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To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state. [ABSTRACT FROM AUTHOR]

The number of meta‐analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy‐to‐use, and specialised statistical software. Even when meta‐analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta‐analysis provides an example of the variation of effect 'naturally' observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (i) breakdown of the total observed variability with quantification of the variability generated by the replication process and (ii) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta‐analysis results, a bivariate linear mixed‐effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta‐analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism. [ABSTRACT FROM AUTHOR]

Network meta‐analysis (NMA) allows the combination of direct and indirect evidence from a set of randomized clinical trials. Performing NMA using individual patient data (IPD) is considered as a "gold standard" approach as it provides several advantages over NMA based on aggregate data. For example, it allows to perform advanced modeling of covariates or covariate‐treatment interactions. An important issue in IPD NMA is the selection of influential parameters among terms that account for inconsistency, covariates, covariate‐by‐treatment interactions or nonproportionality of treatments effect for time to event data. This issue has not been deeply studied in the literature yet and in particular not for time‐to‐event data. A major difficulty is to jointly account for between‐trial heterogeneity which could have a major influence on the selection process. The use of penalized generalized mixed effect model is a solution, but existing implementations have several shortcomings and an important computational cost that precludes their use for complex IPD NMA. In this article, we propose a penalized Poisson regression model to perform IPD NMA of time‐to‐event data. It is based only on fixed effect parameters which improve its computational cost over the use of random effects. It could be easily implemented using existing penalized regression package. Computer code is shared for implementation. The methods were applied on simulated data to illustrate the importance to take into account between trial heterogeneity during the selection procedure. Finally, it was applied to an IPD NMA of overall survival of chemotherapy and radiotherapy in nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion Level of Evidence Multiligament knee injuries (MLKIs) are devastating injuries that can have life‐long consequences. A management plan requires the decision to perform surgery or not, timing of surgery, consideration of repair versus reconstruction, reconstruction technique and reconstruction graft choice. The purpose of this study was to analyze development of clinical outcomes of MLKIs over time at a minimum of 2 years of follow‐up.Four databases were queried for surgical outcome‐based studies of MLKIs published from 01/2000 through 09/2022 with a minimum 2‐year follow‐up. Technique articles, nonoperative treatment, arthroplasty, pediatric and review articles were excluded. Study characteristics including design, number of patients, age, follow‐up period, anatomical region and posterior‐cruciate ligament (PCL)‐based injury were collected. Primary outcomes were Lysholm, International Knee Documentation Committee (IKDC) outcome scores and Tegner activity score. Random‐effects model analysis was performed.After the application of inclusion and exclusion criteria, 3571 patients in 79 studies were included in the analysis. The mean age at surgery was 35.6 years. The mean follow‐up was 4.06 years (range 2–12.7). The mean Lysholm score at 2‐year follow‐up was 86.09 [95% confidence interval [CI]: 82.90–89.28], with a yearly decrease of −0.80 [95% CI: −1.47 −0.13], (p = 0.0199). The mean IKDC at 2 years was 81.35 [95% CI: 76.56–86.14], with a yearly decrease of −1.99 [95% CI: −3.14 −0.84] (p < 0.001). Non‐PCL‐based injuries had a higher IKDC 83.69 [75.55–91.82] vs. 75.00 [70.75–79.26] (p = 0.03) and Lysholm score 90.84 [87.10–94.58] versus 84.35 [82.18–86.52] (p < 0.01) than PCL‐based injuries, respectively.According to the present systematic review and meta‐analysis of MLKIs with minimum 2‐year follow‐ups, the patients who suffered an MLKI can expect to retain around 80‐85% of knee function at 2 years and can expect a yearly deterioration of knee function, depending on the score used. Inferior outcomes can be expected for PCL‐based injuries at 2 years postoperative.Level IV meta‐analysis. [ABSTRACT FROM AUTHOR]

Purpose: Multiple myeloma (MM) is the second most common neoplastic blood disease worldwide. Belantamab mafodotin is a new antibody conjugate anti-B-cell maturation antigen effective against refractory myelomas. It induces intracorneal microcysts leading to refractive fluctuations. The aim of this study is to assess the value of monitoring refractive fluctuations based on the location of microcystic-like epithelial changes (MECs) to facilitate patient follow-up. Methods: This observational and multicentric study was conducted using data collected from several French centers contacted through secure email through a standardized data collection table. Results: The fluctuation of objective refraction in spherical equivalent confirms a significant myopic shift from peripheral to central forms. A decrease in the best-corrected visual acuity (BCVA), an increase in keratometry, and an increase in central epithelial pachymetry have also been observed when MECs migrate toward the center. Conclusion: The myopization found in our study in patients with central and paracentral MECs is consistent with current literature. Fluctuations in BCVA, keratometry, and epithelial pachymetry are also consistent. This study is the first real-world study and highlights heterogeneity in follow-up, emphasizing the need to establish multidisciplinary follow-up strategies. The analysis of refractive fluctuations appears to be a reproducible and noninvasive screening method that could facilitate patient follow-up without the need for consultation focused on corneal diseases.

Visual Abstract: http://links.lww.com/EJA/A927., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Aims: As the antithrombotic regimen that may best prevent ischaemic complications along with the lowest bleeding risk offset following transcatheter aortic valve implantation (TAVI) remains unclear, we aimed to compare the safety and efficacy of antithrombotic regimens in patients without having an indication for chronic oral anticoagulation., Methods and Results: We conducted a PROSPERO-registered (CRD42021247924) systematic review and network meta-analysis of randomized controlled trials evaluating post-TAVI antithrombotic regimens up to April 2022. We estimated the relative risk (RR) and 95% confidence intervals (95% CIs) using a random-effects model in a frequentist pairwise and network metanalytic approach. We included seven studies comprising 4006 patients with a mean weighted follow-up of 12.9 months. Risk of all-cause death was significantly reduced with dual antiplatelet therapy (DAPT) compared with low-dose rivaroxaban + 3-month single antiplatelet therapy (SAPT) (RR 0.60, 95% CI 0.41-0.88), while no significant reduction was observed with SAPT vs. DAPT (RR 1.02, 95% CI 0.67-1.58) and SAPT and DAPT compared with apixaban or edoxaban (RR 0.60, 95% CI 0.32-1.14 and RR 0.59, 95% CI 0.34-1.02, respectively). SAPT was associated with a significant reduction of life-threatening, disabling, or major bleeding compared with DAPT (RR 0.45, 95% CI 0.29-0.70), apixaban or edoxaban alone (RR 0.45, 95% CI 0.25-0.79), and low-dose rivaroxaban + 3-month SAPT (RR 0.30, 95% CI 0.16-0.57). There were no differences between the various regimens with respect to myocardial infarction, stroke, or systemic embolism., Conclusion: Following TAVI in patients without an indication for chronic oral anticoagulant, SAPT more than halved the risk of bleeding compared with DAPT and direct oral anticoagulant-based regimens without significant ischaemic offset., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)