data for the identified patients. We then compared the severity of myocardial dysfunction or damage (cardiac enzymes, left ventricular end diastolic pressure, and left ventricular ejection fraction) between patients taking outpatient ß-adrenergic antagonist therapy upon admission vs those who were not. Arrival and peak values for cardiac enzymes were analyzed when available. Analysis of parameters related to the severity of myocardial dysfunction or damage was conducted using the Mann-Whitney U test. Means for age were compared using the Student t test. Statistical significance was set at P < 0.05 (2-tailed). RESULTS: Out of 64 patients identified, 16 (25%) were on one of 3 ß-adrenergic antagonists on presentation: metoprolol succinate, metoprolol tartrate, or atenolol, with mean doses of 75 mg daily, 52.5 mg twice daily, and 37.5 mg daily, respectively. Patients on ß-blockers were older (mean age 73.1 years vs 66 years; P < 0.05). There was no statistically significant difference in levels of cardiac enzymes, left ventricular end diastolic pressure, or left ventricular ejection fraction between the 2 groups. CONCLUSION: Prior therapy with low-dose ß-adrenergic antagonists does not affect the severity of presentation and clinical course of Takotsubo cardiomyopathy as measured by common markers of myocardial dysfunction.

Quantitative assessment of severity of mitral regurgitation by serial echocardiography in a multicenter clinical trial of percutaneous mitral valve repair.

The aims of the echocardiographic substudy of this multicenter trial were to evaluate the use of quantitative assessment of mitral regurgitation (MR) severity using serial echocardiography and to assess the efficacy of percutaneous mitral valve repair. Previous surgical repair studies did not use quantitative echocardiographic methods. Results of a percutaneous mitral valve repair clip device in a core echocardiographic laboratory were evaluated. Published parameters for quantifying MR were used in a systematic protocol to qualify patients for study entry and evaluate treatment efficacy at discharge and 6 months after clip repair. Baseline results were presented for 55 patients, and follow-up results, for 49. Ninety-eight percent of required echocardiographic studies were submitted to the core laboratory, and >85% of required measurements were possible. At baseline, mean regurgitant volume was 54.8 +/- 24 ml, regurgitant fraction was 46.9 +/-16.2%, effective regurgitant orifice area was 0.71 +/- 0.40 cm(2), and vena contracta width was 0.66 +/- 0.20 cm. Based on a severity scale of 1 to 4, mean color flow grade was 3.4 +/- 0.7, and mean pulmonary vein flow was 2.8 +/- 1.2. In patients with a clip at 6 months, all measurements of MR severity were significantly decreased versus baseline, with mean regurgitant volume decreased from 50.3 to 27.5 ml (change -22.8 ml; p <0.0001), regurgitant fraction from 44.6% to 28.9% (change -15.7%; p <0.0001), color flow grade from an average of 3.4 to 1.8 (change -1.6; p <0.0001), and pulmonary vein flow from 2.8 to 1.8 (change -1.0; p <0.0018). In conclusion, quantitative assessment of MR is feasible in a multicenter trial, and percutaneous mitral repair with the MitraClip produces a sustained decrease in MR severity to moderate or less for > or =6 months.

Echocardiographic guidance and assessment of percutaneous repair for mitral regurgitation with the Evalve MitraClip: lessons learned from EVEREST I.

OBJECTIVE: Percutaneous mitral repair is rapidly developing as an alternative to cardiac surgery in select patients. The Evalve percutaneous E2E system uses the MitraClip to replicate the surgical suture-based approach. This procedure requires real-time echocardiographic guidance in a unique and significant collaboration between echocardiographer and interventionalist. transesophageal echocardiography (TEE) is used as the primary imaging modality to guide this procedure and is essential to its success. METHODS: In EVEREST I, the US multicenter phase I safety and feasibility trial, 47 patients with 3 or 4+ mitral regurgitation (MR) were enrolled. The trial involved a standardized echocardiographic imaging protocol with a standardized anatomic-based vocabulary, predetermined standard TEE views, preprocedural strategy meetings, and display of echocardiographic aids to optimize communication and procedural efficiency during placement of the clip. RESULTS: TEE guidance facilitated the creation of a double-orifice mitral valve in all 47 patients enrolled (100%), and 40 patients were discharged with 1 or more clips (85%). At discharge, successful placement of a clip and

Mitral valve hemodynamic effects of percutaneous edge-to-edge repair with the MitraClip device for mitral regurgitation.

INTRODUCTION: The Endovascular Valve Edge-to-Edge REpair STudies (EVEREST) are investigating a percutaneous technique for edge-to-edge mitral valve repair with a repositionable clip. The effects on the mitral valve gradient (MVG) and mitral valve area (MVA) are not known. METHODS: Twenty seven patients with moderate to severe or severe mitral regurgitation (MR) were enrolled. Echocardiography was performed preprocedure, at discharge, and at 1, 6, and 12 months. Mean MVG was measured by Doppler and MVA by planimetry and pressure half-time, and evaluated in a central core laboratory. Pre- and postclip deployment, simultaneous left atrial/pulmonary capillary wedge and left ventricular pressures were obtained in eight patients. RESULTS: Three patients did not receive a clip, six patients had their clip(s) explanted by 6 months (none for mitral stenosis), and four were repaired with two clips. Results are notable for a slight increase in mean MVG by Doppler postclip deployment (1.79 +/- 0.89 to 3.31 +/- 2.09 mm Hg, P < 0.01) and an expected decrease in MVA by planimetry (6.49 +/- 1.61 to 4.46 +/- 2.14 cm(2), P < 0.001) and by pressure half time (4.35 +/- 0.98 to 3.01 +/- 1.42 cm(2), P < 0.05). There were no significant changes in hemodynamic parameters postclip deployment by direct pressure measurements. There was no change in MVA by planimetry from discharge to 12 months (3.90 +/- 1.90 to 3.79 +/- 1.54 cm(2), P = 0.78). CONCLUSIONS: Echocardiographic and hemodynamic measurements after percutaneous mitral valve repair with the MitraClip show an expected decrease in mitral valve area with no evidence of clinically significant mitral stenosis either immediately after clip deployment or after 12 months of follow-up.

Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I Clinical Trial.

OBJECTIVES: This study sought to evaluate the clinical results of a percutaneous approach to mitral valve repair for mitral regurgitation (MR). BACKGROUND: A surgical technique approximating the middle scallops of the mitral leaflets to create a double orifice with improved leaflet coaptation was introduced in the early 1990s. Recently, a percutaneous method to create the same type of repair was developed. A trans-septal approach was used to deliver a clip device that grasps the mitral leaflet edges to create the double orifice. METHODS: General anesthesia, fluoroscopy, and echocardiographic guidance are used. A 24-F guide is positioned in the left atrium. The clip is centered over the mitral orifice, passed into the left ventricle, and pulled back to grasp the mitral leaflets. After verification that MR is reduced, the clip is released. RESULTS: Twenty-seven patients had six-month follow-up. Clips were implanted in 24 patients. There were no procedural complications and four 30-day major adverse events: partial clip detachment in three patients, who underwent elective valve surgery, and one patient with post-procedure stroke that resolved at one month. Three additional patients had surgery for unresolved MR, leaving 18 patients free from surgery. In 13 of 14 patients with reduction of MR to < or =2+ after one month, the reduction was maintained at six months. CONCLUSIONS: Percutaneous edge-to-edge mitral valve repair can be performed safely and a reduction in MR can be achieved in a significant proportion of patients to six months. Patients who required subsequent surgery had elective mitral valve repair or intended replacement.

Reduced myocardial blood flow during left ventricular assist device support: a possible cause of premature bypass graft closure.

Our aim was to determine the effect of left ventricular assist device (LVAD) implantation on bypass graft patency and to measure myocardial oxygen consumption (MVO2) and blood flow during LVAD support. Five patients who underwent coronary artery bypass grafting and required LVAD implantation for post-cardiotomy cardiogenic shock had coronary angiography during device support to assess graft patency. Positron emission tomography measurements were made in a separate cohort of LVAD patients with dilated cardiomyopathy to assess the effects of LVAD support on MVO2 and myocardial blood flow. In this small series, LVAD unloading led to a high rate of premature graft occlusion in post-cardiotomy cardiogenic shock patients supported with a device; whereas, positron emission tomography measurements showed significantly reduced MVO2 and myocardial flood flow in dilated cardiomyopathy patients supported with an LVAD, compared with healthy subjects. Reduced myocardial blood flow may be implicated in the premature graft failure observed in post-cardiotomy cardiogenic shock patients and may negatively impact the potential for myocardial recovery and device weaning in this population.

Surgical revision after percutaneous mitral valve repair with a clip: initial multicenter experience.

PURPOSE: Almost 50,000 mitral valve operations are performed annually in the United States, with an increasing number of repairs. Recently, a percutaneous mitral valve repair option that achieves edge-to-edge approximation with a clip has been described in patients with mitral regurgitation. DESCRIPTION: We describe 6 patients from three centers with mitral regurgitation after percutaneous repair who underwent reintervention. During open surgical revision, the clips were uneventfully removed in all patients with no limitation in surgical options. Five patients underwent repair and 1 underwent replacement. EVALUATION: After surgical revision, mitral regurgitation was significantly decreased, and all but 1 patient underwent uneventful recovery. One patient developed ilio-femoral deep venous thrombosis that was treated successfully with anticoagulation. CONCLUSIONS: Preserving standard of care options is critical with any evolving technology in the event of initial treatment failure. Standard surgical options were preserved in all of the patients who underwent percutaneous mitral valve edge-to-edge repair. Furthermore, a thorough understanding of the clip design, in particular its unlocking mechanism, is essential and facilitates surgical clip removal.

Anterior myocardial infarction, acute aortic dissection, and anomalous coronary artery.

Acute dissection of the ascending aorta has, on rare occasions, been accompanied by myocardial infarction due to the compression of the ostium of a coronary artery. Rarer still is the presence of an aortic dissection, myocardial infarction, and an anomalous coronary artery. A case is described of a patient who survived an acute aortic dissection complicated by anterior myocardial infarction due in part to the presence of an anomalous circumflex artery. The anatomy, diagnosis, and consequences of aortic dissection are discussed.