Physical model of neutron scattering by clathrate hydrate and C60hosting paramagnetic oxygen molecules.

This paper describes the physical modelling of neutron scattering in two polycrystalline inclusion compounds, fully deuterated clathrate hydrate andC60, each with paramagnetic oxygen as guest molecules. For studying the suitability of these materials for neutron moderation to very low energies, the model includes, in addition to the magnetic neutron scattering by the oxygen, the nuclear scattering by all constituents. The theoretical total cross sections are calculated based on the phonon density of states obtained by density functional theory and molecular dynamics simulations. At low temperatures, the developed scattering kernels are in good agreement with experimental neutron scattering data reported in the literature. At 20 K and above, a Lorentzian distribution for the zero-field splitting of the magnetic substates of the spin triplet of the oxygen molecules helps to reproduce magnetic peaks observed in inelastic neutron scattering experiments better than the original theory based on a single-valued splitting constant. Neutron spectra obtained by Monte Carlo simulations in infinite media are presented, highlighting the potential use ofO2-containing fully deuterated clathrate hydrate as a neutron moderator for the production of very cold neutrons.

[Translation into French and republication of: "Management of cancer-associated thromboembolism in vulnerable population"]. / Traduction et republication de : « Prise en charge de la maladie thromboembolique veineuse associée au cancer chez les populations vulnérables ¼.

Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with TAC on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR less than 30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (less than 50,000platelets/µL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.

[Translation into French and republication of: "Anticoagulant treatment of cancer-associated thromboembolism"]. / Traduction et republication de : « Traitement anticoagulant de la maladie veineuse thromboembolique associée au cancer ¼.

Venous thromboembolism (VTE) is a frequent and potentially fatal complication in patients with cancer. During the initial period after the thromboembolic event, a patient receiving anticoagulant treatment is exposed both to a risk of VTE recurrence and also to an elevated bleeding risk conferred by the treatment. For this reason, the choice of anticoagulant is critical. The choice should take into account patient-related factors (such as functional status, age, body mass index, platelet count and renal function), VTE-related factors (such as severity or site), cancer-related factors (such as activity and progression) and treatment related factors (such as drug-drug interactions), which all potentially influence bleeding risk, and patient preference. These should be evaluated carefully for each patient during a multidisciplinary team meeting. For most patients, apixaban or a low molecular-weight heparin is the most appropriate initial choice for anticoagulant treatment. Such treatment should be offered to all patients with active cancer for at least 6months. The patient and treatment should be re-evaluated regularly, and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond 6months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first 6months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists.

Model of calf muscle tear during a simulated eccentric contraction, comparison between ex-vivo experiments and discrete element model.

The tearing of the muscle-tendon complex (MTC) is one of the common sports-related injuries. A better understanding of the mechanisms of rupture and its location could help clinicians improve the way they manage the rehabilitation period of patients. A new numerical approach using the discrete element method (DEM) may be an appropriate approach, as it considers the architecture and the complex behavior of the MTC. The aims of this study were therefore: first, to model and investigate the mechanical elongation response of the MTC until rupture with muscular activation. Secondly, to compare results with experimental data, ex vivo tensile tests until rupture were done on human cadavers {triceps surae muscle + Achilles tendon}. Force/displacement curves and patterns of rupture were analyzed. A numerical model of the MTC was completed in DEM. In both numerical and experimental data, rupture appeared at the myotendinous junction (MTJ). Moreover, force/displacement curves and global rupture strain were in agreement between both studies. The order of magnitude of rupture force was close between numerical (858 N for passive rupture and 996 N-1032 N for rupture with muscular activation) and experimental tests (622 N ± 273 N) as for the displacement of the beginning of rupture (numerical: 28-29 mm, experimental: 31.9 mm ± 3.6 mm). These differences could be explained by choices of DEM model and mechanical properties of MTC's components or their rupture strain values. Here we show that he MTC was broken by fibers' delamination at the distal MTJ and by tendon disinsertion at the proximal MTJ in agreement with experimental data and literature.

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.

Société de Biomécanique Young Investigator Award 2021: Numerical investigation of the time-dependent stress-strain mechanical behaviour of skeletal muscle tissue in the context of pressure ulcer prevention.

BACKGROUND: Pressure-induced tissue strain is one major pathway for Pressure Ulcer development and, especially, Deep Tissue Injury. Biomechanical investigation of the time-dependent stress-strain mechanical behaviour of skeletal muscle tissue is therefore essential. In the literature, a viscoelastic formulation is generally assumed for the experimental characterization of skeletal muscles, with the limitation that the underlying physical mechanisms that give rise to the time dependent stress-strain behaviour are not known. The objective of this study is to explore the capability of poroelasticity to reproduce the apparent viscoelastic behaviour of passive muscle tissue under confined compression. METHODS: Experimental stress-relaxation response of 31 cylindrical porcine samples tested under fast and slow confined compression by Vaidya and collaborators were used. An axisymmetric Finite Element model was developed in ABAQUS and, for each sample a one-to-one inverse analysis was performed to calibrate the specimen-specific constitutive parameters, namely, the drained Young's modulus, the void ratio, hydraulic permeability, the Poisson's ratio, the solid grain's and fluid's bulk moduli. FINDINGS: The peak stress and consolidation were recovered for most of the samples (N=25) by the poroelastic model (normalised root-mean-square error ≤0.03 for fast and slow confined compression conditions). INTERPRETATION: The strength of the proposed model is its fewer number of variables (N=6 for the proposed poroelastic model versus N=18 for the viscohyperelastic model proposed by Vaidya and collaborators). The incorporation of poroelasticity to clinical models of Pessure Ulcer formation could lead to more precise and mechanistic explorations of soft tissue injury risk factors.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence.

Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Experimental analysis of the lower cervical spine in flexion with a focus on facet tracking.

Cervical traumas are among the most common events leading to serious spinal cord injuries. While models are often used to better understand injury mechanisms, experimental data for their validation remain sparse, particularly regarding articular facets. The aim of this study was to assess the behavior of cervical FSUs under quasi-static flexion with a specific focus on facet tracking. 9 cadaveric cervical FSUs were imaged and loaded under a 10 Nm flexion moment, exerted incrementally, while biplanar X-rays were acquired at each load increment. The relative vertebral and facet rotations and displacements were assessed using radio-opaque markers implanted in each vertebra and CT-based reconstructions registered on the radiographs. The only failures obtained were due to specimen preparation, indicating a failure moment of cervical FSUs greater than 10 Nm in quasistatic flexion. Facet motions displayed a consistent anterior sliding and a variable pattern regarding their normal displacement. The present study offers insight on the behavior of cervical FSUs under quasi-static flexion beyond physiological thresholds with accurate facet tracking. The data provided should prove useful to further understand injury mechanisms and validate models.

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.