A ortic stenosis (AS) is common in elderly people, affecting 2% of the population ≥65 years old and 4.6% of population ≥75 years old based on Doppler echocardiographic or community studies.1,2 Nowadays, the most common cause of AS is degenerative, and aortic valve calcification (AVC) is the intrinsic mechanism of valvular stiffening and obstruction. [3][4][5][6] Although degenerative AS has long been considered age related, recent studies have demonstrated that it is an active process involving biological pathways with many similarities to atherosclerosis. 7,8 Epidemiological studies identified similar risk factors for calcific AS and coronary atherosclerosis such as age, smoking, elevated cholesterol levels, diabetes mellitus, metabolic syndrome, hypertension, and increase in lipoprotein-a levels. 9 Male sex was also touted as an independent risk factor for AS similar to atherosclerosis, 9 but studies linking valve tissue alterations 10,11 and calcification to AS 12 have not differentiated between men and women. Moreover, studies of aortic valve weight as a surrogate for calcification load showed discordant results with regard to sex, 13,14 and clinically, guidelines do not differentiate between men and women for AS pathophysiology and management. 6 However, the analogy to atherosclerosis suggests that there may be important, yet thus far undefined, sex-related differences in the development of AVC and the transition to AS. This issue can now be analyzed because cardiac computed tomography (CT) provides accurate and reproducible quantification of AVC load, 15 and multidetector CT (MDCT) may prove to be a useful adjunct tool for the evaluation of AS severity. However, previous studies suggested a single set of cutoff values for detecting severe AS regardless of sex, 16 so the impact of sex on the relation between aortic cusp calcification measured by MDCT and hemodynamic severity of AS remains uncertain. The aim of the present study was to determine the differential physiological relationship between AVC Background-Aortic valve calcification (AVC) is the intrinsic mechanism of valvular obstruction leading to aortic stenosis (AS) and is measurable by multidetector computed tomography. The link between sex and AS is controversial and that with AVC is unknown. Methods and Results-We Conclusions-In Aggarwal et al Aortic Valve Calcification in Women 41load and AS hemodynamic severity between men and women. We hypothesized that women reach thresholds for severe AS for lower calcification loads than men and that when MDCT is used for the diagnosis of AS severity, criteria of AVC load would need to be adjusted specifically for each sex. Methods Study PopulationWe prospectively enrolled patients with at least mild calcific AS in whom we performed noncontrast MDCT scan for the evaluation of AVC and comprehensive transthoracic echocardiography within 90 Creatinine Clearance age k gPatients from the Bichat Hospital were enrolled in 2 ongoing prospective studies on aortic valve calcification/stenosis (COFRASA; www.clinica...

Among patients with AS, MG is often discordant from AVA and is determined by multiple factors, valvular (AVC) and non-valvular (arterial compliance) independently of flow. The AVC-load by MDCT, strongly associated with AS severity, allows diagnosis of severe calcified aortic valve disease. At least one-half of the patients with discordant low gradient present with heavy AVC-load reflective of severe calcified aortic valve disease, emphasizing the clinical yield of AVC quantification by MDCT to diagnose and manage these complex patients.

In the unlikely event that a World Wide Web page reports high-quality, accurate, and credible health information it is typically challenging for a lay audience to comprehend. Health care professionals, and the wider community, should inform women with endometriosis of the risk of outdated, inaccurate, or even dangerous information online. The implementation of an information standard will incentivize providers of online information to establish and adhere to codes of conduct.

OBJECTIVEHeart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.RESEARCH DESIGN AND METHODSWe studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.RESULTSAt baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).CONCLUSIONSHeart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.

Purpose To determine whether increasing epinephrine infusion in an in-vivo pig model is associated with an increase in end-systolic magnetic resonance elastography (MRE)-derived effective stiffness. Methods Finite element modeling (FEM) was performed to determine range of myocardial wall thicknesses that could be used for analysis. Then MRE was performed on 5-pigs to measure the end-systolic effective stiffness with epinephrine infusion. Epinephrine was continuously infused intravenously in each pig to increase the heart-rate in increments of 20%. For each such increase end-systolic effective stiffness was measured using MRE. In each pig, Student’s t-test was used to compare effective end-systolic stiffness at baseline and at initial infusion of epinephrine. Least-square linear regression was performed to determine the correlation between normalized end-systolic effective stiffness and increase in heart-rate with epinephrine infusion. Results FEM showed that phase gradient inversion could be performed on wall thickness ~≥1.5cm. In pigs, effective end-systolic stiffness significantly increased from baseline to the first infusion in all pigs (p=0.047). A linear correlation was found between normalized effective end-systolic stiffness and percent increase in heart-rate by epinephrine infusion with R2 ranging from 0.86–0.99 in 4-pigs. In one of the pigs the R2 value was 0.1. A linear correlation with R2=0.58 was found between normalized effective end-systolic stiffness and percent increase in heart-rate when pooling data points from all pigs. Conclusion Noninvasive MRE-derived end-systolic effective myocardial stiffness may be a surrogate for myocardial contractility.

The KRAS p.G12C mutation, prevalent in non-small-cell lung cancer (NSCLC), has only recently become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS p.G12C in patients with advanced NSCLC. Materials and Methods: Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different mutation profiles (KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011 to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed. Results: Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma histology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver mutations, but non-driver co-mutations were common (STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C patients, median (95 % CI) rwOS was 12.0 (9.6-15.3), 9.5 (8.1-13.1), and 6.7 (5.9-10.7) months after first, second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4-5.8), 4.0 (2.8-5.3), and 3.1 (2.4-4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts. Conclusion:The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need for more effective novel treatments.Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; CGDB, clinico-genomic database; CGP, comprehensive genomic profiling; EGFR, epidermal growth factor receptor; EHR, electronic health records; FH-FMI, Flatiron Health-Foundation Medicine; G12C, patients with KRAS p.G12C mutated NSCLC included in study; KEAP1, Kelch-like ECH-associated protein 1 oncogene; KRAS, Kirsten rat sarcoma viral oncogene homolog; KRAS p.G12C, codon 12 glycine-tocysteine substitution of KRAS; MET, mesenchymal-epithelial transition; NGS, next-generation sequencing; NSCLC, non-small-cell lung cancer; NTRK1-3, neurotrophic tyrosine kinases 1-3 gene; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RAS, rat sarcoma viral oncogene homolog; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged-during-transfection gene; ROS1, ROS proto-oncogene 1; rwOS, real-world overall survival; rwPFS, real-world progression-free survival; STK11/LKB1, serine/threonine kinase 11, liver kinase B1; TP53, tumor protein p53; Triple WT, KRAS/EGFR/ALK wild-type; VEGF, vascular endothelial growth factor.

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45–0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33–0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.

Objectives Study was conducted to determine acceptability, efficacy, safety, return of fertility with Implanon. Methods Volunteers having regular menstruation, requiring spacing formed study population. Implanon was inserted within 5 days of LMP or concurrent with MTP. Woman was asked to record bleeding pattern, side effects. Implanon duration was 3 years but Implanon was removed before, if patient wanted pregnancy/for side effects. Subjects who did not adopt family planning method after removal were followed up for return of ovulation and pregnancy. Results 200 subjects were enrolled (160 within 5 days of LMP, 40 concurrent with MTP). 74 implanon removals were done. (16 after tenure completion, 58 for other reasons.) 16% cases discontinued implanon for polymenorrhagia, 10% for irregular bleeding, 4.5% for amenorrhea. There was no failure of implanon. 40% had return of ovulation within one month, 95.8% conceived within 12 months. Conclusions Implanon is safe, effective, well accepted method of contraception.