Comparison of Transcatheter Edge-to-Edge Mitral Valve Repair for Primary Mitral Regurgitation Outcomes to Hospital Volumes of Surgical Mitral Valve Repair.

BACKGROUND: Transcatheter edge-to-edge mitral valve (MV) repair (TEER) is an effective treatment for patients with primary mitral regurgitation at prohibitive risk for surgical MV repair (MVr). High-volume MVr centers and high-volume TEER centers have better outcomes than low-volume centers, respectively. However, whether MVr volume predicts TEER outcomes remains unknown. We hypothesized that high-volume MV surgical centers would have superior risk-adjusted outcomes for TEER than low-volume centers. METHODS: We combined data from the American College of Cardiology/Society of Thoracic Surgeons Transcatheter Valve Therapy registry and the Society of Thoracic Surgeons adult cardiac surgery database. MVr was defined as leaflet resection or artificial chords with or without annuloplasty and was evaluated as a continuous variable and as predefined categories (<25, 25-49, and ≥50 MV repairs/year). A generalized linear mixed model was used to evaluate risk-adjusted in-hospital/30-day mortality, 30-day heart failure readmission, and TEER success (mitral regurgitation ≤2+ and gradient <5 mm Hg). RESULTS: The study comprised 41 834 patients from 500 sites of which 332 (66.4%) were low, 102 (20.4%) intermediate, and 66 (13.2%) high-volume surgical centers (P<0.001). TEER success was 54.6% and was not statistically significantly different across MV surgical site volumes (P=0.4271). TEER mortality at 30 days was 3.5% with no significant difference across MVr volume on unadjusted (P=0.141) or adjusted (P=0.071) analysis of volume as a continuous variable. One-year mortality was 15.0% and was lower for higher MVr volume centers when adjusted for clinical and demographic variables (P=0.027). Heart failure readmission at 1 year was 9.4% and was statistically significantly lower in high-volume centers on both unadjusted (P=0.017) or adjusted (P=0.015) analysis. CONCLUSIONS: TEER can be safely performed in centers with low volumes of MV repair. However, 1-year mortality and heart failure readmission are superior at centers with higher MVr volume.

Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study.

Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively associated with prescribed (standardized) antipsychotic dose (beta(SE) = 0.0435(0.009), p = 0.0006) and antipsychotic polypharmacy defined as taking ≥2 antipsychotics (OR = 1.10, CI = 1.05-1.21, p = 0.0073). The direction of effect was similar in all five independent cohorts. These findings indicate that genotypes may aid clinically relevant decisions on individual patients´ antipsychotic treatment. Further, the findings illustrate how real-world data have the potential to generate results needed for future precision medicine approaches in psychiatry.

Novel Identification of Cysteinyl Derivatives of Toxic Clozapine Nitrenium Ions and the Effect of Valproic Acid on Metabolite Formation: A Study Using Reprocessed High-Resolution Mass Spectra of Analyzed Therapeutic Drug Monitoring Samples.

BACKGROUND: Clozapine (CLZ) use is hampered by the risk of granulocyte toxicity, which is associated with the formation of nitrenium ions and the concurrent use of valproic acid (VPA). These highly reactive nitrenium ions cannot be measured in vivo. Instead, deactivated cysteinyl conjugates may potentially be detected. The aim of this study was to develop a novel method for identifying cysteinylated derivates of CLZ nitrenium ions to investigate the effect of VPA on their formation using therapeutic drug monitoring data. METHODS: A population comprising 93 VPA comedicated and 162 control patients from a therapeutic drug monitoring (TDM) service in Oslo, Norway, was included. Reprocessing of ultraperformance liquid chromatography high-resolution mass spectra (UHPLC-HR-MS) of previously analyzed TDM samples, combined with the assessment of MS/MS fragmentation patterns, was performed to identify the CLZ cysteinyl conjugates. Smoking, which induces CLZ metabolism, was assessed by detecting cotinine in the reprocessed mass spectra. RESULTS: By reprocessing the UHPLC-HR-MS files of the TDM analyses and reviewing the MS/MS fragment profiles, four cysteinyl conjugates of CLZ were identified. The formations of CLZ cysteinyl (CLZ-Cys 1+ ) and CLZ- N -oxide cysteinyl (CLZ-NOX-Cys 1+ ) were 1.5-fold ( P = 0.038) and 2.1-fold ( P < 0.001) higher in VPA-treated patients than those in the controls. In agreement with previous studies, a 45% reduction in N -desmethylclozapine formation was observed in VPA-treated patients ( P < 0.001). CONCLUSIONS: A novel method for detecting cysteinyl conjugates of CLZ was developed. Application of this method indicated that VPA significantly increased the formation of CLZ-Cys 1+ metabolites, which might explain the granulocyte toxicity reported after adding VPA to CLZ treatment. The developed method opens new avenues for investigating CLZ toxicity, e.g. by correlating cysteinyl conjugates and granulocyte counts in patients.

Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism.

AIMS: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes. METHODS: The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio. RESULTS: A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P < .0001). CONCLUSION: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.

Echocardiographic Outcomes With Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients.

BACKGROUND: The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). OBJECTIVES: This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. METHODS: An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. RESULTS: In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). CONCLUSIONS: The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833).

Mitral Valve Transcatheter Edge-to-Edge Repair Volumes and Trends.

Background: Despite an association between operator volumes and procedural success, there remains an incomplete understanding of the contemporary utilization and procedural volumes for mitral valve transcatheter edge-to-edge repair (MTEER). We aimed to identify annual operator procedural volumes, temporal trends, and geographic variability for MTEER among Medicare patients in the United States (US). Methods: We queried the National Medicare Provider Utilization and Payment Database for a CPT code (33418) specific for MitraClip device from 2015 through 2019. We analyzed annual operator procedural volumes and incidence and identified longitudinal and geographic trends in MTEER utilization. Results: From 2015 through 2019, a total of 27,034 MTEER procedures were performed among Medicare patients in the US. The nationwide incidence increased from 6.2 per 100,000 patients in 2015 to 23.8 per 100,000 patients in 2019, a 283% increase over the study period (Ptrend < 0.001). The incidence of MTEER by state varied by nearly 900% (range 5.5 to 54.9 per 100,000 person-years). In 2019, the mean annual MTEER operator annual volume was 9.1 MTEER procedures and had grown from 6.2 per year in 2015. Conclusions: In this nationwide study of Medicare beneficiaries in the United States, we identified a significant and sustained increase in the utilization of MTEER devices and operators and growth in annual procedural volumes from 2015 through 2019 with considerable variability in utilization by state. Further studies are needed to understand the clinical impact of variability in utilization and the optimal procedural volumes to ensure high efficacy outcomes and maintain critical access to MTEER therapies.

One-Year Outcomes From the CLASP IID Randomized Trial for Degenerative Mitral Regurgitation.

BACKGROUND: The CLASP IID (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical) trial is the first randomized controlled trial comparing the PASCAL system and the MitraClip system in prohibitive risk patients with significant symptomatic degenerative mitral regurgitation (DMR). OBJECTIVES: The study sought to report primary and secondary endpoints and 1-year outcomes for the full cohort of the CLASP IID trial. METHODS: Prohibitive-risk patients with 3+/4+ DMR were randomized 2:1 (PASCAL:MitraClip). One-year assessments included secondary effectiveness endpoints (mitral regurgitation [MR] ≤2+ and MR ≤1+), and clinical, echocardiographic, functional, and quality-of-life outcomes. Primary safety (30-day composite major adverse events [MAE]) and effectiveness (6-month MR ≤2+) endpoints were assessed for the full cohort. RESULTS: Three hundred patients were randomized (PASCAL: n = 204; MitraClip: n = 96). At 1 year, differences in survival, freedom from heart failure hospitalization, and MAE were nonsignificant (P > 0.05 for all). Noninferiority of the PASCAL system compared with the MitraClip system persisted for the primary endpoints in the full cohort (For PASCAL vs MitraClip, the 30-day MAE rates were 4.6% vs 5.4% with a rate difference of -0.8% and 95% upper confidence bound of 4.6%. The 6-month MR≤2+ rates were 97.9% vs 95.7% with a rate difference of 2.2% and 95% lower confidence bound (LCB) of -2.5%, for, respectively). Noninferiority was met for the secondary effectiveness endpoints at 1 year (MR≤2+ rates for PASCAL vs MitraClip were 95.8% vs 93.8% with a rate difference of 2.1% and 95% LCB of -4.1%. The MR≤1+ rates were 77.1% vs 71.3% with a rate difference of 5.8% and 95% LCB of -5.3%, respectively). Significant improvements in functional classification and quality of life were sustained in both groups (P <0.05 for all vs baseline). CONCLUSIONS: The CLASP IID trial full cohort met primary and secondary noninferiority endpoints, and at 1 year, the PASCAL system demonstrated high survival, significant MR reduction, and sustained improvements in functional and quality-of-life outcomes. Results affirm the PASCAL system as a beneficial therapy for prohibitive-surgical-risk patients with significant symptomatic DMR.

Cavity Click Chemistry: Cavity-Catalyzed Azide-Alkyne Cycloaddition.

Click chemistry, which refers to chemical reactions that are fast and selective with high product yields, has become a powerful approach in organic synthesis and chemical biology. Due to the cytotoxicity of the transition metals employed in click chemistry reactions, a search for novel metal-free alternatives continues. Herein, we demonstrate that an optical cavity can be utilized as a metal-free alternative in the click chemistry cycloaddition reaction between cyanoacetylene and formylazide using the quantum electrodynamics coupled cluster method. We show that by changing the molecular orientation with respect to the polarization of the cavity mode(s), the reaction can be selectively catalyzed to form a major 1,4-disubstituted or 1,5-disubstituted product. This work highlights that a cavity has the same effect on the investigated cycloaddition as the transition metal catalysts traditionally employed in click chemistry reactions. We expect our findings to further stimulate research on cavity-assisted click chemistry reactions.

1-Year Outcomes of Transcatheter Edge-to-Edge Repair in Anatomically Complex Degenerative Mitral Regurgitation Patients.

BACKGROUND: Favorable 6-month outcomes from the CLASP IID Registry (Edwards PASCAL transcatheter valve repair system pivotal clinical trial) demonstrated that mitral valve transcatheter edge-to-edge repair with the PASCAL transcatheter valve repair system is safe and beneficial for treating prohibitive surgical risk degenerative mitral regurgitation (DMR) patients with complex mitral valve anatomy. OBJECTIVES: The authors sought to assess 1-year safety, echocardiographic and clinical outcomes from the CLASP IID Registry. METHODS: Patients with 3+ or 4+ DMR who were at prohibitive surgical risk, had complex mitral valve anatomy based on the MitraClip Instructions for Use, and deemed suitable for treatment with the PASCAL system were enrolled prospectively. Safety, clinical, echocardiographic, functional, and quality-of-life outcomes were assessed at 1 year. Study oversight included a central screening committee, echocardiographic core laboratory, and clinical events committee. RESULTS: Ninety-eight patients were enrolled. One-year Kaplan-Meier (KM) estimates of freedom from composite major adverse events, all-cause mortality, and heart failure hospitalization were 83.5%, 89.3%, and 91.5%, respectively. Significant mitral regurgitation (MR) reduction was achieved at 1 year (P < 0.001 vs baseline) including 93.2% at MR ≤2+ and 57.6% at MR ≤1+ with improvements in related echocardiographic measures. NYHA functional class and Kansas City Cardiomyopathy Questionnaire score also improved significantly (P < 0.001 vs baseline). CONCLUSIONS: At 1 year, treatment with the PASCAL system demonstrated safety and significant MR reduction, with continued improvement in clinical, echocardiographic, functional, and quality-of-life outcomes, illustrating the value of the PASCAL system in the treatment of prohibitive surgical risk patients with 3+ or 4+ DMR and complex mitral valve anatomy.

Draft genome sequence of Enterobacter hormaechei DVZ29, an iodide-oxidizing bacterium isolated from the Hanford site.

Enterobacter hormaechei DVZ29 was isolated from a sediment trap incubated in an 129I plume at the Hanford Site (Washington State, USA). A whole genome sequencing of the strain resulted in 32 contigs and revealed that the genome is 4.90 Mb, with a G + C content of 55.61%.

National trends in utilization of transatrial transcatheter mitral valve replacement and postoperative outcomes.

OBJECTIVE: Transatrial transcatheter mitral valve replacement reduces complexity during mitral valve replacements involving high-risk patients with mitral annular calcification. This study examines trends in transatrial transcatheter mitral valve replacement use and outcomes. METHODS: Patients in the Society of Thoracic Surgeons database from 2014 to 2021 with mitral annular calcification undergoing transatrial transcatheter mitral valve replacement were included. Exclusion criteria were hypertrophic cardiomyopathy, congenital mitral valve disease, ventricular assist device placement, or prior mitral valve surgery. Primary outcomes were operative mortality and major adverse cardiac events compared between the Early (2014-2017, N = 71) and Recent (2018-2021, N = 151) eras. Parsimonious multivariable regression assessed select possible confounders for trends in major adverse cardiac events. RESULTS: Overall, 222 transatrial transcatheter mitral valve replacements at 104 hospitals were identified. Annual volume increased from 6 in 2014 to 43 in 2021. Median hospital volume was 1, maximum hospital volume was 17, and 10 or more replacements were performed at 4 hospitals. Mortality and major adverse cardiac events occurred in 10.4% and 22.5% of patients, respectively. Compared with the Early era patients, Recent era patients were more often elective (79.5% vs 64.8%) and were approached via sternotomy (90.1% vs 80.3%, all P < .05). Despite similar predicted risk of mortality (9.6% ± 11.1% vs 11.0% ± 6.0%; P = .61), Recent patients had reduced mortality (3.3% vs 25.4%, P < .001) and major adverse cardiac events (18.5% vs 31.0%; P = .057). On univariate and multivariable analyses, the Recent surgical era was significantly associated with lower mortality (0.10 [0.04-0.29]; P < .001) and lower major adverse cardiac events (0.48 [0.25-0.94]; P = .032), respectively. There were no preoperative characteristics that were significant confounders for the difference in major adverse cardiac events. CONCLUSIONS: Mortality and major adverse cardiac events after transatrial transcatheter mitral valve replacement have decreased significantly in the contemporary era independent of changes in major patient and operative characteristics. Transatrial transcatheter mitral valve replacement will have a future role in patients with mitral annular calcification.

Diagnosis, Classification, and Management Strategies for Mitral Annular Calcification: A Heart Valve Collaboratory Position Statement.

Mitral annular calcium (MAC) with severe mitral valvular dysfunction presents a complex problem, as valve replacement, either surgical or transcatheter, is challenging because of anatomy, technical considerations, concomitant comorbidities, and advanced age. The authors review the clinical and anatomical features of MAC that are favorable (green light), challenging (yellow light), or prohibitive (red light) for surgical or transcatheter mitral valve interventions. Under the auspices of the Heart Valve Collaboratory, an expert working group of cardiac surgeons, interventional cardiologists, and interventional imaging cardiologists was formed to develop recommendations regarding treatment options for patients with MAC as well as a proposed grading and staging system using both anatomical and clinical features.

Microbiomes of Blood-Feeding Triatomines in the Context of Their Predatory Relatives and the Environment.

The importance of gut microbiomes has become generally recognized in vector biology. This study addresses microbiome signatures in North American Triatoma species of public health significance (vectors of Trypanosoma cruzi) linked to their blood-feeding strategy and the natural habitat. To place the Triatoma-associated microbiomes within a complex evolutionary and ecological context, we sampled sympatric Triatoma populations, related predatory reduviids, unrelated ticks, and environmental material from vertebrate nests where these arthropods reside. Along with five Triatoma species, we have characterized microbiomes of five reduviids (Stenolemoides arizonensis, Ploiaria hirticornis, Zelus longipes, and two Reduvius species), a single soft tick species, Ornithodoros turicata, and environmental microbiomes from selected sites in Arizona, Texas, Florida, and Georgia. The microbiomes of predatory reduviids lack a shared core microbiota. As in triatomines, microbiome dissimilarities among species correlate with dominance of a single bacterial taxon. These include Rickettsia, Lactobacillus, "Candidatus Midichloria," and Zymobacter, which are often accompanied by known symbiotic genera, i.e., Wolbachia, "Candidatus Lariskella," Asaia, Gilliamella, and Burkholderia. We have further identified a compositional convergence of the analyzed microbiomes in regard to the host phylogenetic distance in both blood-feeding and predatory reduviids. While the microbiomes of the two reduviid species from the Emesinae family reflect their close relationship, the microbiomes of all Triatoma species repeatedly form a distinct monophyletic cluster highlighting their phylosymbiosis. Furthermore, based on environmental microbiome profiles and blood meal analysis, we propose three epidemiologically relevant and mutually interrelated bacterial sources for Triatoma microbiomes, i.e., host abiotic environment, host skin microbiome, and pathogens circulating in host blood. IMPORTANCE This study places microbiomes of blood-feeding North American Triatoma vectors (Reduviidae) into a broader evolutionary and ecological context provided by related predatory assassin bugs (Reduviidae), another unrelated vector species (soft tick Ornithodoros turicata), and the environment these arthropods coinhabit. For both vectors, microbiome analyses suggest three interrelated sources of bacteria, i.e., the microbiome of vertebrate nests as their natural habitat, the vertebrate skin microbiome, and the pathobiome circulating in vertebrate blood. Despite an apparent influx of environment-associated bacteria into the arthropod microbiomes, Triatoma microbiomes retain their specificity, forming a distinct cluster that significantly differs from both predatory relatives and ecologically comparable ticks. Similarly, within the related predatory Reduviidae, we found the host phylogenetic distance to underlie microbiome similarities.

Three-year outcomes for transcatheter repair in patients with mitral regurgitation from the CLASP study.

BACKGROUND: Mitral valve transcatheter edge-to-edge repair (M-TEER) is an effective option for treatment of mitral regurgitation (MR). We previously reported favorable 2-year outcomes for the PASCAL transcatheter valve repair system. OBJECTIVES: We report 3-year outcomes from the multinational, prospective, single-arm CLASP study with analysis by functional MR (FMR) and degenerative MR (DMR). METHODS: Patients with core-lab determined MR ≥ 3+ were deemed candidates for M-TEER by the local heart team. Major adverse events were assessed by an independent clinical events committee to 1 year and by sites thereafter. Echocardiographic outcomes were evaluated by the core laboratory to 3 years. RESULTS: The study enrolled 124 patients, 69% FMR; 31% DMR (60% NYHA class III-IVa, 100% MR ≥ 3+). The 3-year Kaplan-Meier estimate for survival was 75% (66% FMR; 92% DMR) and freedom from heart failure hospitalization (HFH) was 73% (64% FMR; 91% DMR), with 85% reduction in annualized HFH rate (81% FMR; 96% DMR) (p < 0.001). MR ≤ 2+ was achieved and maintained in 93% of patients (93% FMR; 94% DMR) and MR ≤ 1+ in 70% of patients (71% FMR; 67% DMR) (p < 0.001). The mean left ventricular end-diastolic volume (181 mL at baseline) decreased progressively by 28 mL [p < 0.001]. NYHA class I/II was achieved in 89% of patients (p < 0.001). CONCLUSIONS: The 3-year results from the CLASP study demonstrated favorable and durable outcomes with the PASCAL transcatheter valve repair system in patients with clinically significant MR. These results add to the growing body of evidence establishing the PASCAL system as a valuable therapy for patients with significant symptomatic MR.

Computational study on the catalytic control of endo/exo Diels-Alder reactions by cavity quantum vacuum fluctuations.

Achieving control over chemical reaction's rate and stereoselectivity realizes one of the Holy Grails in chemistry that can revolutionize chemical and pharmaceutical industries. Strong light-matter interaction in optical or nanoplasmonic cavities might provide the knob to reach such control. In this work, we demonstrate the catalytic and selectivity control of an optical cavity for two selected Diels-Alder cycloaddition reactions using the quantum electrodynamics coupled cluster (QED-CC) method. Herein, we find that by changing the molecular orientation with respect to the polarization of the cavity mode the reactions can be significantly inhibited or selectively enhanced to produce major endo or exo products on demand. This work highlights the potential of utilizing quantum vacuum fluctuations of an optical cavity to modulate the rate of Diels-Alder cycloaddition reactions and to achieve stereoselectivity in a practical and non-intrusive way. We expect that the present findings will be applicable to a larger set of relevant reactions, including the click chemical reactions.

1-Year Outcomes of Transcatheter Tricuspid Valve Repair.

BACKGROUND: Surgical management of isolated tricuspid regurgitation (TR) is associated with high morbidity and mortality, thereby creating a significant need for a lower-risk transcatheter solution. OBJECTIVES: The single-arm, multicenter, prospective CLASP TR (Edwards PASCAL TrAnScatheter Valve RePair System in Tricuspid Regurgitation [CLASP TR] Early Feasibility Study) evaluated 1-year outcomes of the PASCAL transcatheter valve repair system (Edwards Lifesciences) to treat TR. METHODS: Study inclusion required a previous diagnosis of severe or greater TR and persistent symptoms despite medical treatment. An independent core laboratory evaluated echocardiographic results, and a clinical events committee adjudicated major adverse events. The study evaluated primary safety and performance outcomes, with echocardiographic, clinical, and functional endpoints. Study investigators report 1-year all-cause mortality and heart failure hospitalization rates. RESULTS: Sixty-five patients were enrolled: mean age of 77.4 years; 55.4% female; and 97.0% with severe to torrential TR. At 30 days, cardiovascular mortality was 3.1%, the stroke rate was 1.5%, and no device-related reinterventions were reported. Between 30 days and 1 year, there were an additional 3 cardiovascular deaths (4.8%), 2 strokes (3.2%), and 1 unplanned or emergency reintervention (1.6%). One-year postprocedure, TR severity significantly reduced (P < 0.001), with 31 of 36 (86.0%) patients achieving moderate or less TR; 100% had at least 1 TR grade reduction. Freedom from all-cause mortality and heart failure hospitalization by Kaplan-Meier analyses were 87.9% and 78.5%, respectively. Their New York Heart Association functional class significantly improved (P < 0.001) with 92% in class I or II, 6-minute walk distance increased by 94 m (P = 0.014), and overall Kansas City Cardiomyopathy Questionnaire scores improved by 18 points (P < 0.001). CONCLUSIONS: The PASCAL system demonstrated low complication and high survival rates, with significant and sustained improvements in TR, functional status, and quality of life at 1 year. (Edwards PASCAL TrAnScatheter Valve RePair System in Tricuspid Regurgitation [CLASP TR] Early Feasibility Study [CLASP TR EFS]; NCT03745313).

Transcatheter Edge-to-Edge Repair in Patients With Anatomically Complex Degenerative Mitral Regurgitation.

BACKGROUND: Mitral valve transcatheter edge-to-edge repair is safe and effective in treating degenerative mitral regurgitation (DMR) patients at prohibitive surgical risk, but outcomes in complex mitral valve anatomy patients vary. OBJECTIVES: The PASCAL IID registry assessed safety, echocardiographic, and clinical outcomes with the PASCAL system in prohibitive risk patients with significant symptomatic DMR and complex mitral valve anatomy. METHODS: Patients in the prospective, multicenter, single-arm registry had 3+ or 4+ DMR, were at prohibitive surgical risk, presented with complex anatomic features based on the MitraClip instructions for use, and were deemed suitable for the PASCAL system by a central screening committee. Enrolled patients were treated with the PASCAL system. Safety, effectiveness, and functional and quality-of-life outcomes were assessed. Study oversight also included an echocardiographic core laboratory and clinical events committee. RESULTS: The study enrolled 98 patients (37.2% ≥2 independent significant jets, 15.0% severe bileaflet/multi scallop prolapse, 13.3% mitral valve orifice area <4.0 cm2, and 10.6% large flail gap and/or large flail width). The implant success rate was 92.9%. The 30-day composite major adverse event rate was 11.2%. At 6 months, 92.4% patients achieved MR ≤2+ and 56.1% achieved MR ≤1+ (P < 0.001 vs baseline). The Kaplan-Meier estimates for survival, freedom from major adverse events, and heart failure hospitalization at 6 months were 93.7%, 85.6%, and 92.6%, respectively. Patients experienced significant symptomatic improvement compared with baseline (P < 0.001). CONCLUSIONS: The outcomes of the PASCAL IID registry establish the PASCAL system as a useful therapy for prohibitive surgical risk DMR patients with complex mitral valve anatomy. (PASCAL IID Registry within the Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID] NCT03706833).

Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites-a study in 839 patients with known CYP2D6 genotype.

PURPOSE: Poor metabolizers (PMs) of the highly polymorphic enzyme CYP2D6 are usually at high risk of adverse effects during standard recommended dosing of CYP2D6-metabolized drugs. We studied if the metabolism of solanidine, a dietary compound found in potatoes, could serve as a biomarker predicting the CYP2D6 PM phenotype for precision dosing. METHODS: The study included 839 CYP2D6-genotyped patients who were randomized by a 4:1 ratio into test or validation cohorts. Full-scan high-resolution mass spectrometry data files of previously analyzed serum samples were reprocessed for identification and quantification of solanidine and seven metabolites. Metabolite-to-solanidine ratios (MRs) of the various solanidine metabolites were calculated prior to performing receiver operator characteristic (ROC) and multiple linear regression analyses on the test cohort. The MR thresholds obtained from the ROC analyses were tested for the prediction of CYP2D6 PMs in the validation cohort. RESULTS: In the test cohort, the M414-to-solanidine MR attained the highest sensitivity and specificity parameters from the ROC analyses (0.98 and 1.00) and highest explained variance from the linear models (R2 = 0.68). Below these thresholds, CYP2D6 PM predictions were tested in the validation cohort providing positive and negative predictive values of 100% for the MR of M414, while similar values for the other MRs ranged from 20.5 to 73.3% and 96.7 to 99.3%, respectively. CONCLUSION: The M414-to-solanidine MR is an excellent predictor of the CYP2D6 PM phenotype. By measuring solanidine and metabolites using liquid chromatography-mass spectrometry in patient serum samples, CYP2D6 PMs can easily be identified, hence facilitating the implementation of precision dosing in clinical practice.