Regional anaesthesia via parasternal catheters inserted preoperatively and postoperative delirium after cardiac surgery: A prospective unrandomised clinical trial.

VISUAL ABSTRACT: http://links.lww.com/EJA/A927.

Factors Influencing Unfractionated Heparin Pharmacokinetics and Pharmacodynamics During a Cardiopulmonary Bypass.

BACKGROUND: Unfractionated heparin (UFH) is commonly used during cardiac surgery with a cardiopulmonary bypass to prevent blood clotting. However, empirical administration of UFH leads to variable responses. Pharmacokinetic and pharmacodynamic modeling can be used to optimize UFH dosing and perform real-time individualization. In previous studies, many factors that could influence UFH pharmacokinetics/pharmacodynamics had not been taken into account such as hemodilution or the type of UFH. Few covariates were identified probably owing to a lack of statistical power. This study aims to address these limitations through a meta-analysis of individual data from two studies. METHODS: An individual patient data meta-analysis was conducted using data from two single-center prospective observational studies, where different UFH types were used for anticoagulation. A pharmacodynamic/pharmacodynamic model of UFH was developed using a non-linear mixed-effects approach. Time-varying covariates such as hemodilution and fluid infusions during a cardiopulmonary bypass were considered. RESULTS: Activities of UFH's anti-activated factor/anti-thrombin were best described by a two-compartment model. Unfractionated heparin clearance was influenced by body weight and the specific UFH type. Volume of distribution was influenced by body weight and pre-operative fibrinogen levels. Pharmacodynamic data followed a log-linear model, accounting for the effect of hemodilution and the pre-operative fibrinogen level. Equations were derived from the model to personalize UFH dosing based on the targeted activated clotting time level and patient covariates. CONCLUSIONS: The population model effectively characterized UFH's pharmacokinetics/pharmacodynamics in cardiopulmonary bypass patients. This meta-analysis incorporated new covariates related to UFH's pharmacokinetics/pharmacodynamics, enabling personalized dosing regimens. The proposed model holds potential for individualization using a Bayesian estimation.

Dose-response relationships of intravenous and perineural dexamethasone as adjuvants to peripheral nerve blocks: a systematic review and model-based network meta-analysis.

BACKGROUND: Superiority of perineural over intravenous dexamethasone at extending nerve block analgesia has been suggested but without considering the dose-response relationships for each route of administration. METHODS: Randomised control studies that evaluated intravenous or perineural dexamethasone as an adjuvant to unilateral peripheral nerve blocks in adults were searched up to October 2023 in MEDLINE, Central, Google Scholar, and reference lists of previous systematic reviews. The Cochrane Risk-of-Bias tool was used. A maximum effect (Emax) model-based network meta-analysis was undertaken to evaluate the dose-response relationships of dexamethasone. RESULTS: A total of 118 studies were selected (9284 patients; 35 with intravenous dexamethasone; 106 with perineural dexamethasone; dose range 1-16 mg). Studies with unclear or high risk of bias overestimated the effect of dexamethasone. Bias-corrected estimates indicated a maximum fold increase in analgesia duration of 1.7 (95% credible interval (CrI) 1.4-1.9) with dexamethasone, with no difference between perineural and intravenous routes. Trial simulations indicated that 4 mg of perineural dexamethasone increased the mean duration of analgesia for long-acting local anaesthetics from 11.1 h (95% CrI 9.4-13.1) to 16.5 h (95% CrI 14.0-19.3) and halved the rate of postoperative nausea and vomiting. A similar magnitude of effect was observed with 8 mg of intravenous dexamethasone. CONCLUSIONS: Used as an adjuvant for peripheral nerve block, intravenous dexamethasone can be as effective as perineural dexamethasone in prolonging analgesic duration, but is less potent, hence requiring higher doses. The evidence is limited because of the observational nature of the dose-response relationships and the quality of the included studies. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42020141689.

A framework to characterise the reproducibility of meta-analysis results with its application to direct oral anticoagulants in the acute treatment of venous thromboembolism.

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.

Proteomic biomarkers for survival in systemic sclerosis-associated pulmonary hypertension.

BACKGROUND: Interstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and combined PH and ILD (SSc-PH-ILD) generally have a poor prognosis. Predictors of survival and of potential benefit of treatment are lacking in patients with SSc-PH-ILD. OBJECTIVE: To identify specific plasma protein expression patterns associated with survival in patients with SSc-PH-ILD. MATERIALS AND METHODS: Post-hoc analysis of a prospective multicenter French study in patients with PH-ILD. An untargeted proteomic analysis using mass spectrometry was performed to identify plasma protein changes associated with long-term overall survival in patients with SSc-PH-ILD. RESULTS: Thirty two patients were included in the analysis, of whom 13 died during follow-up (median survival: 76.5 months). At baseline, survivors had less severe hemodynamic impairment [pulmonary vascular resistance of 4.4 Wood Units (IQR 3-5.2) vs. 6.2 Wood Units (IQR 4.2-10.7)] and higher carbon monoxide diffusing capacity [median 39% (IQR 35-44%) vs. 25% (IQR 22-30.5%)], than the 13 patients who died. Seven proteins, associated with haemostasis and fibrosis, were differentially expressed according to patients' survival. In the survivor group, two proteins were increased (ADAMTS13, SERPIND1) and five were decreased (PTGDS, OLFM1, C7, IGFBP7, FBN1) compared to the non-survivor groups. CONCLUSION: The prognosis of SSc-PH-ILD patients is poor. This proteomic approach found 7 plasma proteins (involved in haemostasis and fibrosis pathways) associated with survival. These potential biomarkers may be good candidates to prognostic enrichment.

Replication of systematic reviews: is it to the benefit or detriment of methodological quality?

OBJECTIVES: To perform an overview of the overlap of systematic reviews (SRs) assessing direct oral anticoagulants and characterize these reviews in terms of bias and methodological quality (PROSPERO: CRD42022316273). STUDY DESIGN AND SETTING: A PubMed-indexed search was performed from inception to January 31, 2022 to identify SRs evaluating direct oral anticoagulants in patients treated for an acute venous thromboembolism. The risk of bias of these SRs was assessed according to the Risk Of Bias In Systematic reviews tool. Redundancy was defined as overlap in terms of the type of population considered, the interventions compared, and the studies included. RESULTS: A total of 144 SRs were evaluated, of which 26 (18.1%) were classified as original, 87 (60.4%) as conceptual replications, and 31 (21.5%) as excessive replications. The risk of bias was high in 19 (73.1%) of the original SRs, 65 (74.7%) of the conceptual replications, and 21 (67.7%) of the excessive replications. Compared to the original SRs, the overall methodological quality was not improved in either conceptual or excessive replications. CONCLUSION: A large number of SRs was classified as replications; a fifth constituted excessive replications. The replications showed no improvement in overall methodological quality compared to the original SRs.

Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations.

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.

Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve implantation in patients without indications for chronic oral anticoagulation: a systematic review and network meta-analysis of randomized controlled trials.

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.

Adjusted versus fixed doses of LMWHs in trauma patients: A systematic review and meta-analysis.

PURPOSE: Venous thromboembolism (VTE) causes significant morbidity and mortality in patients with traumatic injuries, despite thromboprophylaxis. To decrease both thrombotic and bleeding risks, some authors suggest adjusting the thromboprophylactic doses of low-molecular-weight heparins (LMWH), in particular according to body weight at treatment initiation or to changes in anti-factor Xa level during treatment. Our objective was to estimate in trauma patients the efficacy and safety of such adjustments, compared with the conventional strategy of fixed-dose LMWH thromboprophylaxis. SOURCE: A systematic review and a meta-analysis were conducted to identify and assess randomised control trials and observational studies with prospective enrolment that included trauma patients and compared adjustment of LMWH thromboprophylaxis versus no adjustment. The primary and secondary endpoints were VTE and bleeding, respectively. The Odds Ratio (OR) and 95% Confidence Interval (95% CI) were calculated using the Mantel-Haenszel method. PRINCIPAL FINDINGS: Nine studies were included in the meta-analysis. No significant reduction in the risk of VTE was observed with adjusted doses of LMWH compared with fixed doses when considering only randomised control trials (OR 1.02 [95% CI, 0.09 to 11.6]) or all trials (OR 0.70 [95% CI, 0.34 to 1.42]). Similarly, there was no significant difference in bleeding risk (OR 1.36, 95% CI 0.59 to 3.10). CONCLUSION: This meta-analysis shows that, to date, there is no evidence to justify adjusting LMWH doses, in agreement with the recommendations of the American College of Chest Physicians.

A retrospective study of the efficacy of intense pulsed light delivered by the Lacrystim® for meibomian gland dysfunction therapy.

BACKGROUND: Meibomian gland dysfunction is the most common etiology of dry eye disease worldwide and intense pulsed light appears to be a promising treatment with encouraging results. Lacrystim® is a new IPL device (CE marking in 2019) and no studies have yet been published on it. We propose the first study on this device with an objective assessment of its efficacy and an extended follow-up over 6 months. METHODS: Patients presenting with a dry eye disease (DED) with stable mild to moderate MGD and having received Lacrystim® treatment between june 2019 and june 2020 were included. 3 IPL sessions were performed at D0, D15 and D45 with 4 shots per side at a fluence of 8 mJ/cm2. DED clinical evaluation was performed at D0, D15, D45, 3rd month and 6th month: Oxford scale and break up time, Schirmer test and Ocular Surface Disease Index (OSDI) questionnaire. Lacrydiag® imaging device carried out an objective examination of tear film: interferometry, meibography, tear meniscus height and non-invasive break up time (NIBUT). The primary endpoint was the evolution in NIBUT between the first visit D0 and 3rd month. Data collection was done retrospectively. Statistical analysis was done using a linear mixed-effects model and a non-parametric linear mixed-effects model (R software). RESULTS: Forthy five consecutive patients were included. NIBUT significantly increased between D0 and 3rd month: mean difference of 1.63 seconds, IC95% [0.51; 2.62], (p = 0.002) with a prolonged effect at 6th month. OSDI and OXFORD scores and interferometry were also significantly improved at 3rd month and 6th month. There was no significant change in BUT, Schirmer test and tear meniscus height. No adverse event was noted. CONCLUSIONS: IPL delivered by Lacrystim® appears effective and safe to treat MGD although a randomized controlled trial is needed to validate its results. TRIAL REGISTRATION: This work was approved by a local ethics committee "Terre d'éthique" (institutional review board number: IRBN672019/CHUSTE) and registered on the clinicaltrial.gov website ( NCT04147962 , 01/11/2019).

TNF-α and IL-1ß Exposure Modulates the Expression and Functionality of P-Glycoprotein in Intestinal and Renal Barriers.

Inflammation is characterized by an increased secretion of proinflammatory cytokines known to alter the expression and functionality of drug transporters. Since P-glycoprotein (P-gp) plays a key role in the pharmacokinetics of several drugs, these modulations could further affect drug exposure. In this context, this study aims to investigate the impact of in vitro cytokine exposure on the expression and activity of P-gp using the intestinal model Caco-2 and the human renal cells RPTEC/TERT1. Cells were exposed to various concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß for 24 or 72 h. Gene expression was then assessed by RT-qPCR followed by absolute quantification of P-gp using liquid chromatography coupled with mass spectrometry. Then, the activity of P-gp was assessed by the intracellular accumulation of rhodamine 123. TNF-α increased both the gene expression and P-gp activity by 15-40% in each model. Minor modulations were observed at the protein level with increases of up to 8% for RPTEC/TERT1 cells and 24% for Caco-2 cells. Conversely, IL-1ß led to a downregulation of gene, protein, and functionality by 48 and 25% in intestinal and renal cells, respectively. Taken together, these data highlighted that gene expression levels and functional activity of P-gp are altered by the pro-inflammatory cytokines in intestinal and renal cells. Such pronounced changes in human P-gp could result in altered exposure to drug substrates. Further in vivo studies are needed to confirm the impact of inflammation on drug pharmacokinetics.

Time impact on the antidiabetic effects of key bariatric surgeries: a network meta-analysis of randomized controlled trials with meta-regression.

BACKGROUND: Few studies compare the efficacy of the key bariatric procedures in type 2 diabetes management over the long term. None offer a reliable comparison of their respective efficacy loss over time. OBJECTIVES: To analyze and compare the time evolution of the antidiabetic effects of the key bariatric procedures. SETTING: Obesity surgery departments in America, Europe, and Asia. METHODS: All the randomized clinical trials assessing the efficacy of bariatric surgery in type 2 diabetes management with 1-5 years of follow-up were reviewed. A network meta-analysis with meta-regression was performed to compare the effectiveness of each technique and its respective efficacy loss temporal dynamics. RESULTS: Thirty-one trials involving 1906 patients were included. In comparison to Roux-en-Y gastric bypass, the 5-year complete or partial diabetes remission rates were inferior with medical treatment (odds ratio [OR] = .05; 95% credible interval [CrI]: .02-.13) and gastric banding (OR = .38; 95% CrI: .16-.87), equivalent with sleeve gastrectomy (OR = 1.08; 95% CrI: .59-1.97), and superior with 1 anastomosis gastric bypass (OR = 3.00; 95% CrI: 1.12-8.33) and biliopancreatic diversion and its affiliated techniques (OR = 3.71; 95% CrI: 1.16-12.55). However, remission rates and glycemic control progressively decreased whatever the treatment option evaluated. Moreover, this loss of efficacy followed a statistically comparable temporal dynamic to those of Roux-en-Y gastric bypass regardless of the therapeutic strategy implemented. CONCLUSIONS: No therapeutic modality offered stable antidiabetic effects. The gap observed between the techniques after a 5-year follow up concerning remission rates and glycemic control could depend essentially on the magnitude of the effects initially obtained. However, these results need to be confirmed over longer follow-up periods.

Development of a Bayesian estimation tool to determine the optimal duration of apixaban discontinuation before a high-bleeding risk procedure.

Apixaban is a direct oral anticoagulant (DOAC). Many studies have shown that it shows high pharmacokinetic interindividual and intraindividual variability (IIV). The risk of hemorrhage is a major concern for patients treated with apixaban to undergo an operation or an invasive procedure. Due to this large pharmacokinetic variability, the current recommendations concerning the optimal duration of apixaban discontinuation before a high-bleeding risk procedure concern the general population and not a specific patient. The aim of this study was (1) to investigate by simulation the distribution of decay time of apixaban concentration and (2) to develop and validate an easy-to-use web tool to estimate the individual decay time of apixaban in a "real-life" situation. A systematic review of the literature was conducted to select the relevant pharmacokinetic models for the creation of the web tool. For each model, pharmacokinetic profiles were simulated and the time to reach concentrations below the threshold of 30 ng/ml (T30) was calculated. One of the selected models was chosen to perform a Bayesian estimation and predict the optimal duration of apixaban discontinuation before a high-bleeding risk procedure. All these results were concatenated into the PrevBleed application developed with the R Shiny package.

Time course response after single injection of botulinum toxin to treat spasticity after stroke: Systematic review with pharmacodynamic model-based meta-analysis.

BACKGROUND: The time-course response after a single injection of botulinum toxin (BoNT) for post-stroke spasticity is debated. We addressed this issue by conducting a systematic review and a pharmacodynamic model-based meta-analysis. METHODS: We searched Medline, PeDro and Google Scholar databases up to March 2020, selecting randomized controlled trials of post-stroke and traumatic brain injury patients with arm or leg muscle hypertonia, comparing BoNT to placebo, or different BoNT preparations. The main outcome was change in Modified Ashworth Scale (MAS) score. A non-linear mixed effect model was used to estimate maximal toxin and placebo effects (Emax and EPlacebo), the effect disappearance half-life (T1/2off) of BoNT and the doses achieving 50 and 80% of Emax (D50 and D80). The equivalence ratios between different BoNT preparations were calculated from D50 values. Adverse events were recorded. RESULTS: Altogether, 2,236 unique records were screened by 2 independent reviewers: 35 eligible trials including 3011 patients (95% post-stroke) were identified. For all BoNT preparations, the BoNT Emax of -1.11 (95% credible interval -1.31; -0.29) was reached at 5 weeks; the maximal placebo effect was -0.30 (-0.37; -0.22). Both D50 and D80 differed significantly by muscle volume. At D50, the equivalence ratio was significantly higher for abobotulinumtoxinA (3.35) than onabotulinumtoxinA and lower for letibotulinumtoxinA (0.41). T1/2off was longer for abobotulinumtoxinA than for onabotulinumtoxinA and the other preparations (13.1 weeks [95% credible interval 7.7; 19.3] vs 8.6 weeks [7.1; 10.1]). Adverse events were minor, with a weak, but significant, dose-response relation for muscle weakness. CONCLUSIONS: This first pharmacodynamic model-based meta-analysis of individuals with stroke revealed that for all BoNT-A preparations, BoNT-A injections to treat spasticity have maximal effect at 5 weeks. The T1/2off was longer for abobotulinumtoxinA than other preparations. Differences between certain BoNT unit scales were also confirmed.

Penalized Poisson model for network meta-analysis of individual patient time-to-event data.

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.

In Vitro Evaluation of P-gp-Mediated Drug-Drug Interactions Using the RPTEC/TERT1 Human Renal Cell Model.

BACKGROUND AND OBJECTIVES: In vitro evaluation of the P-glycoprotein (P-gp) inhibitory potential is an important issue when predicting clinically relevant drug-drug interactions (DDIs). Located within all physiological barriers, including intestine, liver, and kidneys, P-gp plays a major role in the pharmacokinetics of various therapeutic classes. However, few data are available about DDIs involving renal transporters during the active tubular secretion of drugs. In this context, the present study was designed to investigate the application of the human renal cell line RPTEC/TERT1 to study drug interactions mediated by P-gp. METHODS: The P-gp inhibitory potentials of a panel of drugs were first determined by measuring the intracellular accumulation of rhodamine 123 in RPTEC/TERT1 cells. Then four drugs were selected to assess the half-maximal inhibitor concentration (IC50) values by measuring the intracellular accumulation of two P-gp-substrate drugs, apixaban and rivaroxaban. Finally, according to the FDA guidelines, the [I1]/IC50 ratio was calculated for each combination of drugs to assess the clinical relevance of the DDIs. RESULTS: The data showed that drugs which are known P-gp inhibitors, including cyclosporin A, ketoconazole, and verapamil, caused great increases in rhodamine 123 retention, whereas noninhibitors did not affect the intracellular accumulation of the P-gp substrate. The determined IC50 values were in accordance with the inhibition profiles observed in the rhodamine 123 accumulation assays, confirming the reliability of the RPTEC/TERT1 model. CONCLUSIONS: Taken together, the data demonstrate the feasibility of the application of the RPTEC/TERT1 model for evaluating the P-gp inhibitory potentials of drugs and consequently predicting renal drug interactions.

Robust K-PD model for activated clotting time prediction and UFH dose individualisation during cardiopulmonary bypass.

BACKGROUND AND OBJECTIVE: Activated clotting time (ACT) is a point-of-care test used to monitor the effect of unfractionated heparin (UFH) during cardiopulmonary bypass (CPB). This test sometimes returns aberrant values, which can lead to the administration of an inappropriate dosing regimen. The development of a population-robust K-PD model of UFH could allow the individualisation and automation of UFH therapy during CPB. METHODS: We conducted a prospective observational study to collect ACT measurements from patients undergoing surgery using CPB. The ACT data were split into a development and validation cohort. The development cohort was used to estimate a standard and robust population K-PD model characterised by a residual error following a normal distribution and student's t-distribution. The ACT prediction performance using Bayesian estimates of individual K-PD parameters was evaluated by comparing predicted versus observed ACTs. Using estimates of the robust K-PD model, a Bayesian individualisation strategy to automate UFH administration was proposed and evaluated using Monte Carlo simulations. RESULTS: A total of 295 patients were included in the study, and 1561 ACTs were collected. In patients without outlier values, Bayesian estimates (based on four ACT measurements) from both standard and robust K-PD models had similar performances, with a median prediction bias close to 0 s. In patients with outlier measurements, the use of the robust K-PD model greatly improved the prediction bias and root-mean-square error (RMSE), with a mean prediction bias of 3.25 s, IQR = [-19.9; 46.03] versus -86 s IQR = [-135.7; -63.8] for the standard model. Monte Carlo simulations showed that the robust Bayesian individualisation strategy allowed the ACT to be maintained above the target using only two to three ACT measurements. CONCLUSIONS: The use of a robust K-PD model reduced prediction bias and RMSE in patients with outlier ACT measurements. The Bayesian individualisation strategy using robust estimates of individual parameters may help automate UFH dosing regimens. Proper clinical validation is warranted before its use in daily clinical practice.

Functional, proteomic and phenotypic in vitro studies evidence podocyte injury after chronic exposure to heparin.

Unfractionated heparin (UFH) is a widely used anticoagulant that possess numerous properties including anti-inflammatory, anti-viral, anti-angiogenesis, and anti-metastatic effects. The effect of this drug was evaluated on the podocyte, an important actor of the glomerular filtration. Using a functional approach, we demonstrate that heparin treatment leads to a functional podocyte perturbation characterized by the increase of podocyte monolayer permeability. This effect is enhanced with time of exposure. Proteomic study reveals that heparin down regulate focal adhesion and cytoskeletal protein expressions as well as the synthesis of glomerular basement membrane components. This study clearly demonstrates that UFH may affect podocyte function by altering cytoskeleton organization, cell-cell contacts and cell attachment.

Impact of a restrictive antibiotic policy on the acquisition of extended-spectrum beta-lactamase-producing Enterobacteriaceae in an endemic region: a before-and-after, propensity-matched cohort study in a Caribbean intensive care unit.

BACKGROUND: High-level antibiotic consumption plays a critical role in the selection and spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in the ICU. Implementation of a stewardship program including a restrictive antibiotic policy was evaluated with respect to ESBL-E acquisition (carriage and infection). METHODS: We implemented a 2-year, before-and-after intervention study including all consecutive adult patients admitted for > 48 h in the medical-surgical 26-bed ICU of Guadeloupe University Hospital (French West Indies). A conventional strategy period (CSP) including a broad-spectrum antibiotic as initial empirical treatment, followed by de-escalation (period before), was compared to a restrictive strategy period (RSP) limiting broad-spectrum antibiotics and shortening their duration. Antibiotic therapy was delayed and initiated only after microbiological identification, except for septic shock, severe acute respiratory distress syndrome and meningitis (period after). A multivariate Cox proportional hazard regression model adjusted on propensity score values was performed. The main outcome was the median time of being ESBL-E-free in the ICU. Secondary outcome included all-cause ICU mortality. RESULTS: The study included 1541 patients: 738 in the CSP and 803 in the RSP. During the RSP, less patients were treated with antibiotics (46.8% vs. 57.9%; p < 0.01), treatment duration was shorter (5 vs. 6 days; p < 0.01), and administration of antibiotics targeting anaerobic pathogens significantly decreased (65.3% vs. 33.5%; p < 0.01) compared to the CSP. The incidence of ICU-acquired ESBL-E was lower (12.1% vs. 19%; p < 0.01) during the RSP. The median time of being ESBL-E-free was 22 days (95% CI 16-NA) in the RSP and 18 days (95% CI 16-21) in the CSP. After propensity score weighting and adjusted analysis, the median time of being ESBL-E-free was independently associated with the RSP (hazard ratio, 0.746 [95% CI 0.575-0.968]; p = 0.02, and hazard ratio 0.751 [95% CI 0.578-0.977]; p = 0.03, respectively). All-cause ICU mortality was lower in the RSP than in the CSP (22.5% vs. 28.6%; p < 0.01). CONCLUSIONS: Implementation of a program including a restrictive antibiotic strategy is feasible and is associated with less ESBL-E acquisition in the ICU without any worsening of patient outcome.

An epidemic of redundant meta-analyses.

BACKGROUND: Meta-analyses are widely used to strengthen available evidence and obtain more precise estimates of treatment effect than any individual trial. Paradoxically, multiplication of meta-analyses on the same topic can lead to confusion as practitioners no longer benefit from a rapid and synthetic response. This phenomenon may appear disproportionate when the number of published meta-analyses exceeds the number of original studies. OBJECTIVES: To describe an example of redundant meta-analyses published in the same area with the same randomized clinical trials (RCTs). METHODS: A systematic review was performed to identify all published meta-analyses of original RCTs that compared direct oral anticoagulants with low molecular weight heparins in cancer patients with venous thromboembolism (VTE). Forest plots were used to represent the meta-analyses results for efficacy (VTE recurrence) and safety (major bleeding) endpoints. An authors' network was constructed to explore the links between the authors of the published meta-analyses. RESULTS: In the past 3 years, four original RCTs were the subject of 20 published meta-analyses by 142 authors: five, four, and 11 meta-analyses pooled the data of two, three, and four RCTs, respectively. The results of meta-analyses were similar regarding the risks of VTE recurrence and major bleeding. The 11 meta-analyses of four RCTs were published within 6 months of the publication of the last RCT. CONCLUSIONS: The epidemic proportions of such redundant literature and authorship could be moderated by developing "living" meta-analyses and encouraging authors of new RCTs to update the corresponding meta-analysis in the same paper as their original research.