Chimeric mRNA-based COVID-19 vaccine induces protective immunity against Omicron and Delta variants.

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the effectiveness of currently approved mRNA vaccines. To achieve wider coverage of VOCs, we first constructed a cohort of mRNAs harboring a furin cleavage mutation in the spike (S) protein of predominant VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). The mutation abolished the cleavage between the S1 and S2 subunits. Systematic evaluation in vaccinated mice discovered that individual VOC mRNAs elicited strong neutralizing activity in a VOC-specific manner. In particular, the neutralizing antibodies (nAb) produced by immunization with Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross-reactivity with other VOCs. However, neither mRNA elicited strong neutralizing activity against the Omicron variant. Hence, we further developed an Omicron-specific mRNA vaccine that restored protection against the original Omicron variant and some sublineages. Finally, to broaden the protection spectrum of the new Omicron mRNA vaccine, we engineered an mRNA-based chimeric immunogen by introducing the receptor-binding domain of Delta variant into the entire S antigen of Omicron. The resultant chimeric mRNA induced potent and broadly nAbs against Omicron and Delta, which paves the way to developing new vaccine candidates to target emerging variants in the future.

Idiopathic chronic pancreatitis treated with ivacaftor in a CFTR carrier with methylmalonic acidemia.

CFTR mutation carriers, numbering 1 in 25 among Caucasians, have an increased risk of developing chronic pancreatitis due to the underlying dysfunction of ion channels created by the mutant allele. Carriers do not frequently manifest disease due to the remaining wild-type CFTR protein sufficiently maintaining normal pancreatic homeostasis. However, additional risk factors for pancreatitis, such as organic acidemias (as seen in our patient) that further impact function of pancreatic acinar cells can result in the precipitation of CFTR related pancreatitis. Here we report a CFTR carrier with methylmalonic acidemia who was treated with ivacaftor and subsequently experienced resolution of her chronic pancreatitis. Our report suggests that ivacaftor may rescue the function of mutant CFTR in carriers and treat pancreatitis caused by CFTR dysfunction in situations where there are additional precipitating factors.

Continuously Updated Estimation of Heart Transplant Waitlist Mortality.

BACKGROUND: Heart transplant allocation in the United States is made on the basis of coarse tiers, defined by mechanical circulatory devices and therapy for advanced heart failure, updated infrequently as a patient's condition deteriorates. Thus, many patients die awaiting heart transplantation. What is needed is a tool that continuously updates risk of mortality as a patient's condition changes to inform clinical decision making. OBJECTIVES: This study sought to develop a decision aid that aggregates adverse events and measures of end-organ function into a continuously updated waitlist mortality estimate. METHODS: From 2008 to 2013, 414 patients were listed for heart transplantation at Cleveland Clinic, Cleveland, Ohio. The endpoint was waitlist death. Pre-listing patient characteristics and events and laboratory results during listing were analyzed. At each event or measurement change, mortality was recomputed from the resulting model. RESULTS: There were 77 waitlist deaths, with 1- and 4-year survival of 85% and 57%, respectively. When time-varying events and measurements were incorporated into a mortality model, pre-listing patient characteristics became nonsignificant. Neurological events (hazard ratio [HR]: 13.5; 95% confidence interval [CI]: 7.63 to 23.8), new requirement for dialysis (HR: 3.67; 95% CI: 1.88 to 7.14), more respiratory complications (HR: 1.79 per episode; 95% CI: 1.23 to 2.59), and higher serum bilirubin (p < 0.0001) and creatinine (p < 0.0001) yielded continuously updated estimates of patient-specific mortality across the waitlist period. CONCLUSIONS: Mortality risk for patients with advanced heart failure who are listed for transplantation is related to adverse events and end-organ dysfunction that change over time. A continuously updated mortality estimate, combined with clinical evaluation, may inform status changes that could reduce mortality on the heart transplant waiting list.

The Carpentier-Edwards Perimount Magna mitral valve bioprosthesis: intermediate-term efficacy and durability.

BACKGROUND: The Carpentier-Edwards Perimount Magna mitral valve bioprosthesis (Edwards Lifesciences, Irvine, CA) is a low-profile version of the earlier Perimount valve that uses the ThermaFix process for enhanced calcium removal. The Magna valve has been in use since 2008, yet no publication, until now, has verified its intermediate-term safety and efficacy. METHODS: From 2008 through 2011 (our 4-year study period), 70 Magna valves were implanted in the mitral position at a single institution (the Cleveland Clinic). Echocardiograms were prospectively interpreted. For this study, we reviewed patients' charts; endpoints included hemodynamic measurements, in-hospital morbidity and mortality, valve-related events, resource utilization, and 5-year survival rates. RESULTS: The mean patient age was 68 years; 43 % of the patients had New York Heart Association (NYHA) class III or IV disease, and 51.4 % had moderately severe, or worse, mitral regurgitation (MR). For 43 % of the patients, the Magna valve implantation was a reoperation. For 83 %, the Magna valve implantation also included a concomitant cardiac procedure. The median survival rate was 4.7 years and 90 % of patients were free from significant structural valve degeneration at 5 years. Preoperative atrial fibrillation, ischemic MR, intraaortic balloon pump placement, cardiogenic shock, cardiac arrest, and renal failure were associated with increased mortality. Right ventricular systolic pressure decreased from 50 mmHg preoperatively to 40 mmHg postoperatively, according to our matched-pair analysis (P = 0.003). Per their final echocardiogram during our study period, 98 % of surviving patients had trivial or no MR, one patient had mild MR, and one patient had severe MR. CONCLUSIONS: Our 5-year experience indicates that the Magna valve offers excellent intermediate-term durability and substantial echocardiographic improvement; its low-profile design make it ideal for reoperations and for concomitant cardiac procedures, including valve replacement.

Human Fitting Studies of Cleveland Clinic Continuous-Flow Total Artificial Heart.

Implantation of mechanical circulatory support devices is challenging, especially in patients with a small chest cavity. We evaluated how well the Cleveland Clinic continuous-flow total artificial heart (CFTAH) fit the anatomy of patients about to receive a heart transplant. A mock pump model of the CFTAH was rapid-prototyped using biocompatible materials. The model was brought to the operative table, and the direction, length, and angulation of the inflow/outflow ports and outflow conduits were evaluated after the recipient's ventricles had been resected. Thoracic cavity measurements were based on preoperative computed tomographic data. The CFTAH fit well in all five patients (height, 170 ± 9 cm; weight, 75 ± 24 kg). Body surface area was 1.9 ± 0.3 m (range, 1.6-2.1 m). The required inflow and outflow port orientation of both the left and right housings appeared consistent with the current version of the CFTAH implanted in calves. The left outflow conduit remained straight, but the right outflow direction necessitated a 73 ± 22 degree angulation to prevent potential kinking when crossing over the connected left outflow. These data support the fact that our design achieves the proper anatomical relationship of the CFTAH to a patient's native vessels.

Using near-infrared spectroscopy to monitor lower extremities in patients on venoarterial extracorporeal membrane oxygenation.

Patients on peripheral extracorporeal membrane oxygenation (ECMO) are at risk for lower extremity ischemia. Effective monitoring is needed to identify complications quickly and allow timely correction. Near-infrared spectroscopy has been used extensively in cerebral monitoring during cardiac surgery. We present its use in monitoring lower extremity perfusion in patients on ECMO. Five patients on ECMO had near-infrared spectroscopy monitors placed on the calf of both lower extremities. Continuous real-time tissue oxygen saturation data (stO2) was displayed and recorded. Two patients had lower extremity complications in the leg with the arterial cannula. The patients with complications had lower stO2 in the cannulated leg at the time of ECMO insertion, larger differences in stO2 between the legs at the time of insertion, lower nadir stO2s, and larger peak differences in stO2 between the legs than patients without limb complications. The use of near-infrared spectroscopy for continuous monitoring of tissue oxygenation in the lower extremities in patients on ECMO may allow early identification of patients with lower extremity complications.

Surgically intractable epilepsy associated with focal cortical dysplasia and congenital cutaneous hemangiomas.

We describe a 6-month-old girl with medically intractable seizures, multiple congenital hemangiomas, and developmental delay. The patient underwent two surgical resections. Pathological findings at both the first and second resections were consistent with focal cortical dysplasia. The literature was reviewed on focal cortical dysplasia associated with cutaneous hemangiomas.

Myocardial recovery: a focus on the impact of left ventricular assist devices.

Heart failure remains one of the most prevalent diseases worldwide and in recent decades, left ventricular assist devices (LVADs) have become an important treatment option. With increasing device experience, there is particular interest in the use of LVADs as a bridge to recovery that allows the patient's heart to undergo reverse remodeling, whereby the device can be explanted and the heart can function at an improved state. There are many considerations that play a role in this process, including the ability of the device to unload the heart, the innate physiology of the heart to recover and the use of concomitant therapies. This review provides an overview of the most current literature as it pertains to these processes and gives a view into the future directions of LVADs as a tool for achieving myocardial recovery.

Predictors of right ventricular failure after left ventricular assist device implantation.

Number of left ventricular assist device (LVAD) implantations increases every year, particularly LVADs for destination therapy (DT). Right ventricular failure (RVF) has been recognized as a serious complication of LVAD implantation. Reported incidence of RVF after LVAD ranges from 6% to 44%, varying mostly due to differences in RVF definition, different types of LVADs, and differences in patient populations included in studies. RVF complicating LVAD implantation is associated with worse postoperative mortality and morbidity including worse end-organ function, longer hospital length of stay, and lower success of bridge to transplant (BTT) therapy. Importance of RVF and its predictors in a setting of LVAD implantation has been recognized early, as evidenced by abundant number of attempts to identify independent risk factors and develop RVF predictor scores with a common purpose to improve patient selection and outcomes by recognizing potential need for biventricular assist device (BiVAD) at the time of LVAD implantation. The aim of this article is to review and summarize current body of knowledge on risk factors and prediction scores of RVF after LVAD implantation. Despite abundance of studies and proposed risk scores for RVF following LVAD, certain common limitations make their implementation and clinical usefulness questionable. Regardless, value of these studies lies in providing information on potential key predictors for RVF that can be taken into account in clinical decision making. Further investigation of current predictors and existing scores as well as new studies involving larger patient populations and more sophisticated statistical prediction models are necessary. Additionally, a short description of our empirical institutional approach to management of RVF following LVAD implantation is provided.

Neuropathology in patients with multiple surgeries for medically intractable epilepsy.

Outcomes following surgery for chronic epilepsy are generally good; however, seizures persist/recur following initial surgery in some patients. We hypothesize that in patients who require multiple surgeries for intractable epilepsy, an identifiable pathologic substrate can be found in the subsequent surgical specimen, which accounts for the recurrent seizures. We retrospectively studied 102 patients (56 females) with medically intractable epilepsy who have had at least 2 surgeries more than 60 days apart from 1990-2010. Patient age at time of 1st surgery ranged from 3 months-60 years (mean 18.1 years). Mean duration of seizures prior to 1st surgery was 9.7 years. Time between the 1st and 2nd surgeries ranged from 0.28-15.3 years (mean 4.3 years). The most common pathologies at initial resection included focal cortical dysplasia (45%), tumor (19%), hippocampal sclerosis (16%), and non-specific changes (13%); 10% of patients had multiple significant pathologies. Of the 89 patients that had a significant initial surgical finding, 74 (83.1%) had a significant pathology at 2nd surgery; the same pathology was identified in 49 (66.2%) of these cases. The most commonly identified pathologies at 2nd surgery included remote infarcts (likely postoperative) (N=51) and focal cortical dysplasia (N=29). Three out of the 13 patients with initially non-specific findings had a significant finding at 2nd surgery, excluding postoperative infarct. Follow-up after last surgery ranged from 0.5-190 months (mean 48 months); 83% of patients were on anti-convulsive medication and 57% were seizure-free at last known follow-up. In the majority of cases of recurrent epilepsy with at least 2 surgeries (84%), pathologic findings accounting for seizures were found at the 2nd surgery. In most cases with significant initial pathology, a similar pathology was present at 2nd surgery (55%). Post-operative contusional damage may account for persistent seizures following initial surgery in a subset of patients.