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Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 ( ), with the goal of lifelong control of angioedema attacks after a single dose. In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

In this randomized, controlled trial, the number of angioedema attacks per month was approximately 75% lower among adults with hereditary angioedema who received a CRISPR-Cas9–based therapy than among those who received placebo.

Background: Vasoactive-inotrope score (VIS) has recently been proposed as a surrogate marker of illness severity after cardiac surgery for pediatric patients with congenital heart disease (CHD). However, it has not been validated in an exclusively pediatric population as a robust outcome predictor in the early postoperative period. Furthermore, as a result of advances in the treatment of CHD, the majority of these children now survive to adulthood when they will require additional surgical intervention. However, there are no risk prediction tools for these adult patients with CHD; and pediatric and adult non-CHD cardiac risk scores perform poorly in this population. A simple yet robust risk prediction tool is crucial to support clinical decision making and optimize quantity and quality of life for both pediatric and adult CHD patients undergoing cardiac surgery. Objectives: This research aims to 1) externally validate VIS risk predictive performance of early outcome in pediatric CHD patients after cardiac surgery; 2) propose a simplified VIS Index model with robust predictive performance of early postoperative mortality and morbidity by incorporating both the magnitude and duration of inotrope support required for pediatric CHD patients after cardiac surgery; 3) evaluate whether the proposed VIS Index has strong discriminative performance of early mortality and morbidity outcome for adult CHD patients after cardiac surgery. Methods: Automated data capture of the electronic medical record (EMR) system was utilized in conjunction with retrospective clinical chart review. A total number of 244 infant CHD patients and 243 adult CHD patients undergoing cardiac surgery at the Mayo Clinic Rochester, MN were included in the study. Inotrope and vasoactive dose values were collected at 15-minute intervals for the first 96 hours after cardiac Intensive Care Unit (ICU) admission. Demographic and clinical data were collected from both Mayo Clinic institutional Society of Thoracic Surgeons database and clinical chart review. Maximum vasoactive inotrope support (maxVIS) values were calculated and VIS postoperative temporal characteristics were further assessed to evaluate their relationship with early mortality and morbidity. The logistic regression model with generalized estimating equation methodology was applied to address the correlated outcomes from the same patient. The maxVIS model was validated on pediatric CHD patients. A simplified VIS index model incorporating both the magnitude and duration of inotrope support was developed with superior predictive performance of early mortality and morbidity for both pediatric and adult CHD patients following cardiac surgery. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was used to evaluate the discriminative performance; Hosmer-Lemeshow (H-L) test was used to assess the goodness of fit of the model. Results: The maxVIS model proposed by recent research was externally validated in our institution to exhibit good predictive ability (H-L test, P = 0.791) and discriminate reasonably well between CHD patients with high- and low-risk for early mortality and morbidity (AUC = 0.77, 95% CI: 0.72 to 0.82). The new VIS index risk prediction model shows superior discriminative performance over the existing maxVIS model for pediatric CHD patients undergoing cardiac surgery (AUC = 0.84, 95% CI: 0.78 to 0.88; H-L test, P = 0.725). A high VIS index is strongly associated with a poor clinical outcome compared to a low VIS index. Patients with a VIS index of 6 have an estimated risk of 98% (95% CI: 85% to 100%) of having a poor outcome after cardiac surgery, compared with a risk of 20% (95% CI: 11% to 34%) for patients with a VIS index of 1. Furthermore, both maxVIS model and VIS index model presents robust predictive performance for adult CHD patients after cardiac surgery with the VIS index model consistently showing superior discriminative performance over the maxVIS model for early postoperative mortality and morbidity (MaxVIS model AUC = 0.82, 95% CI: 0.76 to 0.88; VIS index model AUC = 0.88, 95% CI: 0.82 to 0.93). Adult CHD patients with a VIS index of 6 have an estimated risk of 95% (95% CI: 72% to 99%) of experiencing a poor clinical outcome during early postoperative period, compared with a risk of 6% (95% CI: 3% to 11%) for patients with a VIS index of 1. Conclusions: The maxVIS model is a strong predictive tool of early mortality and morbidity for CHD patients undergoing cardiac surgery. The VIS index we proposed is a more robust, yet much simpler tool to predict early postoperative mortality and morbidity for both pediatric and adult CHD patients after cardiac surgery. More importantly, this is the first analysis evaluating the correlation between VIS and poor clinical outcomes in adult CHD patients undergoing cardiac surgery. The findings of this research will facilitate earlier detection of high risk patients to direct clinical interventions and preventative measures that will improve outcome for pediatric and adult CHD patients after cardiac surgery.

It was one o'clock, and the bell of the Pine Street School was ringing for afternoon session. Half a score of boys were gathered at the entrance door, talking eagerly. The topic under discussion seemed to be one of unusual interest.

How well I remember the first time I saw him--my boy Hector.

Charlie Murdock came sauntering np the path, and threw himself down listlessly by his Bister's hammock on the shadowy veranda. \"I say, sis, it's awfully lonesome here! What's a fellow going to do with himself all these long, hot afternoons, I'd like to know?\"

Cerium oxide/montmorillonite nanocomposite films were synthesized electrochemically from solutions containing 0.5 to 50% Na-montmorillonite. The nanocomposites were characterized by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and Raman spectroscopy. Nanocomposite films synthesized from montmorillonite concentrations lower than 10% were continuous, uniform, and dense. X-ray diffraction confirmed that the nanocomposite films retain the face-centered cubic structure of cerium oxide while incorporating exfoliated platelets of the montmorillonite into the matrix. In addition, calculations from XRD data showed particle sizes ranging from 4.50 to 6.50 nm for the nanocomposite coatings. Raman and FTIR spectroscopy had peaks present for cerium oxide and the layered silicates in the coatings. Cross-sectional scanning electron microscopy and energy-dispersive X-ray spectroscopy confirmed the presence of montmorillonite throughout the cerium oxide matrix.

Cerium oxide films of preferred orientation are electrodeposited under anodic conditions. A complexing ligand, acetate, was used to stabilize the cerium (III) ion in solution for deposition of the thin films. Fourier transform infrared spectroscopy showed that the ligand and metal tended to bind as a weakly bidentate complex. The crystallite size of the films was in the nanometer range as shown by Raman spectroscopy and was calculated from X-ray diffraction data. Crystallite sizes from 6 to 20 nm were obtained under the anodic deposition conditions. Sintering of the (111) oriented films showed an increase in the (111) orientation with temperatures up to 900°C. Also, the crystallite size increased from 20 nm to 120 nm under sintering conditions. Addition of the deposited films to the substrate improved corrosion resistance for the substrate.