[Systematic analysis of evaluations of Objective Structured Clinical Exam (OSCE) multiple circuits: Explanatory variables and inter-rater correlations]. / Analyse systématique des évaluations de circuits multiples d'examen clinique objectif structuré (ECOS) : variables explicatives et corrélations inter-évaluateurs.

INTRODUCTION: Objective Structured Clinical Examinations (OSCEs) assess professional performance in a simulated environment. Following their integration into the reform of the 2nd cycle of medical studies (R2C), this pedagogical modality was implemented in France. This study investigates the variability of students' OSCE scores, as well as their inter-rater reproducibility. METHODS: This single-center retrospective study covered several sessions of evaluative OSCE circuits conducted between January 2022 and June 2023. Variables collected were: baseline situation family, competency domain, presence of a standardized participant for stations; gender and professional status for evaluators; scores (global, clinical and communication skills), number of previously completed OSCE circuits and faculty scores for students. RESULTS: The variability of the overall score was explained mainly (79.7%, CI95% [77.4; 82.0]) by the station factor. The student factor and the circuit factor explained 7.5% [12.9; 20.2] and<0.01% [2.10-13; 2.10-9] respectively. The inter-rater intra-class correlation coefficient was 87.2% [86.4; 87.9] for the global score. Station characteristics (starting situation, domain) and evaluator characteristics (gender, status) were significantly associated with score variations. CONCLUSION: This first study on the variability of OSCE circuit scores in France shows good reproducibility with influence of station characteristics. In order to standardize circuits, variability linked to the domain competency should be considered as well.

Prevention of venous thromboembolic events in patients with lower leg immobilization after trauma: Systematic review and network meta-analysis with meta-epsidemiological approach.

BACKGROUND: Lower limb trauma requiring immobilization is a significant contributor to overall venous thromboembolism (VTE) burden. The clinical effectiveness of thromboprophylaxis for this indication and the optimal agent strategy are still a matter of debate. Our main objective was to assess the efficacy of pharmacological thromboprophylaxis to prevent VTE in patients with isolated temporary lower limb immobilization after trauma. We aimed to estimate and compare the clinical efficacy and the safety of the different thromboprophylactic treatments to determine the best strategy. METHODS AND FINDINGS: We conducted a systematic review and a Bayesian network meta-analysis (NMA) including all available randomized trials comparing a pharmacological thromboprophylactic treatment to placebo or to no treatment in patients with leg immobilization after trauma. We searched Medline, Embase, and Web of Science until July 2021. Only RCT or observational studies with analysis of confounding factors including adult patients requiring temporary immobilization for an isolated lower limb injury treated conservatively or surgically and assessing pharmacological thromboprophylactic agents or placebo or no treatment were eligible for inclusion. The primary endpoint was the incidence of major VTE (proximal deep vein thrombosis, symptomatic VTE, and pulmonary embolism-related death). We extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses for NMA and appraised selected trials with the Cochrane review handbook. Fourteen studies were included (8,198 patients). Compared to the control group, rivaroxaban, fondaparinux, and low molecular weight heparins were associated with a significant risk reduction of major VTE with an odds ratio of 0.02 (95% credible interval (CrI) 0.00 to 0.19), 0.22 (95% CrI 0.06 to 0.65), and 0.32 (95% CrI 0.15 to 0.56), respectively. No increase of the major bleeding risk was observed with either treatment. Rivaroxaban has the highest likelihood of being ranked top in terms of efficacy and net clinical benefit. The main limitation is that the network had as many indirect comparisons as direct comparisons. CONCLUSIONS: This NMA confirms the favorable benefit/risk ratio of thromboprophylaxis for patients with leg immobilization after trauma with the highest level of evidence for rivaroxaban. TRIAL REGISTRATION: PROSPERO CRD42021257669.

Population pharmacokinetic model of cefazolin in total hip arthroplasty.

Cefazolin is an antibiotic recommended for infection prevention in total hip arthroplasty (THA). However, the dosing regimen necessary to achieve therapeutic concentrations in obese patients remains unclear. The aim of this study was to conduct a population analysis of cefazolin pharmacokinetics (PK) and assess whether cefazolin administration should be weight adapted in THA. Adult patients undergoing THA surgery received an injection of 2000 mg of cefazolin, doubled in the case of BMI > 35 kg/m2 and total body weight > 100 kg. A population PK study was conducted to quantify cefazolin exposure over time compared to the therapeutic concentration threshold. A total of 484 cefazolin measurements were acquired in 100 patients, of whom 29% were obese. A 2-compartment model best fitted the data, and creatinine clearance determined interpatient variability in elimination clearance. Our PK simulations using a 2000 mg cefazolin bolus showed that cefazolin concentrations remained above the threshold throughout surgery, regardless of weight or renal function. A 2000 mg cefazolin single injection without adaptation to weight or renal function and without intraoperative reinjection was efficient in maintaining therapeutic concentrations throughout surgery. The optimal target concentration and necessary duration of its maintenance remain unclear.

Pharmacokinetic Model for Cefuroxime Dosing during Cardiac Surgery under Cardiopulmonary Bypass.

Cefuroxime (CXM) is an antibiotic recommended for surgical site infection prevention in cardiac surgery. However, the dosing regimens commonly used do not sustain therapeutic concentrations throughout surgery. The aim of this study was to conduct a population analysis of CXM pharmacokinetics (PK), and to propose an optimized dosing regimen. Adult patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) received a 1,500 mg CXM intravenous bolus followed by a 750 mg bolus at CPB priming, then every 2 h thereafter. Model-based PK simulations were used to develop an optimized dosing regimen and evaluate its efficacy in attaining various concentration thresholds, including those recommended in US and European guidelines. In total, 447 CXM measurements were acquired in 50 patients. A two-compartment model best fit the data, with total body weight and creatinine clearance determining interpatient variability in the central and peripheral volumes of distribution, and in elimination clearance, respectively. Using our optimized dosing regimen, different dosing schemes adapted to body weight and renal function were calculated to attain total concentration thresholds ranging from 12 to 96 mg/liter. Our simulations showed that the dosing regimens recommended in US and European guidelines failed to maintain concentrations above 48 mg/liter. Our individualized dosing strategy was capable of ensuring therapeutic CXM concentrations conforming to each target threshold. Our model yielded an optimized CXM dosing regimen adapted to body weight and renal function, and sustaining therapeutic concentrations consistent with each desired threshold. The optimal target concentration and necessary duration of its maintenance in cardiac surgery still remain unclear.

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

AIMS: Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min-1 ). METHODS: Data including fondaparinux anti-Xa activities from two multicentre prospective cohorts were used. In the first cohort, patients (n = 957) received fondaparinux 2.5 mg once a day. In the second, patients with moderate renal impairment (n = 436) received 1.5 mg once per day. The time-to-major bleeding after the end of surgery was modelled using a parametric survival analysis in NONMEM. RESULTS: The observed rate of major bleeding up to day 11 was 5.2%. The time-to-event analysis indicated that the hazard of bleeding was highest in the first days following surgery and then remained low thereafter. Independent significant predictors of an increased hazard of major bleeding were male sex, lower body weight and increased drug exposure. Simulated rates of major bleeding up to day 11 in patients with moderate renal impairment were 6.5% with fondaparinux 2.5 mg once daily and 3.8% with fondaparinux 1.5 mg once daily. CONCLUSION: The hazard of major bleeding is highest in the first postoperative days and increases with fondaparinux exposure. To reduce the risk of bleeding in patients with moderate renal impairment, this study supports the use of a lower dose of fondaparinux 1.5 mg once daily.

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis.

Background: Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods: We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results: The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions: Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

Navigating the highlights of phase III trials: a watchful eye on evidence-based radiotherapy.

BACKGROUND: Phase III randomized controlled trials (RCTs) are the cornerstone of evidence-based oncology. However, there is no exhaustive review describing the radiotherapy RTCs characteristics. The objective of the present study was to describe features of all phase III RCTs including at least a radiation therapy. METHODS AND MATERIALS: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase III as topic', 'radiotherapy', 'brachytherapy', as keywords. RESULTS: A total of 454 phase III RCTs were identified. Studies were mainly based on open (92.1%) multicenter (77.5%) designs, analyzed in intend to treat (67.6%), aiming at proving superiority (91.6%) through overall survival assessment (46.5%). Most frequently studied malignancies were head and neck (21.8%), lung (14.3%) and prostate cancers (9.9%). Patients were mainly recruited with a locally advanced disease (73.7%). Median age was 59 years old. Out of 977 treatment arms, 889 arms experienced radiotherapy, mainly using 3D-conformal radiotherapy (288 arms, 32.4%). Intensity-modulated techniques were tested in 12 arms (1.3%). The intervention was a non-cytotoxic agent addition in 89 studies (19.6%), a radiation dose/fractionation modification in 74 studies (16.3%), a modification of chemotherapy regimen in 63 studies (13.9%), a chemotherapy addition in 63 studies (13.9%) and a radiotherapy addition in 53 trials (11.7%). With a median follow-up of 50 months, acute all-grade and grade 3-5 toxicities were reported in 49.6% and 69.4% of studies, respectively. Radiotherapy technique, follow-up and late toxicities were reported in 60.1%, 74%, and 31.1% of studies, respectively. CONCLUSION: Phase III randomized controlled trials featured severe limitations, since a third did not report radiotherapy technique, follow-up or late toxicities. The fast-paced technological evolution creates a discrepancy between literature and radiotherapy techniques performed in daily-routine, suggesting that phase III methodology needs to be reinvented.

Endoscopic or arthroscopic iliopsoas tenotomy for iliopsoas impingement following total hip replacement. A prospective multicenter 64-case series.

INTRODUCTION: Impingement between the acetabular component and the iliopsoas tendon is a cause of anterior pain after total hip replacement (THR). Treatment can be non-operative, endoscopic or arthroscopic, or by open revision of the acetabular component. Few studies have assessed these options. The present study hypothesis was that endo/arthroscopic treatment provides rapid pain relief with a low rate of complications. METHODS: A prospective multicenter study included 64 endoscopic or arthroscopic tenotomies for impingement between the acetabular component and the iliopsoas tendon, performed in 8 centers. Mean follow-up was 8months, with a minimum of 6months and no loss to follow-up. Oxford score, patient satisfaction, anterior pain and iliopsoas strength were assessed at last follow-up. Complications and revision procedures were collated. Forty-four percent of patients underwent rehabilitation. RESULTS: At last follow-up, 92% of patients reported pain alleviation. Oxford score, muscle strength and pain in hip flexion showed significant improvement. The complications rate was 3.2%, with complete resolution. Mean hospital stay was 0.8 nights. In 2 cases, arthroscopy revealed metallosis, indicating revision of the acetabular component. The only predictive factor was acetabular projection on oblique view. Rehabilitation significantly improved muscle strength. CONCLUSION: Endoscopic or arthroscopic tenotomy for impingement between the acetabular component and the iliopsoas tendon following THR significantly alleviated anterior pain in more than 92% of cases. The low complications rate makes this the treatment of choice in case of failure of non-operative management. Arthroscopy also reorients diagnosis in case of associated joint pathology. Projection of the acetabular component on preoperative oblique view is the most predictive criterion, guiding treatment.

Outcomes of cup revision for ilio-psoas impingement after total hip arthroplasty: Retrospective study of 46 patients.

BACKGROUND: Impingement of the ilio-psoas tendon on the acetabular component is a cause of pain after total hip arthroplasty (THA). Studies of cup revision for ilio-psoas impingement (IPI) are scarce and limited in size. We therefore conducted a large multicentre retrospective study with the following objectives: to assess the effectiveness of cup replacement in resolving the impingement syndrome, to determine the frequency and nature of complications after cup revision for IPI, and to identify pre-operative factors associated with good outcomes of cup revision for IPI. HYPOTHESIS: Cup revision is effective in resolving the pain due to IPI in selected patients. METHODS: This retrospective multicentre study included 46 patients who underwent cup revision because of IPI. Before the revision, 38 (83%) patients had prominence of the anterior cup rim (mean, 9.9±4.5mm (range, 2-22mm) by radiography and 35 (76%) had cup malposition (anteversion<10° and/or inclination>50°). Mean follow-up was 21months (range, 6months to 6 years) and no patient was lost to follow-up. Outcomes at last follow-up were assessed based on the Oxford Hip Score (OHS), patient satisfaction index, complications, and revisions. RESULTS: At last follow-up, 39 (85%) patients were satisfied with the revision procedure, a significant improvement versus baseline was noted in the OHS (mean, 43±6; range, 25-48; P<0.001), and 41 patients were free of pain during hip flexion (P<0.001 versus baseline). Complications occurred in 3 (6.5%) patients, but only one complication was severe (deep infection). Recurrent groin pain was reported by 4 (8.7%) patients at last follow-up. None of the factors studied predicted the outcome of revision surgery. DISCUSSION: Cup revision for IPI after THA is effective in relieving the groin pain in 80% of patients with anterior cup rim prominence and/or cup malposition. However, complications can occur. Tenotomy may be preferable when the diagnosis is in doubt and/or cup position is acceptable. LEVEL OF EVIDENCE: IV, retrospective observational study.

Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass.

BACKGROUND: High-dose heparin is used during cardiopulmonary bypass (CPB) to prevent thrombosis in the circuits used for extracorporeal circulation. The aim of this study was, initially, to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess the variability of PK/PD parameters and their correlation with the results of the routine haemostatic test activated clotting time (ACT) and thereafter to develop a Bayesian estimator enabling an individualized dosing strategy. METHODS: Fifty consecutive patients undergoing cardiac surgery with CPB were included in the study. Heparin was administered as an initial bolus of 300 IU kg -1 followed by additional boluses of 5000 IU to maintain ACT <400 s. In total, 361 blood samples were collected. The PK and PD data were analysed using a non-linear mixed effect model. RESULTS: A two-compartment model with a linear elimination link to an E max model best described heparin anti-factor Xa activities and ACT. Covariate analysis showed that body weight was positively correlated with clearance and central compartment volume. Inclusion of body weight with these parameters decreased their variability by 11 and 15%, respectively. The Bayesian estimator performed well in predicting individual parameters in an independent group of patients. CONCLUSIONS: A population PK/PD analysis of heparin during CPB, using a routine haemostatic test, shows that Bayesian estimation might help to predict ACT on the basis of only one or two blood samples.

Assessment of clinically relevant bleeding as a surrogate outcome for major bleeding: validation by meta-analysis of randomized controlled trials.

Essentials Surrogacy of clinically relevant bleeding (CRB) for major bleeding has never been validated. Our meta-analysis evaluated CRB surrogacy in trials of new versus traditional anticoagulants. Surrogacy was not validated in orthopedic surgery, venous thromboembolism or atrial fibrillation The difficulty in demonstrating the surrogacy may reflect a lack of homogeneity in its definition SUMMARY: Background Clinically relevant bleeding (CRB), comprising major bleeding and clinically relevant non-major bleeding, has been used as a surrogate for major bleeding in most anticoagulant trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in clinical trials was never assessed. Methods We systematically reviewed randomized phase III trials comparing new anticoagulants with the standard of care for venous thromboembolism prevention following major orthopedic surgery, venous thromboembolism (VTE) treatment, or stroke and systemic embolism prevention in atrial fibrillation (AF), and reporting both major bleeding and CRB rates. The validity of CRB as a surrogate for major bleeding was assessed according to the strength of the association between the relative risks of major bleeding and CRB, measured by the use of R2trial and its 95% confidence interval (CI). Results In the postoperative prophylactic setting (13 studies), major bleeding and CRB rates were 1.12% and 3.56%, respectively, and R2trial was 0.69 (95% CI 0.34-0.93). For acute VTE studies (n = 12), major bleeding and CRB rates were 1.87% and 9.07%; the corresponding R2trial values were 0.28 (95% CI 0.01-0.80) and 0.68 (95% CI 0.09-1.00) when only double-blind studies were considered (n = 7). For AF studies (n = 7; 22 strata), major bleeding and CRB rates were 4.82% and 15.3%, and R2trial was 0.59 (95% CI 0.15-0.82). Conclusion Despite an apparent correlation between CRB and major bleeding in major orthopedic surgery, AF, and double-blind acute VTE studies, the wide CIs suggest that CRB might not be an acceptable surrogate outcome in any of these settings.

[Influence of anticoagulant therapy during pregnancy on the peripartum and anesthesia delivery terms]. / Influence d'un traitement anticoagulant pendant la grossesse sur l'anesthésie per-partum et les modalités d'accouchement.

OBJECTIVES: The objective of the study was to evaluate the influence of anticoagulation on intrapartum anesthesia and delivery modalities. METHODS: This ancillary study is concerned with anticoagulated patients included in the study STRATHEGE, in the Saint-Etienne and Lyon University Hospital from 2007 to 2012, which are compared to a control population. The primary endpoint is to evaluate the type of anesthesia received by women in labor, according to the center at the time of delivery compared to no treatment. The secondary endpoints are comparing the input mode to work, mode of delivery, stop management arrangements of these treatments, the rate of thromboembolic and hemorrhagic complications. RESULTS: Two hundred and three cases were included and 812 controls, matched on age, body mass index and parity. 61.6% of the cases had an epidural during childbirth against 87% of controls (p<0.05), spinal rates (22.5% versus 1.85%) and general anesthesia (5.4% versus 0.7%) were higher in the case group. The delivery rate vaginally was 90% in controls, against 65% of cases. The postpartum hemorrhage rate was similar in both groups (p> 0.05). A relay of the low molecular weight heparin was performed in 63% of the cases in Lyon, but the types of anesthesia received according to the centers were similar. CONCLUSION: Anticoagulant therapy at the time of delivery, does not limit access to effective analgesia, but with an increased rate of spinal anesthesia and general anesthesia at the expense of epidural anesthesia. The management of a parturient anticoagulant is complex and still exists today, great care disparities in the various maternity hospitals.

Tunable thermal conductivity of thin films of polycrystalline AlN by structural inhomogeneity and interfacial oxidation.

The effect of the structural inhomogeneity and oxygen defects on the thermal conductivity of polycrystalline aluminum nitride (AlN) thin films deposited on single-crystal silicon substrates is experimentally and theoretically investigated. The influence of the evolution of crystal structure, grain size, and out-of plane disorientation along the cross plane of the films on their thermal conductivity is analyzed. The impact of oxygen-related defects on thermal conduction is studied in AlN/AlN multilayered samples. Microstructure, texture, and grain size of the films were characterized by X-ray diffraction and scanning and transmission electron microscopy. The measured thermal conductivity obtained with the 3-omega technique for a single and multiple layers of AlN is in fairly good agreement with the theoretical predictions of our model, which is developed by considering a serial assembly of grain distributions. An effective thermal conductivity of 5.92 W m(-1) K(-1) is measured for a 1107.5 nm-thick multilayer structure, which represents a reduction of 20% of the thermal conductivity of an AlN monolayer with approximately the same thickness, due to oxygen impurities at the interface of AlN layers. Our results show that the reduction of the thermal conductivity as the film thickness is scaled down, is strongly determined by the structural inhomogeneities inside the sputtered films. The origin of this non-homogeneity and the effect on phonon scattering are also discussed.

Piezoresistance of top-down suspended Si nanowires.

Measurements of the gauge factor of suspended, top-down silicon nanowires are presented. The nanowires are fabricated with a CMOS compatible process and with doping concentrations ranging from 2 × 10(20) down to 5 × 10(17) cm(-3). The extracted gauge factors are compared with results on identical non-suspended nanowires and with state-of-the-art results. An increase of the gauge factor after suspension is demonstrated. For the low doped nanowires a value of 235 is measured. Particular attention was paid throughout the experiments to distinguishing real resistance change due to strain modulation from resistance fluctuations due to charge trapping. Furthermore, a numerical model correlating surface charge density with the gauge factor is presented. Comparison of the simulations with experimental measurements shows the validity of this approach. These results contribute to a deeper understanding of the piezoresistive effect in Si nanowires.