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.

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.

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.

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.

Contemporary Outcomes of Isolated Tricuspid Valve Surgery.

INTRODUCTION: Isolated tricuspid valve (TV) surgery is uncommonly performed and has historically been associated with excessive operative mortality. We previously reported improved short-term outcomes at our center. Understanding contemporary outcomes of isolated TV surgery beyond the perioperative period is essential to properly benchmark outcomes of newer transcatheter interventions. METHODS: Patients who underwent isolated TV surgery from 2007 to 2021 at a single institution were retrospectively reviewed. Survival was estimated using the Kaplan-Meier method and multivariable Cox proportional hazards regression modeling identified independent risk factors for all-cause mortality. RESULTS: Among 173 patients undergoing isolated TV surgery, 103 (60%) underwent TV repair and 70 (40%) underwent TV replacement. Mean age was 60.3 ± 18.9 y and 55 (32%) were male. The most common etiology of TV disease was functional (46%). In-hospital mortality was 4.1% (7/173), with no difference between TV repair and replacement (P = 0.06). Overall survival at 1 y and 5 y was 78.3% (111/142) and 64.5% (53/82), respectively. After median (interquartile range) follow-up of 2.0 (0.6-4.4) y, patients undergoing TV repair experienced a higher unadjusted survival as compared to those undergoing TV replacement (log-rank P = 0.02). However, after adjusting for covariates, TV replacement was not an independent predictor of all-cause mortality (hazard ratio 1.40; 95% confidence interval, 0.71-2.76; P = 0.33). CONCLUSIONS: Isolated TV surgery can be performed with lower operative mortality than historically reported. Establishing survival benchmarks from TV surgery is important in the era of developing transcatheter interventions.

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.

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.

Association Between CYP2D6 Metabolizer Status and Vortioxetine Exposure and Treatment Switching: A Retrospective, Naturalistic Cohort Study Using Therapeutic Drug Monitoring Data From 640 Patients.

PURPOSE: The antidepressant vortioxetine is mainly metabolized by the polymorphic enzyme CYP2D6. The aim of this study was to investigate the absolute serum concentrations of vortioxetine and frequency of switching to an alternative antidepressant in relation to CYP2D6 genotype in a naturalistic patient population. METHODS: The analyses included data from 640 CYP2D6 -genotyped patients treated with vortioxetine from a Norwegian therapeutic drug monitoring database. Serum concentration of vortioxetine was determined using ultrahigh-performance liquid chromatography-high-resolution mass spectrometry, whereas longitudinal reviews of therapeutic drug monitoring profiles were performed to identify cases of patients switching from vortioxetine to an alternative antidepressant. RESULTS: Compared with CYP2D6 normal metabolizers (n = 342), the median vortioxetine serum concentration (ng/mL) was 2.1-fold ( P < 0.001) increased in poor metabolizers (PMs) (n = 48), 1.5-fold ( P < 0.001) increased in intermediate metabolizers (n = 238), and not significantly changed in ultrarapid metabolizers (n = 12). Compared with CYP2D6 normal metabolizers, treatment switch from vortioxetine to alternative antidepressants was 5.1-fold (95% confidence interval, 1.6-15.4, P = 0.003) more frequent among PMs. The prescribed doses did not differ significantly between the subgroups ( P = 0.26). A possible explanation for the increased frequency of treatment switch among PMs is that concentration-dependent adverse events were more frequent in this group because of increased drug exposure. CONCLUSIONS: This naturalistic study provides novel data on the association between CYP2D6 genotype and treatment switch of vortioxetine, which likely reflects the significant effect of CYP2D6 genotype on vortioxetine exposure.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Premorbid angiotensin converting enzyme inhibitors or angiotensin II receptor blockers in patients with sepsis.

OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis to investigate the effect of the premorbid use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) on short-term mortality in patients with sepsis. DATA SOURCES: Embase, the Cochrane Central Register of Controlled Trials, and MEDLINE were searched for studies based on the below eligibility criteria. The protocol was registered at the PROSPERO (CRD42022309129). STUDY SELECTION: Eligibility criteria were as follows: (1) randomized controlled trials, cohort studies, cross-sectional studies, (2) patients with sepsis aged ≥16 years, and (3) received premorbid ACEI/ARB, or not. DATA EXTRACTION: The patient and study characteristics and outcomes were extracted. All analyses were presented with the use of random-effects models. The primary outcome was short-term mortality defined as ≤30-day, in-hospital, or intensive care unit (ICU)- mortality. The secondary outcome was acute kidney injury (AKI). DATA SYNTHESIS: Fifteen studies (N = 96,159) met the eligibility criteria. Of these, eleven studies (N = 40,360) reported unadjusted short-term mortalities. The pooled odds ratio (OR) of short-term mortality with the premorbid use of ACEI/ARB was as follows: OR, 0.86; 95% confidence interval (CI), 0.67 to 1.11; P = 0.24, I2 = 88%. Five studies reported an adjusted OR of short-term mortality with the premorbid use of ACEI/ARB as follows: OR, 0.74; 95%CI, 0.59 to 0.93; P < 0.01, I2 = 93%. Seven studies reported the pooled adjusted OR of AKI with the premorbid use of ACEI/ARB as follows: OR: 1.57, 95%CI: 1.26-1.96, p < 0.01, I2 = 69%. CONCLUSION: In this meta-analysis, the premorbid ACEI/ARB was associated with significantly lower short-term mortality in patients with sepsis despite the significantly higher risk of AKI.

Development of a non-transplant left ventricular assist device program.

INTRODUCTION: Although the established long-term benefit of left ventricular assist device (LVAD) therapy has led to its proliferation as destination therapy (DT), few studies have evaluated LVAD outcomes at nontransplant centers. We undertook this study to better evaluate our experience in building a nontransplant, DT LVAD program. METHODS: We conducted a retrospective review of all LVADs implanted from 2010 to 2021. Patient, operative, and outcome data were extracted from the electronic medical record. Secular trends were evaluated by organizing the data into eras of implant. Survival was assessed using the Kaplan-Meier method. Multivariable Cox proportional hazards regression models further evaluated outcomes. RESULTS: From 2010 to 2021, 100 primary LVAD implants were performed. Annual volume grew from 1 to 30 implants per year. The average age of our cohort was 65.7 years, most patients (80%) were male, 51% had an ischemic etiology, and 65 (65%) were INTERMACS profile 1 or 2. Our 1- and 2-year survival were 82% and 79%, respectively. Multivariable analysis of 1-year mortality demonstrated that decreasing renal function and increased cardiopulmonary bypass (CPB) time were associated with increased mortality while preoperative hemoglobin was protective. When stratified by era of implant, our most recent patients were more likely to be INTERMACS profile 1 or 2; had shorter CPB and aortic cross clamp times; required fewer reoperations for bleeding; and suffered less right ventricular failure requiring mechanical support. CONCLUSIONS: A single, nontransplant LVAD center can experience significant growth in volume in a high-acuity cohort while maintaining acceptable outcomes and quality of care.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Early outcomes from the CLASP IID trial roll-in cohort for prohibitive risk patients with degenerative mitral regurgitation.

OBJECTIVES: We report the 30-day outcomes from the roll-in cohort of the CLASP IID trial, representing the first procedures performed by each site. BACKGROUND: The currently enrolling CLASP IID/IIF pivotal trial is a multicenter, prospective, randomized trial assessing the safety and effectiveness of the PASCAL transcatheter valve repair system in patients with clinically significant MR. The trial allows for up to three roll-in patients per site. METHODS: Eligibility criteria were: DMR ≥3+, prohibitive surgical risk, and deemed suitable for transcatheter repair by the local heart team. Trial oversight included a central screening committee and echocardiographic core laboratory. The primary safety endpoint was a 30-day composite MAE: cardiovascular mortality, stroke, myocardial infarction (MI), new need for renal replacement therapy, severe bleeding, and non-elective mitral valve re-intervention, adjudicated by an independent clinical events committee. Thirty-day echocardiographic, functional, and quality of life outcomes were assessed. RESULTS: A total of 45 roll-in patients with mean age of 83 years and 69% in NYHA class III/IV were treated. Successful implantation was achieved in 100%. The 30-day composite MAE rate was 8.9% including one cardiovascular death (2.2%) due to severe bleeding from a hemorrhagic stroke, one MI, and no need for re-intervention. MR≤1+ was achieved in 73% and ≤2+ in 98% of patients. 89% of patients were in NYHA class I/II (p < .001) with improvements in 6MWD (30 m; p = .054) and KCCQ (17 points; p < .001). CONCLUSIONS: Early results representing sites with first experience with the PASCAL repair system showed favorable 30-day outcomes in patients with DMR≥3+ at prohibitive surgical risk.

Minimally invasive mitral valve surgery after previous sternotomy: A propensity-matched analysis.

BACKGROUND: Although the incidence of mitral valve (MV) surgery after previous open-heart surgery is increasing, there is no consensus regarding the optimal surgical approach. Reoperative MV surgery is most commonly performed via sternotomy (ST). We sought to determine whether minimally-invasive (MIS) reoperative MV surgery is safe and feasible. METHODS: All patients with a history of ST undergoing MV surgery with or without concomitant tricuspid or atrial fibrillation surgery at a single institution from 2007 to 2018 were retrospectively reviewed. ST and MIS approaches were compared using propensity-matched analysis. The coprimary endpoints were operative mortality and 1-year survival, and secondary endpoints were operative complications and length of stay. RESULTS: A total of 305 isolated MV reoperations were performed: 199 (65%) MIS and 106 (35%) ST. MIS patients were older than ST patients (71 [63, 76.5] vs. 66 [56, 72] years, p < .01), more likely to have undergone prior coronary artery bypass grafting (57% vs. 27%, p < .01), and less likely to have had prior valve surgery (55% vs. 78%, p < .01). In unmatched comparisons, operative mortality was significantly lower among MIS patients (3.0% vs. 8.5%, p = .04), but 1-year mortality was similar (14.4% vs. 15.6%, p = .8). After propensity matching, 88 pairs had excellent balance across baseline characteristics. Mortality was similar among MIS and ST patients at 30 days (3.4% vs. 8%, p = .19) and 1 year (15.9% vs. 16.5%, p = .9). RBC and fresh frozen plasma transfusions were significantly lower in the MIS group (p < .01). CONCLUSIONS: A minimally invasive approach is a safe alternative in patients with prior ST undergoing MV surgery.

Electrically tuned hyperfine spectrum in neutral Tb(II)(CpiPr5)2 single-molecule magnet.

Molecular spin qubits with long spin coherence time as well as non-invasive operation methods on such qubits are in high demand. It was shown that both molecular electronic and nuclear spin levels can be used as qubits. In solid state systems with dopants, an electric field was shown to effectively change the spacing between the nuclear spin qubit levels when the electron spin density is high at the nucleus of the dopant. Inspired by such solid-state systems, we propose that divalent lanthanide (Ln) complexes with an unusual electronic configuration of Ln2+ have a strong interaction between the Ln nuclear spin and the electronic degrees of freedom, which renders electrical tuning of the interaction. As an example, we study electronic structure and hyperfine interaction of the 159Tb nucleus in a neutral Tb(ii)(CpiPr5)2 single-molecule magnet (SMM), which exhibits unusually long magnetization relaxation time, using the complete active space self-consistent field (CASSCF) method with spin-orbit interaction included within the restricted active space state interaction (RASSI). Our calculations show that the low-energy states arise from 4f8(6s,5dz2)1, 4f8(5dx2-y2)1, and 4f8(5dxy)1 configurations. We compute the hyperfine interaction parameters and the electronic-nuclear spectrum within our multiconfigurational approach. We find that the hyperfine interaction is about one order of magnitude greater than that for Tb(iii)Pc2 SMMs. This stems from the strong Fermi contact interaction between the Tb nuclear spin and the electron spin density at the nucleus that originates from the occupation of the (6s,5d) orbitals. We also uncover that the response of the Fermi contact term to electric field results in electrical tuning of the electronic-nuclear level separations. This hyperfine Stark effect may be useful for applications of molecular nuclear spins for quantum computing.

Pharmacogenetics and drug metabolism: historical perspective and appraisal.

The events leading up to the discovery of genetically controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field.The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a success or failure within the present clinical arena.

Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery.

BACKGROUND: Atrial fibrillation after cardiac surgery is associated with increased rates of death, complications, and hospitalizations. In patients with postoperative atrial fibrillation who are in stable condition, the best initial treatment strategy--heart-rate control or rhythm control--remains controversial. METHODS: Patients with new-onset postoperative atrial fibrillation were randomly assigned to undergo either rate control or rhythm control. The primary end point was the total number of days of hospitalization within 60 days after randomization, as assessed by the Wilcoxon rank-sum test. RESULTS: Postoperative atrial fibrillation occurred in 695 of the 2109 patients (33.0%) who were enrolled preoperatively; of these patients, 523 underwent randomization. The total numbers of hospital days in the rate-control group and the rhythm-control group were similar (median, 5.1 days and 5.0 days, respectively; P=0.76). There were no significant between-group differences in the rates of death (P=0.64) or overall serious adverse events (24.8 per 100 patient-months in the rate-control group and 26.4 per 100 patient-months in the rhythm-control group, P=0.61), including thromboembolic and bleeding events. About 25% of the patients in each group deviated from the assigned therapy, mainly because of drug ineffectiveness (in the rate-control group) or amiodarone side effects or adverse drug reactions (in the rhythm-control group). At 60 days, 93.8% of the patients in the rate-control group and 97.9% of those in the rhythm-control group had had a stable heart rhythm without atrial fibrillation for the previous 30 days (P=0.02), and 84.2% and 86.9%, respectively, had been free from atrial fibrillation from discharge to 60 days (P=0.41). CONCLUSIONS: Strategies for rate control and rhythm control to treat postoperative atrial fibrillation were associated with equal numbers of days of hospitalization, similar complication rates, and similarly low rates of persistent atrial fibrillation 60 days after onset. Neither treatment strategy showed a net clinical advantage over the other. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02132767.).

Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism.

BACKGROUND: Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. METHODS: A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. RESULTS: The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). CONCLUSIONS: The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ~4% of unsolved MAE cases.

Age Impacts Olanzapine Exposure Differently During Use of Oral Versus Long-Acting Injectable Formulations: An Observational Study Including 8,288 Patients.

PURPOSE: Olanzapine is a commonly prescribed antipsychotic available as oral and long-acting injectable (LAI) formulations. Data are lacking on the use and safety of olanzapine-LAI in older patients. The aim of this study was to investigate the effect of increasing age on olanzapine exposure during oral versus LAI administration in a real-life setting. METHODS: This observational study was based on routine therapeutic drug monitoring data collected during 2005-2017. As a measure of exposure, absolute concentrations and concentration/dose ratios of olanzapine were defined as outcome variables. Linear mixed-model analyzes were used to allow for inclusion of multiple samples per patient and adjustment for covariate effects. RESULTS: Olanzapine concentrations and doses from 8,288 patients (21,378 measurements) were included. The number of patients on oral treatment was 7,893 (42%, 50 years or older), while 395 were using olanzapine-LAI (27%, 50 years or older). In contrast to oral use, where the dose-adjusted concentration of olanzapine increased significantly for patients 50 years or older (P < 0.001), increasing age had no effect on olanzapine concentration following LAI administration (P = 0.550). The effects of smoking habits and gender were equal in oral and olanzapine-LAI users. CONCLUSION: While the dose-adjusted systemic exposure of olanzapine increases by age after oral administration, these novel findings from a large patient population show that systemic exposure of olanzapine-LAI is unaffected by age, probably due to the lacking influence of age-related changes in gastrointestinal absorption and/or presystemic metabolism. From a pharmacokinetic point of view, it is therefore no reason to restrict the use of olanzapine-LAI in older patients requiring long-term treatment.