This paper presents a novel and robust three-dimensional plain concrete cracking model applicable to the study of structural stability of large structures, such as dams, while considering the ...presence of pressurized water in propagating cracks. When leaving the elastic range, there is a transition from a continuum approach to a XFEM approach. This mechanical model is coupled with a poro-damage model where the permeability is increased as micro-cracks coalesce into macro-cracks. The crack opening computation during continuum damage is based on a local XFEM formulation without the need for a reference length in a strongly coupled hydro-mechanical formulation to update the uplift pressures. The 3D crack path computation is adapted from an analogy to the heat conduction problem to draw the envelope of the discontinuities’ tangent vector field. Six benchmark problems available from the literature, including a 96m-high arch dam, are considered and indicate the very good performance of the proposed model as well as its applicability to real industrial structures.
•Robust three-dimensional plain concrete XFEM cracking model applicable to the study of structural stability of large structures.•New method to compute crack opening using continuous damage model.•Strongly coupled hydro-mechanical formulation to compute hydofracturation.•CDM to XFEM transition with permeability increase during crack evolution
This paper presents a crack model that couples the benefits of the damage mechanics approach and the extended finite element method (XFEM). A crack-tracking technique is developed to propagate the ...crack path along a single row of finite elements as a function of the stress-based nonlocal method. The level sets are computed to predict the crack path, and the path is corrected with the use of continuum damage mechanics. Once a certain level of damage is reached inside an element, the previously-computed level sets are used to apply the XFEM formulation. A cohesive XFEM formulation is used to transfer energy dissipation from the damage mechanics approach to the XFEM model. Using numerous test cases, it is shown that the model is mesh independent and that it removes the spurious stress transfer exhibited by continuum damage models. Various transition damage criteria are compared, and the optimal one is determined.
Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the ...primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca(2+) release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.
The presence of uplift pressures in cracked plain concrete hydraulic structures is a major concern for their durability, serviceability and stability. To assess the performance of cracked structures ...several mechanical and hydraulic response parameters must be computed. This paper presents the development, implementation and application of a new nonlinear combined segregated fully-coupled hydromechanical model for application to non-planar 3D hydraulic fractures where complex flow is occurring. The eXtended Finite Element Method (XFEM) formulation is used, as it facilitates the computation of the crack aperture as well as the application of water pressure on crack surfaces for the simulation of hydraulic fracture initiation and propagation. To take into consideration the effects of drainage in numerical modeling and simulation, two coupled (multi-physics) finite element models are used; (1) one for the uplift pressures where a hydraulic mesh with refinement around drains is used, and (2) one for the mechanical response coupled with the computation of the unsaturated interstitial seepage problem. The two subproblems are solved using a partitioned procedure, as they have different resolution requirements. Finally, the mechanical mesh and the hydraulic mesh have non-matching discrete interfaces that must be coupled while respecting the equilibrium of the applied loads. Applications of the proposed hydromechanical constitutive model and numerical solution strategy to different problems are presented on a wedge splitting test and a full scale gravity dam including multiple drainage configurations. A case study adapted from a real dam is also given with a complex 3D non-planar discontinuity surface.
•Robust three-dimensional plain concrete XFEM hydrofracturation model applicable to the study of large structures structural stability.•Coupling with an unsaturated interstitial seepage problem.•Strongly coupled hydro-mechanical formulation to compute hydrofracturation including complex nonlinear flow in discontinuities.•Consideration of the effects of drainage in numerical modeling and simulation.
Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and ...survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug-drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer.
A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included "proton pump inhibitors," "cancer," "chemotherapy," "immunotherapy," "hormonotherapies," "targeted therapies," "tyrosine kinase inhibitors," and "gut microbiome". Recent and relevant clinical trials, meta-analyses, and reviews were included.
PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system.
PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.
Off-label use of vemurafenib (VMF) to treat
mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.
Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They ...were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.3) and therapeutic responses according to Disease Activity Score.
LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (
< .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood
allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment;
< .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the
clone.
VMF seemed safe and effective in children with refractory
-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
Residual contamination by intravenous conventional antineoplastic drugs (ICAD) is still a daily issue in hospital facilities. This study aimed to compare the efficiency (EffQ) of 4 different ...solutions to remove 23 widely used ICADs from surfaces.
A solution containing 23 ICADs (4 alkylating agents, 8 antimetabolites, 2 topo-I inhibitors, 6 topo-II inhibitors and 3 spindle poisons) was spread over 100 cm2 stainless steel. After drying, decontamination was carried out using 10×10 cm wipes moistened with 300 μL of one of the following solutions: 70% isopropanol (S1); ethanol-hydrogen peroxide 91.6-50.0 mg/g (S2); 10-2 M sodium dodecyl sulphate/isopropanol 80/20 (S3) or 0.5% sodium hypochlorite (S4). Six tests were performed for each decontamination solution. Two modalities were tested: a single wipe motion from top to bottom or vigorous wiping (n = 6 for each modality). Residual contamination was measured with a validated liquid chromatography with tandem mass spectrometry detection method. Solution efficiency (in %) was computed as follows: EffQ = 1-(quantity after decontamination/quantity before decontamination), as median (min-max) for the 23 ICADs. The overall decontamination efficiency (EffQ) of the 4 solutions was compared by a Kruskall-Wallis test. Decontamination modalities were compared for each solution and per ICAD with a Mann-Whitney test (p<0.05). EffQ were significantly different from one solution to the next for single wipe motion decontamination: 79.9% (69.3-100), 86.5% (13.0-100), 85.4% (56.5-100) and 100% (52.9-100) for S1, S2, S3 and S4 (p<0.0001), respectively. Differences were also significant for vigorous decontamination: EffQ of 84.3% (66.0-100), 92.3% (68.7-100), 99.6% (84.8-100) and 100% (82.9-100) for S1, S2, S3 and S4, respectively (p<0.0001). Generally, vigorous decontamination increased EffQ for all tested solutions and more significantly for the surfactant.
Decontamination efficiency depended on the solution used but also on the application modality. An SDS admixture seems to be a good alternative to sodium hypochlorite, notably after vigorous chemical decontamination with no hazard either to materials or workers.
Thermoset polyesters are prepared from epoxidized waste frying sunflower oil (ESO), commercially available epoxy compounds and glutaric acid. Influence of the nature and concentration of bi‐ and ...trifunctionnal epoxy compounds on mechanical properties is studied. Static and dynamic mechanical tests are performed. The molar amount of commercial epoxy compounds used ranges from 20% to 80% regarding the molar amount of ESO. It enables to obtain thermosetting polyesters with glass transition temperatures ranging from 6°C to 102°C, as well as storage modulus ranging from 8 GPa to 14 GPa. 40% of trifunctional epoxy compound and 60% of commercial epoxy compound are found to be the best compromises between bio‐based content and mechanical properties. Furthermore, shape memory and vitrimer behavior of those epoxy‐acid based networks with 60% of commercial epoxy compounds are evaluated both qualitatively and quantitatively by cyclic thermo‐mechanical and stress relaxation tests. Excellent shape memory behavior with fixity ratios above 94% and recovery ratios above 98% is demonstrated. A transesterification catalyst is needed to obtain good vitrimer behavior. Overall, thanks to the previously mentioned properties of those partially biobased thermosets polyesters, industrial applications such as protective coatings, foams and temperature‐memory polymer actuators might be considered.
The avoidance of post-herniorrhaphy pain can be challenging for hernia repair and has the greatest impact on patient's quality of life, health care utilisation and cost to society. Visceral meshes, ...functionalised with an efficient drug carrier system – hydroxypropyl beta-cyclodextrin polymer (polyHPβCD) coating, were developed to give a prolonged intraperitoneal analgesic drug release. We attempted to evaluate the in vivo pain-relief efficacy of ropivacaine loaded polyHPβCD functionalised polyester meshes in a rat model of visceral pain induced by colorectal distension (CRD). In vivo safety, pharmacokinetic profile and biodegradation were measured via histological analysis and high-performance liquid chromatography, etc. The results confirmed that the polyHPβCD on the functionalised meshes has a high adsorption capacity of ropivacaine and resulted in a sustained drug release in rats after mesh implantation. This was further reaffirmed by an elevated pain threshold (30%) up to 4 days after implantation in the rat CRD model, compared to 1–2 days for non-adapted meshes. Neither polyHPβCD nor the loaded ropivacaine had a major impact on the inflammatory response. This evidence strongly suggests that polyHPβCD functionalised visceral mesh could be a promising approach for post-operative pain control by improving the intraperitoneal drug delivery and bioavailability.
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New antipsychotics continuously arrive on the market, which thereby influences the approved and off-label prescribing (OLP) schemes. We aimed to identify the recent trends in the OLP of ...antipsychotics. We conducted a literature review based on three different populations: adult, pediatric, and elderly patients.
A literature search was performed in the PubMed and ScienceDirect databases using the following keyword algorithm: "offlabel" AND ("antipsychotic*" OR "neuroleptic*"). The period investigated ranged from January 2000 to January 2015. Only Englishwritten pharmacoepidemiological studies were included.
Seventy-seven relevant results were identified. Among adults, OLP consisted of 40 to 75% of all antipsychotic prescriptions. The main indications were mood disorders, anxiety disorders, insomnia and agitation. Quetiapine was the most frequently prescribed offlabel antipsychotic, especially for anxiety and insomnia. Among children, OLP was estimated between 36 and 93.2% of all antipsychotic prescriptions. Risperidone and aripiprazole were primarily used and were most often prescribed for attention deficit hyperactivity disorder, anxiety, or mood disorders. Among elderly individuals, OLP consisted of 22 to 86% of all antipsychotic prescriptions. Antipsychotic OLP was particularly frequent for agitation; however, a recent decrease in this OLP was identified.
Antipsychotics have largely been prescribed off-label in recent years. The types of antipsychotic OLP practices differ according to the age category of patients. OLP is often used in cases of therapeutic dead-ends or for specific disorders with few or no currently approved medications. However, other OLP practices only reflect temporary prescription trends for mild symptoms, which may induce safety concerns.
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