Bjerrerossen5990

Background The cardiac ryanodine receptor type 2 (RyR2) is a large homotetramer, located in the sarcoplasmic reticulum (SR), which releases Ca2+ from the SR during systole. The molecular mechanism underlying Ca2+ sensing and gating of the RyR2 channel in health and disease is only partially elucidated. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1) is the most prevalent syndrome caused by RyR2 mutations. Methods and Results This study involves investigation of a family with 4 cases of ventricular fibrillation and sudden death and physiological tests in HEK 293 cells and normal mode analysis (NMA) computation. We found 4 clinically affected members who were homozygous for a novel RyR2 mutation, G3118R, whereas their heterozygous relatives are asymptomatic. G3118R is located in the periphery of the protein, far from the mutation hotspot regions. HEK293 cells harboring G3118R mutation inhibited Ca2+ release in response to increasing doses of caffeine, but decreased the termination threshold for store-overload-induced Ca2+ release, thus increasing the fractional Ca2+ release in response to increasing extracellular Ca2+. NMA showed that G3118 affects RyR2 tetramer in a dose-dependent manner, whereas in the model of homozygous mutant RyR2, the highest entropic values are assigned to the pore and the central regions of the protein. Conclusions RyR2 G3118R is related to ventricular fibrillation and sudden death in recessive mode of inheritance and has an effect of gain of function on the protein. Despite a peripheral location, it has an allosteric effect on the stability of central and pore regions in a dose-effect manner.Bioprosthetic mitral structural valve degeneration and failed mitral valve repair (MVr) have traditionally been treated with reoperative mitral valve surgery. Transcatheter mitral valve-in-valve (MVIV) and valve-in-ring (MVIR) replacement are now feasible, but data comparing these approaches are lacking. We sought to compare the outcomes of (1) reoperative mitral valve replacement (redo-MVR) and MVIV for structural valve degeneration, and (2) reoperative mitral valve repair (redo-MVr) or MVR and MVIR for failed MVr. A literature search of PubMed, Embase, and the Cochrane Library was conducted up to July 31, 2020. Thirty-two studies involving 25 832 patients were included. Redo-MVR was required in ≈35% of patients after index surgery at 10 years, with 5% to 15% 30-day mortality. MVIV resulted in >95% procedural success with 30-day and 1-year mortality of 0% to 8% and 11% to 16%, respectively. Recognized complications included left ventricular outflow tract obstruction (0%-6%), valve migration (0%-9%), and residual regurgitation (0%-6%). Comparisons of redo-MVR and MVIV showed no statistically significant differences in mortality (11.3% versus 11.9% at 1 year, P=0.92), albeit higher rates of major bleeding and arrhythmias with redo-MVR. MVIR resulted in 0% to 34% mortality at 1 year, whereas both redo-MVr and MVR for failed repairs were performed with minimal mortality and durable long-term results. MVIV is therefore a viable alternative to redo-MVR for structural valve degeneration, whereas redo-MVr or redo-MVR is preferred for failed MVr given the suboptimal results with MVIR. However, not all patients will be candidates for MVIV/MVIR because anatomical restrictions may preclude transcatheter options from adequately addressing the underlying pathology.Background Current American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines and European Society of Cardiology guidelines recommend antiarrhythmic drugs (AADs) for maintenance of sinus rhythm in patients with atrial fibrillation. see more We assessed the concordance between healthcare provider real-world practice and current guidelines with respect to first-line AAD rhythm management. Methods and Results Administrative claims data from the deidentified Optum Clinformatics Data Mart database were used. Patients were included if they were initiated on an AAD in 2015 to 2016, had 1 year of continuous data availability before their first AAD pharmacy claim, and had a diagnosis for atrial fibrillation within that period. Concordance was assessed by comparing the AAD initiated by the healthcare provider against guideline recommendations for first-line treatment, given the presence of heart failure, coronary artery disease, both, or neither (as determined by International Classification of Diseases, Ninth Revision and Tenth Revision [ICD-9 and ICD-10] codes). Concordance was also assessed by provider type using Medicare taxonomy codes. For the 15 445 patients included, 51% of healthcare providers initiated AAD treatments with amiodarone, 18% flecainide, 15% sotalol, 8% dronedarone, 5% propafenone, and 2% dofetilide. The overall rate of guideline concordance was 61%, with differences by provider type 67% for electrophysiologists, 61% for cardiologists, and 60% for others (internal medicine, etc). Conclusions There continues to be a sizable gap in concordance between practice and guidelines in first-line rhythm management of patients with atrial fibrillation. Further research is needed to identify possible explanations for non-guideline-recommended use of AADs, in addition to enhanced AAD educational strategies for practitioners.

The causal role of maternal nutrition in orofacial clefts is uncertain. We tested hypotheses that low maternal vitamin B

and low folate status are each associated with an increased risk of isolated cleft lip with or without cleft palate (CL±P) in a case-control study in Tamil Nadu state, India.

Case-mothers of CL±P children (n = 47) and control-mothers of unaffected children (n = 50) were recruited an average of 1.4 years after birth of the index child and plasma vitamin B

, methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured at that time. Logistic regression analyses estimated associations between nutrient biomarkers and case-control status.

Odds ratios (ORs) contrasting biomarker levels showed associations between case-mothers and low versus high plasma vitamin B

(OR = 2.48, 95% CI, 1.02-6.01) and high versus low plasma MMA, an indicator of poor B

status (OR = 3.65 95% CI, 1.21-11.05). Case-control status was not consistently associated with folate or tHcy levels. Low vitamin B

status, when defined by a combination of both plasma vitamin B

and MMA levels, had an even stronger association with case-mothers (OR = 6.54, 95% CI, 1.33-32.09).

Mothers of CL±P children in southern India were 6.5 times more likely to have poor vitamin B

status, defined by multiple biomarkers, compared to control-mothers. Further studies in populations with diverse nutritional backgrounds are required to determine whether poor maternal vitamin B

or folate levels or their interactions are causally related to CL±P.

Mothers of CL±P children in southern India were 6.5 times more likely to have poor vitamin B12 status, defined by multiple biomarkers, compared to control-mothers. Further studies in populations with diverse nutritional backgrounds are required to determine whether poor maternal vitamin B12 or folate levels or their interactions are causally related to CL±P.Background Several randomized trials have compared the patency of coronary artery bypass conduits. All of the published studies, however, have performed pairwise comparisons and a comprehensive evaluation of the patency rates of all conduits has yet to be published. We set out to investigate the angiographic patency rates of all conduits used in coronary bypass surgery by performing a network meta-analysis of the current available randomized evidence. Methods and Results A systematic literature search was conducted for randomized controlled trials comparing the angiographic patency rate of the conventionally harvested saphenous vein, the no-touch saphenous vein, the radial artery (RA), the right internal thoracic artery, or the gastroepiploic artery. The primary outcome was graft occlusion. A total of 4160 studies were retrieved of which 14 were included with 3651 grafts analyzed. The weighted mean angiographic follow-up was 5.1 years. Compared with the conventionally harvested saphenous vein, both the RA (incidence rate ratio [IRR] 0.54; 95% CI, 0.35-0.82) and the no-touch saphenous vein (IRR 0.55; 95% CI, 0.39-0.78) were associated with lower graft occlusion. The RA ranked as the best conduit (rank score for RA 0.87 versus 0.85 for no-touch saphenous vein, 0.23 for right internal thoracic artery, 0.29 for gastroepiploic artery, and 0.25 for the conventionally harvested saphenous vein). Conclusions Compared with the conventionally harvested saphenous vein, only the RA and no-touch saphenous vein grafts are associated with significantly lower graft occlusion rates. The RA ranks as the best conduit. Registration URL https//www.crd.york.ac.uk/prospero; Unique identifier CRD42020164492.A mild and nonreversible tert-butylation of alcohols and phenols can be achieved in high yields using the noncoordinating acid-base catalyst [bis(trifluoromethane)sulfonimide and 2,6-lutidine] with a tert-butylation reagent, tert-butyl 2,2,2-trichloroacetimidate. This method allows the use of substrates containing acid sensitive groups such as ketal, Boc, and boronate esters.Mapping of the local lattice distortion is required to understand the details of the chemical and physical properties of thin films. However, the resolution by the direct microscopic methods was insufficient to detect the local distortion. Here, we have demonstrated that the local distortion of a monatomic film on a substrate is estimated with high resolution using the moiré pattern of the topographic scanning tunneling microscopy image. The analysis focused on the apparently low centers of the moiré pattern of the hexagonal iron nitride monolayer on the Cu(111) substrate. The local distortion was visualized by estimating the displacement of the experimentally detected center position from the ideal position that is extracted from the adjacent center positions. The map of the local distortion revealed that the subsurface impurities are preferentially located on the largely distorted areas. This approach is widely applicable to other thin films on the substrates.This density functional theory (DFT) study reveals a detailed plausible mechanism for the Sc-catalyzed C-H cycloaddition of imidazoles to 1,1-disubstituted alkenes to form all-carbon quaternary stereocenters. The Sc complex binds the imidazole substrate to enable deprotonative C2-H bond activation by the Sc-bound α-carbon to afford the active species. This complex undergoes intramolecular cyclization (C═C into Sc-imidazolyl insertion) with exo-selectivity, generating a β-all-carbon-substituted quaternary center in the polycyclic imidazole derivative. The Sc-bound α-carbon deprotonates the imidazole C2-H bond to deliver the product and regenerate the active catalyst, which is the rate-determining step. Calculations illuminate the electronic effect of the ancillary Cp ligand on the catalyst activity and reveal the steric bias caused by using a chiral catalyst that induce the enantioselectivity. The insights can have implications for advancing rare-earth metal-catalyzed C-H functionalization of imidazoles.