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Tricuspid regurgitation is a prevalent disease associated with high morbidity and mortality, with few treatment options. The aim of the TRILUMINATE trial is to evaluate the safety and effectiveness of TriClip, a minimally invasive transcatheter tricuspid valve repair system, for reducing tricuspid regurgitation. The TRILUMINATE trial is a prospective, multicentre, single-arm study in 21 sites in Europe and the USA. Patients with moderate or greater triscuspid regurgitation, New York Heart Association class II or higher, and who were adequately treated per applicable standards were eligible for enrolment. Patients were excluded if they had systolic pulmonary artery pressure of more than 60 mm Hg, a previous tricuspid valve procedure, or a cardiovascular implantable electronic device that would inhibit TriClip placement. Participants were treated using a clip-based edge-to-edge repair technique with the TriClip tricuspid valve repair system. Tricuspid regurgitation was graded using a five-class grading scheme (mild, moderate, severe, massive, and torrential) that expanded on the standard American Society of Echocardiography grading scheme. The primary efficacy endpoint was a reduction in tricuspid regurgitation severity by at least one grade at 30 days post procedure, with a performance goal of 35%, analysed in all patients who had an attempted tricuspid valve repair procedure upon femoral vein puncture. The primary safety endpoint was a composite of major adverse events at 6 months, with a performance goal of 39%. Patients were excluded from the primary safety analysis if they did not reach 6-month follow-up and did not have a major adverse event during previous follow-ups. The trial has completed enrolment and follow-up is ongoing; it is registered with ClinicalTrials.gov, number NCT03227757. Between Aug 1, 2017, and Nov 29, 2018, 85 patients (mean age 77·8 years [SD 7·9]; 56 [66%] women) were enrolled and underwent successful TriClip implantation. Tricuspid regurgitation severity was reduced by at least one grade at 30 days in 71 (86%) of 83 patients who had available echocardiogram data and imaging. The one-sided lower 97·5% confidence limit was 76%, which was greater than the prespecified performance goal of 35% (p<0·0001). One patient withdrew before 6-month follow-up without having had a major adverse event and was excluded from analysis of the primary safety endpoint. At 6 months, five (6%) of 84 patients experienced a major adverse event, which was less than the prespecified performance goal of 39% (p<0·0001). Single leaflet attachment occurred in five (7%) of 72 patients. No periprocedural deaths, conversions to surgery, device embolisations, or strokes occurred. At 6 months, all-cause mortality had occurred in four (5%) of 84 patients. The TriClip system appears to be safe and effective at reducing tricuspid regurgitation by at least one grade. This reduction could translate to significant clinical improvement at 6 months post procedure. Abbott.

When processed in solid or liquid medium, tuberculosis patient samples yield different proportions of a heterogenous bacterial community over the duration of treatment. We aimed to derive a relationship between methodologies for bacterial load determination and assess the effect of the growth phase of the parent culture and its exposure to stress on the results. Mycobacterium tuberculosis H37Rv was grown with and without antibiotic (isoniazid or rifampicin) and sampled on day 0, 3, 11 and 21 of growth in broth culture. The bacterial load was estimated by colony counts and the BD BACTEC MGIT system. Linear and nonlinear mixed-effects models were used to describe the relationship between time-to-positivity (TTP) and time-to-growth (TTG) versus colony forming units (CFU), and growth units (GU) versus incubation time in MGIT. For samples with the same CFU, antibiotic-treated and stationary phase cells had a shorter TTP than antibiotic-free controls and early-logarithmic phase cells, respectively. Similarly, stationary phase samples reached higher GUs and had shorter TTG than early-log phase ones. This suggests that there is a population of bacterial cells that can be differentially recovered in liquid medium, giving us insight into the physiological states of the original culture, aiding the interpretation of clinical trial outputs.

Modeling optical tweezers in the T-matrix formalism has been of key importance for accurate and efficient calculations of optical forces and their comparison with experiments. Here we extend this formalism to the modeling of chiral optomechanics and optical tweezers where chiral light is used for optical manipulation and trapping of optically active particles. We first use the Bohren decomposition to deal with the light scattering of chiral light on optically active particles. Thus, we show analytically that all the observables (cross sections, asymmetry parameters) are split into a helicity dependent and independent part and study a practical example of a complex resin particle with inner copper-coated stainless steel helices. Then, we apply this chiral T-matrix framework to optical tweezers where a tightly focused chiral field is used to trap an optically active spherical particle, calculate the chiral behaviour of optical trapping stiffnesses and their size scaling, and extend calculations to chiral nanowires and clusters of astrophysical interest. Such general light scattering framework opens perspectives for modeling optical forces on biological materials where optically active amino acids and carbohydrates are present.

Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.

The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Proper handling of data below the lower limit of quantification (BLQ) is crucial for accurate pharmacokinetic parameter estimation. The M3 method proposed by Beal uses a likelihood‐based approach that is precise but has been reported to suffer from numerical issues in converging. Common alternatives include ignoring the BLQs (M1), imputing half of the lower limit of quantification and ignoring trailing BLQs (M6) or imputing zero (M7). The imputation methods fail to account for the additional uncertainty affecting imputed observations. We used NONMEM with FOCE‐I/Laplace to compare the stability, bias, and precision of methods M1, M3, M6, M7, and modified versions M6+ and M7+ that inflate the additive residual error for BLQs. Real and simulated datasets with a two‐compartment model were used to assess stability through parallel retries with perturbed initial estimates. The resulting differences in objective function values (OFV) were compared. Bias and precision were evaluated on simulated data using stochastic simulations and estimations. M3 yielded different OFV across retries (±14.7), though the parameter estimates were similar. All other methods, except M7 (±130), were stable. M3 demonstrated the best bias and precision (average rRMSE 18.7%), but M6+ and M7+ performed comparably (26.0% and 23.3%, respectively). The unstable OFV produced by M3 represents a challenge when used to guide model development. Imputation methods showed superior stability, and including inflated additive error improved bias and precision to levels comparable with M3. For these reasons, M7+ (of simpler implementation than M6+) is an attractive alternative to M3, especially during model development.

Background and Objectives: Mitral valve transcatheter edge-to-edge repair (TEER) is a widely adopted therapeutic approach for managing significant mitral regurgitation (MR) in high-risk surgical candidates. While procedural safety and efficacy have been demonstrated, the impact of institutional expertise on outcomes remains unclear. We aimed at evaluating whether the institutional monthly volume of TEER influences short- and long-term clinical results. Materials and Methods: This analysis from the multicenter, prospective GIOTTO trial study evaluated the impact of institutional monthly volume on outcomes of TEER to remedy significant mitral regurgitation. Centers were stratified into tertiles based on monthly volumes (≤2.0 cases/month, 2.1–3.5 cases/month, >3.5 cases/month), and key clinical, echocardiographic, and procedural outcomes were analyzed. Statistical analysis was based on standard bivariate tests as well as unadjusted and multivariable adjusted Cox models. Results: A total of 2213 patients were included, stratified into tertiles based on institutional procedural volume: 645 (29.1%) patients in the first tertile, 947 (42.8%) patients in the second tertile, and 621 (28.1%) patients in the third tertile. Several baseline differences were found, with some features disfavoring less busy centers (e.g., functional class and surgical risk, both p < 0.05), and others suggesting a worse risk profile in those treated in busier institutions (e.g., frailty and history of prior mitral valve intervention, both p < 0.05). Procedural success rates were higher in busier centers (p < 0.001), and hospital stay was also shorter there (p < 0.001). Long-term follow-up (median 14 months) suggested worse outcomes in patients treated in less busy centers at unadjusted analysis (e.g., p = 0.018 for death, p = 0.015 for cardiac death, p = 0.014 for death or hospitalization for heart failure, p < 0.001 for cardiac death or hospitalization for heart failure), even if these associations proved no longer significant after multivariable adjustment, except for cardiac death or hospitalization for heart failure, which appeared significantly less common in the busiest centers (p < 0.05). Similar trends were observed when focusing on tertiles of overall center volume and when comparing for each center the first 50 cases with the following ones. Conclusions: High institutional monthly volume of TEER mitral valve repair appears to correlate with an improved procedural success rate and shorter hospitalizations. Similarly favorable results were found for long-term rates of cardiac death or hospitalization for heart failure. These findings inform on the importance of operator experience and center expertise in achieving state-of-the-art results with TEER, while confirming the usefulness of the proctoring approach when naïve centers begin a TEER program.

Afterload mismatch, defined as acute impairment of left ventricular function after mitral surgery, is a major issue in patients with low ejection fraction and functional mitral regurgitation (FMR). Safety and efficacy of MitraClip therapy have been assessed in randomized trials, but limited data on its acute hemodynamic effects are available. This study aimed to investigate the incidence and prognostic role of afterload mismatch in patients affected by FMR treated with MitraClip therapy. We retrospectively analyzed patients affected by FMR and submitted to MitraClip therapy from October 2008 to December 2012. Patients were assigned to 2 groups according to the occurrence of the afterload mismatch: patients with afterload mismatch (AM+) and without afterload mismatch (AM−). Of 73 patients, 19 (26%) experienced afterload mismatch in the early postoperative period. Among preoperative variables, end-diastolic diameter (71 ± 8 vs 67 ± 7 mm, p = 0.02) and end-systolic diameter (57 ± 9 vs 53 ± 7 mm, p = 0.04) were both significantly larger in AM+ group. An increased incidence of right ventricular dysfunction (68% vs 31%, p = 0.049) and pulmonary hypertension (49 ± 10 vs 40 ± 10 mm Hg, p = 0.0009) was found in AM+ group. Before hospital discharge, left ventricular ejection fraction (LVEF) became similar in both groups (31 ± 9% vs 33 ± 11%, p = 0.65). Long-term survival was comparable between the 2 groups (p = 0.44). A low LVEF in the early postoperative period (LVEF <17%) was significantly associated with higher mortality rate in long-term follow-up (p = 0.048). In conclusion, reduction of mitral regurgitation with MitraClip can cause afterload mismatch; however, this phenomenon is transient, without long-term prognostic implications.

Ritonavir‐boosted atazanavir (ATV/r) and rifampicin are mainstays of second‐line antiretroviral and multiple anti‐TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug–drug interaction (DDI) which might be exaggerated in pregnancy. Having demonstrated that increasing the dose of ATV/r from once daily (OD) to twice daily (BD) in non‐pregnant adults can safely overcome this DDI, we developed a pregnancy physiologically based pharmacokinetic (PBPK) model to explore the impact of pregnancy. Predicted pharmacokinetic parameters were validated with separate clinical datasets of ATV/r alone (NCT03923231) and rifampicin alone in pregnant women. The pregnancy model was considered validated when the absolute average fold error (AAFE) for Ctrough and AUC0‐24 of both drugs were <2 when comparing predicted vs. observed data. Thereafter, predicted atazanavir Ctrough was compared against its protein‐adjusted IC90 (14 ng/mL) when simulating the co‐administration of ATV/r 300/100 mg OD and rifampicin 600 mg OD. Pregnancy was predicted to increase the rifampicin DDI effect on atazanavir. For the dosing regimens of ATV/r 300/100 mg OD, ATV/r 300/200 mg OD, and ATV/r 300/100 mg BD (all with rifampicin 600 mg OD), predicted atazanavir Ctrough was above 14 ng/mL in 29%, 71%, and 100%; and 32%, 73% and 100% of the population in second and third trimesters, respectively. Thus, PBPK modeling suggests ATV/r 300/100 mg BD could maintain antiviral efficacy when co‐administered with rifampicin 600 mg OD in pregnancy. Clinical studies are warranted to confirm safety and efficacy in pregnancy.

Cefazolin is an antibiotic used to prevent surgical site infections. During cardiac surgery with cardiopulmonary bypass (CPB), its efficacy target could be underachieved. We aimed to develop a population pharmacokinetic model for cefazolin in children and optimize the prophylactic dosing regimen. Children under 25 kg undergoing cardiac surgery with CPB and receiving cefazolin at standard doses (50 mg/kg IV every 4–6 h) were included in this analysis. A population pharmacokinetic model and Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) for efficacy and toxicity with the standard regimen and an alternative regimen of continuous infusion, where loading and maintenance doses were calculated from model‐derived individual parameters. Twenty‐two patients were included, with median (range) age, body weight, and eGFR of 19.5 (1–94) months, 8.7 (2–21) kg, and 116 (48–159) mL/min, respectively. Six patients received an additional dose in the CPB circuit. A two‐compartment disposition model with an additional compartment for the CPB was developed, including weight‐based allometric scaling and eGFR. For a 10 kg patient with eGFR of 120 mL/min/1.73 m2, clearance was estimated as 0.856 L/h. Simulations indicated that the standard dosing regimen fell short of achieving the efficacy target >40% of the time within a dosing duration and in patients with good renal function, PTA ranged from <20% to 70% for the smallest to the largest patients, respectively, at high MICs. In contrast, the alternative regimen consistently maintained target concentrations throughout the procedure for all patients while using a lower overall dose.