Unraveling the Molecular Dance: Insights into TREM2/DAP12 Complex Formation in Alzheimer's Disease through Molecular Dynamics Simulations.

Alzheimer's disease (AD) is a widespread neurodegenerative condition affecting millions globally. Recent research has implicated variants of the triggering receptor expressed in myeloid cells 2 (TREM2) as risk factors for AD. TREM2, an immunomodulatory receptor on microglial surfaces, plays a pivotal role in regulating microglial activation by association with DNAX-activation protein 12 (DAP12). Despite its significance, the mechanism underlying the formation of the complex between the transmembrane domains (TMDs) of TREM2 and DAP12 remains unclear. This study employs multiscale molecular dynamics (MD) simulations to investigate three TMD complex models, including two derived from experiments and one generated by AlphaFold2. Conducted within a lipid membrane consisting of an 80:20 mixture of phosphatidylcholine (POPC) and cholesterol, our analysis reveals hydrogen-bonding interactions between K26 of TREM2 and D16 of DAP12 in all three models, consistent with previous experimental findings. Our results elucidate the different spatial conformations observed in the models and offer insights into the structure of the TREM2/DAP12 TMD complex. Furthermore, we elucidate the role of charged residues in the assembly structure of the complex within the lipid membrane. These findings enhance our understanding of the molecular mechanism governing TREM2/DAP12 complex formation, providing a foundation for designing novel therapeutic strategies to address AD and other neurodegenerative diseases.

Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación / Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes

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Abstract This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Efficacy, Effectiveness, and Safety of COVID-19 Vaccine Compared to Placebo in Preventing COVID-19 Infection among 12-17 Years Old: A Systematic Review.

Objectives: The World Health Organization recently revised their recommendations and considered healthy children and adolescents as low priority group for COVID-19 vaccine. This review comprehensively assessed existing clinical evidence on COVID-19 vaccine in 12-17 years old. Methods: Included in this review were any type of study that investigated the efficacy, immunogenicity, safety, and effectiveness of COVID-19 vaccine on protection against SARS-COV-2 infection in 12-17 years old. Various electronic databases were searched up to March 15, 2023. Studies were screened, data extracted, risk of bias appraised, and certainty of evidence was judged using GRADE. Review Manager 5.4 was used to estimate pooled effects. Difference between the two groups was described as mean difference for continuous variables and as relative risk or odds ratio for categorical variables. Results: There were six randomized controlled trials and 16 effectiveness studies (8 cohorts and 8 case control). Low certainty evidence showed that BNT162b2 (Pfizer) was effective, immunogenic, and safe in healthy adolescents. There were 15 effectiveness studies on BNT162b2 (Pfizer) in healthy adolescent and one on immunocompromised patients. It was protective against infection with any of the variants, with higher protection against Delta than Omicron. BNT162b2 is protective against hospitalization and emergency and urgent care (high certainty); and critical care and MIS-C (low). Very low certainty evidence noted that BNT 162b2 was also immunogenic in 12-21 years old with rheumatic diseases while on immunomodulatory treatment but with possible increased exacerbation of illness. Low certainty evidence demonstrated that mRNA-1273 (Moderna) was effective, immunogenic, and safe. Low to very low certainty evidence were noted on the safety and immunogenicity of two vector base vaccines (ChAdOx1-19 and Ad5 vector COVID vaccine) and two inactivated vaccines (CoronaVac and BBIBP CorV). CONCLUSION: There is presently low certainty evidence on the use of RNA vaccines in 12-17 years old. The recommendation on its use is weak. There is presently insufficient evidence for the use of inactivated and vector-based COVID-19 vaccines. Different countries should consider whether to vaccinate healthy adolescent without comprising the other recommended immunization and health priorities that are crucial for this age group. Other factors including cost-effectiveness of vaccination and disease burden should be accounted.

Secondary nucleation in symmetric binary SALR mixtures.

Monte Carlo simulation is used to study secondary nucleation, fissioning, or 'reproduction', of giant clusters in a symmetric binary model fluid with competing short-range (SA) and long-range (LR) interactions. Previous work [M. B. Sweatman, Mol. Phys., 116(15-16), 1945-1952] suggests that a pure SALR fluid can exhibit secondary nucleation if the solute concentration is slowly increased. We show this is also true for a binary symmetric SALR mixture where the cross-interactions can be tuned to generate clusters with three different kinds of structure; (i) independent clusters of each component, (ii) contact clusters of different components, and (iii) mixed clusters. In each case, the overall concentration of each component is identical. This binary model is an initial step towards using SALR fluids to model the intra-cellular space of biological cells that contain a wide range of membraneless organelles and the chemical 'soup' at the origin of life.

A Core Outcome Set for Research Evaluating Interventions to Enable Communication in Patients With an Artificial Airway: An International Delphi Consensus Study (Comm-COS).

OBJECTIVES: Critically ill adults requiring artificial airways experience profound communication deficits. Studies of interventions supporting communication report disparate outcomes, creating subsequent challenges in the interpretation of their effectiveness. Therefore, we aimed to develop international consensus for a communication core outcome set (Comm-COS) for future trials of communication interventions in this population. DESIGN: 1) Systematic review, 2) patient/family interviews, 3) two-round modified Delphi, and 4) virtual consensus meetings with a final voting round. A multidisciplinary expert steering committee oversaw all stages. SETTING: Interviews and consensus meetings were conducted via videoconferencing. Digital methods were used for Delphi and final Comm-COS voting. SUBJECTS: Three stakeholder groups: 1) patient and family members with lived experience within 3 years, 2) clinicians with experience working in critical care, and 3) researchers publishing in the field. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We identified 59 outcomes via our systematic review, 3 unique outcomes from qualitative interviews, and 2 outcomes from our steering committee. Following item reduction, 32 outcomes were presented in Delphi round 1; 134 participants voted; 15 patient/family (11%), 91 clinicians (68%), and 28 researchers (21%). Nine additional outcomes were generated and added to round 2; 106 (81%) participants voted. Following completion of the consensus processes, the Comm-COS includes seven outcomes: 1) changes in emotions and wellbeing associated with ability to communicate, 2) physical impact of communication aid use, 3) time to functional communication, 4) ability to communicate healthcare needs (comfort/care/safety/decisions), 5) conversation agency, 6) ability to establish a communication connection to develop and maintain relationships, and 7) acceptability of the communication intervention. CONCLUSIONS: This is the first COS to specifically focus on communication for critically ill adults. Limitations for operationalization include selection of measures to use with these outcomes. Identification of suitable measures and adoption of the Comm-COS in future trials will help establish effective interventions to ameliorate the highly prevalent and negative experience of communicative incapacity.

Rapid Peptide Cyclization Inspired by the Modular Logic of Nonribosomal Peptide Synthetases.

Nonribosomal cyclic peptides (NRcPs) are structurally complex natural products and a vital pool of therapeutics, particularly antibiotics. Their structural diversity arises from the ability of the multidomain enzyme assembly lines, nonribosomal peptide synthetases (NRPSs), to utilize bespoke nonproteinogenic amino acids, modify the linear peptide during elongation, and catalyze an array of cyclization modes, e.g., head to tail, side chain to tail. The study and drug development of NRcPs are often limited by a lack of easy synthetic access to NRcPs and their analogues, with selective macrolactamization being a major bottleneck. Herein, we report a generally applicable chemical macrocyclization method of unprecedented speed and selectivity. Inspired by biosynthetic cyclization, it combines the deprotected linear biosynthetic precursor peptide sequence with a highly reactive C-terminus to produce NRcPs and analogues in minutes. The method was applied to several NRcPs of varying sequences, ring sizes, and cyclization modes including rufomycin, colistin, and gramicidin S with comparable success. We thus demonstrate that the linear order of modules in NRPS enzymes that determines peptide sequence encodes the key structural information to produce peptides conformationally biased toward macrocyclization. To fully exploit this conformational bias synthetically, a highly reactive C-terminal acyl azide is also required, alongside carefully balanced pH and solvent conditions. This allows for consistent, facile cyclization of exceptional speed, selectivity, and atom efficiency. This exciting macrolactamization method represents a new enabling technology for the biosynthetic study of NRcPs and their development as therapeutics.

Clinical outcomes with thin versus thick strut polymer-free biolimus-coated stents at 3 years.

BACKGROUND: For high bleeding-risk patients (HBR) undergoing percutaneous coronary intervention (PCI), the LEADERS FREE (LF) and LEADERS FREE II (LF II) trials established the safety and efficacy of a stainless steel polymer-free biolimus-coated stent (SS-BCS) with 30 days of dual antiplatelet treatment (DAPT). The LEADERS FREE III (LF III) trial investigated clinical outcomes after PCI with the next-generation cobalt-chromium thin-strut polymer-free biolimus-coated stent (CoCr-BCS) in HBR patients. AIMS: To report the final 3-year results of the LF III trial and compare them to LF II. METHODS: LF III was a prospective, multicentre, open-label single-arm study to evaluate the safety and efficacy of the CoCr-BCS stent. The primary safety endpoint was the composite of cardiac death (CD), myocardial infarction(MI) or definite/probable stent thrombosis (ST). The primary efficacy endpoint was clinically driven target lesion revascularisation (cd-TLR). We performed a propensity-matched comparison to the 3-year outcomes of LF II. RESULTS: After 3 years, CD/MI/ST had occurred in 57 patients (15%, 95% CI 11.8% to 19%) and cd-TLR in 23 (6.2%, 95% CI 4.1% to 9.2%) patients. In a propensity-matched comparison of patients treated with the CoCr-BCS versus the SS-BCS, there were similar rates of CD (6.6% vs 7.8%, p=0.50), MI (7.1% vs 8.3%, p=0.47) and definite/probable ST (1.1% vs 2%, HR 0.56, 95% CI 0.16 to 1.93, p=0.35). The rates of cd-TLR were 5.3% with CoCr-BCS versus 9.8% with SS-BCS (HR 0.54, 95% CI 0.31 to 0.96, p=0.03). CONCLUSION: LF III confirms the long-term safety and efficacy of the CoCr-BCS in HBR patients treated with 1 month of DAPT. TRIAL REGISTRATION NUMBER: NCT02843633, NCT03118895.

Outcomes of ultra-low contrast percutaneous coronary intervention in patients with advanced chronic kidney disease.

BACKGROUND: Coronary angiography and percutaneous coronary intervention (PCI) in patients with chronic kidney disease (CKD) is associated with increased risk of contrast induced nephropathy (CIN) and requirement for renal replacement therapy (RRT). OBJECTIVES: We aimed to evaluate our single center experience of ultra-low contrast PCI in patients with CKD and to characterize 1 year outcomes. METHODS: We performed a retrospective analysis of ultra-low contrast PCI at our institution between 2016 and 2022. Patients with CKD3b-5 (eGFR <45 mL/min/1.73m2), not on RRT who underwent ultra-low contrast PCI ( < 30 mL of contrast during PCI) were included. Primary outcomes included change in eGFR post-procedurally, and death, RRT requirement, and major adverse cardiac events (MACE) at 1 year follow-up. RESULTS: One hundred patients were included in the study. The median age was 67 years old and 28% were female. The median baseline eGFR was 21.5 mL/min/1.73m2 (IQR 14.08-32.0 mL/min/1.73m2). A median of 8.0 mL (IQR 0-15 mL) of contrast was used during PCI. Median contrast use to eGFR ratio was 0.37 (IQR 0-0.59). There was no significant difference between pre-and postprocedure eGFR (p = 0.84). At 1 year, 8% of patients died, 11% required RRT and 33% experienced MACE. The average time of RRT initiation was 7 months post-PCI. Forty-four patients were undergoing renal transplant evaluation, of which 17 (39%) received a transplant. CONCLUSIONS: In patients with advanced CKD, ultra-low contrast PCI is feasible and safe with minimal need for peri-procedural RRT. Moreover, ultra-low contrast PCI may allow for preservation of renal function in anticipation of renal transplantation.

Effects of basic carbohydrate counting versus standard dietary care for glycaemic control in type 2 diabetes (The BCC Study): a randomised, controlled trial.

BACKGROUND: Clinical guidelines recommend basic carbohydrate counting (BCC), or similar methods to improve carbohydrate estimation skills and to strive for higher consistency in carbohydrate intake potentially improving glycaemic control. However, evidence for this approach in type 2 diabetes (T2D) is limited. OBJECTIVE: To examine the efficacy of a structured education program in BCC as add-on to standard dietary care on glycaemic control in individuals with T2D. METHODS: The BCC Study was a randomized, controlled, open-label, parallel-group trial. Individuals with T2D aged 18-75 years with glycated haemoglobin A1c (HbA1c) 53-97 mmol/mol (7.0-11.0%) were randomly assigned (1:1) to BCC or standard dietary care. The primary outcomes were differences in changes in HbA1c or glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) between groups after six months of intervention. RESULTS: Between September 2018 and July 2021, 48 participants were randomly assigned, 23 to BCC and 25 to standard dietary care. Seven participants did not receive the allocated intervention. From a baseline-adjusted mean of 65 mmol/mol (95% CI 62-68 [8.1%, 7.8-8.4]), HbA1c changed by -5 mmol/mol (-8 to -1 [-0.5%, -0.7 to -0.1]) in BCC and -3 mmol/mol (-7 to 1 [-0.3%, -0.6 to 0.1]) in standard care with an estimated treatment effect of -2 mmol/mol (-7 to 4 [-0.2%, -0.6 to 0.4]); p = 0.554. From a baseline-adjusted mean of 4.2 mmol/l (3.7 to 4.8), MAGE changed by -16% (-33 to 5) in BCC and by -3% (-21 to 20) in standard care with an estimated treatment effect of -14% (-36 to 16); p = 0.319. Only median carbohydrate estimation error in favour of BCC (estimated treatment difference -55% (-70 to -32); p < 0.001) remained significant after multiple testing adjustment. CONCLUSIONS: No glycaemic effects were found but incorporating BCC as a supplementary component to standard dietary care led to improved skills in estimating carbohydrate intake among individuals with T2D.

The Endothelial Glycocalyx in Pig-to-Baboon Cardiac Xenotransplantation-First Insights.

Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation. Despite these achievements, acute vascular rejection still presents a challenge for long-term xenograft acceptance and new insights into innate and adaptive immune responses as well as detailed characterizations of signaling pathways are necessary. In allotransplantation, endothelial cells and their sugar-rich surface-the endothelial glycocalyx-are known to influence organ rejection. In xenotransplantation, however, only in vitro data exist on the role of the endothelial glycocalyx so far. Thus, in the current study, we analyzed the changes of the endothelial glycocalyx components hyaluronan, heparan sulfate and syndecan-1 after pig-to-baboon cardiac xenotransplantations in the perioperative (n = 4) and postoperative (n = 5) periods. These analyses provide first insights into changes of the endothelial glycocalyx after pig-to-baboon cardiac xenotransplantation and show that damage to the endothelial glycocalyx seems to be comparable or even less pronounced than in similar human settings when current strategies of cardiac xenotransplantation are applied. At the same time, data from the experiments where current strategies, like non-ischemic preservation, growth inhibition or porcine cytomegalovirus (a porcine roseolovirus (PCMV/PRV)) elimination could not be applied indicate that damage of the endothelial glycocalyx also plays an important role in cardiac xenotransplantation.

Predictors and 5-Year Clinical Outcomes of Pacemaker After TAVR: Analysis From the PARTNER 2 SAPIEN 3 Registries.

BACKGROUND: Conduction disturbances requiring a permanent pacemaker (PPM) are a frequent complication of transcatheter aortic valve replacement (TAVR) with few reports of rates, predictors, and long-term clinical outcomes following implantation of the third-generation, balloon-expandable SAPIEN 3 (S3) transcatheter heart valve (THV). OBJECTIVES: The aim of this study was to investigate the rates, predictors, and long-term clinical outcomes of PPM implantation following TAVR with the S3 THV. METHODS: The current study included 857 patients in the PARTNER 2 S3 registries with intermediate and high surgical risk without prior PPM, and investigated predictors and 5-year clinical outcomes of new PPM implanted within 30 days of TAVR. RESULTS: Among 857 patients, 107 patients (12.5%) received a new PPM within 30 days after TAVR. By multivariable analysis, predictors of PPM included increased age, pre-existing right bundle branch block, larger THV size, greater THV oversizing, moderate or severe annulus calcification, and implantation depth >6 mm. At 5 years (median follow-up 1,682.0 days [min 2.0 days, max 2,283.0 days]), new PPM was not associated with increased rates of all-cause mortality (Adj HR: 1.20; 95% CI: 0.85-1.70; P = 0.30) or repeat hospitalization (Adj HR: 1.22; 95% CI: 0.67-2.21; P = 0.52). Patients with new PPM had a decline in left ventricular ejection fraction at 1 year that persisted at 5 years (55.1 ± 2.55 vs 60.4 ± 0.65; P = 0.02). CONCLUSIONS: PPM was required in 12.5% of patients without prior PPM who underwent TAVR with a SAPIEN 3 valve in the PARTNER 2 S3 registries and was not associated with worse clinical outcomes, including mortality, at 5 years. Modifiable factors that may reduce the PPM rate include bioprosthetic valve oversizing, prosthesis size, and implantation depth.

First Experience With Augmented Reality Guidance for Cerebral Embolic Protection During TAVR.

Background: Augmented reality (AR) guidance holds potential to improve transcatheter interventions by enabling visualization of and interaction with patient-specific 3-dimensional virtual content. Positioning of cerebral embolic protection devices (CEP) during transcatheter aortic valve replacement (TAVR) increases patient exposure to radiation and iodinated contrast, and increases procedure time. AR may enhance procedural guidance and facilitate a safer intervention. Objectives: The purpose of this study was to develop and test a novel AR guidance system with a custom user interface that displays virtual, patient-specific 3-dimensional anatomic models, and assess its intraprocedural impact during CEP placement in TAVR. Methods: Patients undergoing CEP during TAVR were prospectively enrolled and assigned to either AR guidance or control groups. Primary endpoints were contrast volume used prior to filter placement, times to filter placement, and fluoroscopy time. Postprocedure questionnaires were administered to assess intraprocedural physician experience with AR guidance. Results: A total of 24 patients presenting for TAVR were enrolled in the study (12 with AR guidance and 12 controls). AR guidance eliminated the need for aortic arch angiograms prior to device placement thus reducing contrast volume (0 mL vs 15 mL, P < 0.0001). There was no significant difference in the time required for filter placement or fluoroscopy time. Postprocedure questionnaires indicated that AR guidance increased confidence in wiring of the aortic arch and facilitated easier device placement. Conclusions: We developed a novel AR guidance system that eliminated the need for additional intraprocedural angiograms prior to device placement without any significant difference in time to intervention and offered a subjective improvement in performance of the intervention.

TRISCEND II: Novel Randomized Trial Design for Transcatheter Tricuspid Valve Replacement.

Severe tricuspid regurgitation remains largely undertreated given limited treatment options. Transcatheter tricuspid valve interventions have emerged as a promising therapy for these patients, and the TRISCEND II pivotal trial is the first randomized controlled trial to evaluate transcatheter tricuspid valve replacement (TTVR). The TRISCEND II pivotal trial studies the transcatheter EVOQUE (Edwards Lifesciences, Irvine, California) tricuspid valve replacement system using a United States Food and Drug Administration Breakthrough Device Designation-a program intended to provide timely access to medical devices by speeding up development, assessment, and review. The TRISCEND II trial is a prospective, multicenter trial that randomizes patients with symptomatic severe tricuspid regurgitation to treatment with either TTVR in conjunction with optimal medical therapy or optimal medical therapy alone. The trial's novel 2-phase design evaluates 30-day safety and 6-month effectiveness end points for the first 150 patients in the initial phase and a 1-year safety and effectiveness end point for the full cohort of 400 patients in the second phase. The TRISCEND II trial's 2-phase trial design provided an opportunity for early review and led to the first commercial approval of a TTVR system. In conclusion, the design of the TRISCEND II trial will likely inform future transcatheter tricuspid device trials.

2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II.

BACKGROUND: The REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, "responders" (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. OBJECTIVES: This study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. METHODS: The study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. RESULTS: In 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). CONCLUSIONS: At 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033).

Effect of Sex and Flow Status on Outcomes After Surgical or Transcatheter Aortic Valve Replacement.

Background: Low stroke volume index <35 ml/m2 despite preserved ejection fraction (paradoxical low flow [PLF]) is associated with adverse outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). However, whether the risk associated with PLF is similar in both sexes is unknown. Objectives: The purpose of this study was to analyze the risk associated with PLF in severe aortic stenosis for men and women randomized to TAVR or SAVR. Methods: Patients with ejection fraction ≥50% from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were stratified by sex and treatment arm. The impact of PLF on the 2-year occurrence of the composite of death or heart failure hospitalization (primary endpoint) and of all-cause mortality alone (secondary endpoint) was analyzed. Analysis of variance was used to assess baseline differences between groups. Multivariate Cox regression analysis was used to identify predictors of the endpoint. Results: Out of 2,242 patients, PLF was present in 390 men and 239 women (30% vs 26%, P = 0.06). PLF was associated with a higher rate of NYHA functional class III to IV dyspnea (60% vs 54%, P < 0.001) and a higher prevalence of atrial fibrillation (39% vs 24%, P < 0.001). PLF was a significant predictor of the primary endpoint among women undergoing SAVR in multivariate analysis (adjusted HR: 2.25 [95% CI: 1.14-4.43], P = 0.02) but was not associated with a worse outcome in any of the other groups (all P > 0.05). Conclusions: In women with PLF, TAVR may improve outcomes compared to SAVR. PLF appears to have less impact on outcomes in men.

Stress-dependent condensate formation regulated by the ubiquitin-related modifier Urm1.

The ability of proteins and RNA to coalesce into phase-separated assemblies, such as the nucleolus and stress granules, is a basic principle in organizing membraneless cellular compartments. While the constituents of biomolecular condensates are generally well documented, the mechanisms underlying their formation under stress are only partially understood. Here, we show in yeast that covalent modification with the ubiquitin-like modifier Urm1 promotes the phase separation of a wide range of proteins. We find that the drop in cellular pH induced by stress triggers Urm1 self-association and its interaction with both target proteins and the Urm1-conjugating enzyme Uba4. Urmylation of stress-sensitive proteins promotes their deposition into stress granules and nuclear condensates. Yeast cells lacking Urm1 exhibit condensate defects that manifest in reduced stress resilience. We propose that Urm1 acts as a reversible molecular "adhesive" to drive protective phase separation of functionally critical proteins under cellular stress.

Defining high bleeding risk in patients undergoing transcatheter aortic valve implantation: a VARC-HBR consensus document.

The identification and management of patients at high bleeding risk (HBR) undergoing transcatheter aortic valve implantation (TAVI) are of major importance, but the lack of standardised definitions is challenging for trial design, data interpretation, and clinical decision-making. The Valve Academic Research Consortium for High Bleeding Risk (VARC-HBR) is a collaboration among leading research organisations, regulatory authorities, and physician-scientists from Europe, the USA, and Asia, with a major focus on TAVI-related bleeding. VARC-HBR is an initiative of the CERC (Cardiovascular European Research Center), aiming to develop a consensus definition of TAVI patients at HBR, based on a systematic review of the available evidence, to provide consistency for future clinical trials, clinical decision-making, and regulatory review. This document represents the first pragmatic approach to a consistent definition of HBR evaluating the safety and effectiveness of procedures, devices and drug regimens for patients undergoing TAVI..

Rumination in patients with major depressive disorder before and after antidepressant treatment.

BACKGROUND: Rumination is a maladaptive response to distress characteristic of Major Depressive Disorder (MDD). It is unclear to what degree rumination is associated with depression severity prior to treatment and how it responds to antidepressant treatment. Therefore, we evaluated the association between rumination and depression severity in 92 untreated patients with MDD and explored the changes in rumination after initiation of antidepressant medication. METHOD: We measured rumination using the Rumination Response Scale (RRS) and depression severity with the Hamilton Depression Rating Scale (HDRS17 or HDRS6) before and after initiation of 12 weeks of antidepressant treatment. The association between RRS and pre-treatment HDRS17 was evaluated using a linear regression model. RRS at week 4, 8, and 12 across treatment response categories (remission vs. non-response) were evaluated using a mixed effect model. RESULTS: RRS was positively associated with depression severity prior to treatment at a trend level (p = 0.06). After initiation of treatment RRS decreased significantly (p < 0.0001) and remitters exhibited lower rumination compared to non-responders at week 4 (p = 0.03), 8 (p = 0.01), and 12 (p = 0.007). LIMITATIONS: The study had no placebo group. CONCLUSIONS: Although pre-treatment rumination did not significantly associate with depressive symptoms, rumination was closely connected to change in depressive symptoms. Tormented patients could be reassured that rumination symptoms may be alleviated over the course of antidepressant treatment.

Leaflet modification before transcatheter aortic valve implantation in patients at risk for coronary obstruction: the ShortCut study.

BACKGROUND AND AIMS: This trial sought to assess the safety and efficacy of ShortCut, the first dedicated leaflet modification device, prior to transcatheter aortic valve implantation (TAVI) in patients at risk for coronary artery obstruction. METHODS: This pivotal prospective study enrolled patients with failed bioprosthetic aortic valves scheduled to undergo TAVI and were at risk for coronary artery obstruction. The primary safety endpoint was procedure-related mortality or stroke at discharge or 7 days, and the primary efficacy endpoint was per-patient leaflet splitting success. Independent angiographic, echocardiographic, and computed tomography core laboratories assessed all images. Safety events were adjudicated by a clinical events committee and data safety monitoring board. RESULTS: Sixty eligible patients were treated (77.0 ± 9.6 years, 70% female, 96.7% failed surgical bioprosthetic valves, 63.3% single splitting and 36.7% dual splitting) at 22 clinical sites. Successful leaflet splitting was achieved in all (100%; 95% confidence interval [CI] 94-100.0%, p<0.001) patients. Procedure time, including imaging confirmation of leaflet splitting, was 30.6 ± 17.9 min. Freedom from the primary safety endpoint was achieved in 59 (98.3%; 95% CI [91.1-100%]) patients, with no mortality and one (1.7%) disabling stroke. At 30 days, freedom from coronary obstruction was 95% (95% CI 86.1-99.0%). Within 90 days, freedom from mortality was 95% (95% CI 86.1-99.0%]), without any cardiovascular deaths. CONCLUSIONS: Modification of failed bioprosthetic aortic valve leaflets using ShortCut was safe, achieved successful leaflet splitting in all patients, and was associated with favorable clinical outcomes in patients at risk for coronary obstruction undergoing TAVI.