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Background: Any surgical procedure carries a risk for venous thromboembolism (VTE), albeit variable. Improvements in medical and surgical practices and the shortening of care pathways due to the development of day surgery and enhanced recovery after surgery, have reduced the perioperative risk for VTE., Objective: A collaborative working group of experts in perioperative haemostasis updated in 2024 the recommendations for the Prevention of perioperative venous thromboembolism published in 2011., Methods: The addressed questions were defined by 40 experts (GIHP, SFAR, SFTH and SFMV) and formulated in a PICO format. They performed the literature review and formulated recommendations according to the Grading of GRADE system. Recommendations were then validated by a vote determining the strength of each recommendation. Of note, these recommendations do not cover all surgical specialties. Especially, thromboprophylaxis in cardiac surgery, neurosurgery and obstetrics is not addressed., Results: 78 recommendations were formalized into 17 sections, including patient-related VTE risk factors, types of surgery, extreme body weight, renal impairment, mechanical prophylaxis, distal deep vein thrombosis; 27 were found to have a high level of evidence (GRADE 1) and 41 a low level of evidence (GRADE 2) and 10 were expert opinion. All had strong agreement among the experts., Conclusions: These guidelines help to weigh the perioperative risk for VTE (which includes the risk associated to surgery and the patient-related risk) against the adverse effects of thromboprophylaxis, either pharmacological or mechanical. This includes particularly the bleeding risk induced by antithrombotic drugs as well as costs., (Copyright © 2024. Published by Elsevier Masson SAS.)

Cancer-associated venous thromboembolism (CAT) is common in patients with cancer and associated with significant morbidity and mortality. The incidence of CAT continues to rise, complicating patient care and burdening healthcare systems. Patients with cancer experiencing VTE face poorer prognoses, making prevention and effective management imperative. This narrative review synthesizes evidence on thromboprophylaxis in ambulatory patients with cancer receiving systemic therapy and acute treatment strategies for CAT. Risk assessment models (e.g., Khorana score) aid in identifying high-risk patients who may benefit from thromboprophylaxis. Pharmacological thromboprophylaxis with low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) has been shown to reduce the risk of CAT without significantly increasing the risk of bleeding complications. However, implementation of risk-based strategies remains limited in clinical practice. For acute CAT management, LMWHs have been the standard of care, but DOACs are increasingly favored due to their convenience and efficacy. However, challenges persist, including bleeding risks and drug interactions. Emerging therapies targeting Factor XI inhibitors present promising alternatives, potentially addressing current limitations in anticoagulation management for CAT., Competing Interests: Declaration of competing interest MC reports personal fees from Leo Pharma, BMS, Pfizer, Sanofi, Valeo, Servier, and Bayer, and grant from Leo Pharma, BMS and Pfizer. LB reports personal fees and non-financial support from BMS/Pfizer, Leo Pharma, and Viatris, grants from Bayer, grants, personal fees and non-financial support from MSD, outside the submitted work. SL reports personal fees from Ferring, Pfizer and Lilly, outside the submitted work. PG reports personal fees or travelling expenses from Leo Pharma, BMS-Pfizer and Bayer. PM reports personal fees from Bayer Healthcare, BMS/Pfizer and Sanofi. IM reports grants, personal fees and non-financial support from BMS-Pfizer Alliance and Leo Pharma, personal fees from Sanofi, personal fees and non-financial support from Astra-Zeneca, outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The craniocervical junction (CCJ) forms the bridge between the skull and the spine, a highly mobile group of joints that allows the mobility of the head in every direction. The CCJ plays a major role in protecting the inferior brainstem (bulb) and spinal cord, therefore also requiring some stability. Children are subjected to multiple constitutive or acquired diseases involving the CCJ: primary bone diseases such as in FGFR-related craniosynostoses or acquired conditions such as congenital torticollis, cervical spine luxation, and neurological disorders. To design efficient treatment plans, it is crucial to understand the relationship between abnormalities of the craniofacial region and abnormalities of the CCJ. This can be approached by the study of control and abnormal growth patterns. Here we report a model of normal skull base growth by compiling a collection of geometric models in control children. Focused analyses highlighted specific developmental patterns for each CCJ bone, emphasizing rapid growth during infancy, followed by varying rates of growth and maturation during childhood and adolescence until reaching stability by 18 years of age. The focus was on the closure patterns of synchondroses and sutures in the occipital bone, revealing distinct closure trajectories for the anterior intra-occipital synchondroses and the occipitomastoid suture. The findings, although based on a limited dataset, showcased specific age-related changes in width and closure percentages, providing valuable insights into growth dynamics within the first 2 years of life. Integration analyses revealed intricate relationships between skull and neck structures, emphasizing coordinated growth at different stages. Specific bone covariation patterns, as found between the first and second cervical vertebrae (C1 and C2), indicated synchronized morphological changes. Our results provide initial data for designing inclusive CCJ geometric models to predict normal and abnormal growth dynamics., (© 2024 The Author(s). Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Background: Since the late 2000s, Europe has granted approval for various thrombotic risk-related uses of direct oral anticoagulants (DOACs). Unlike traditional anticoagulants, DOACs do not necessitate routine coagulation monitoring. Nevertheless, clinical practice often encounters bleeding events associated with these medications, making the need for effective reversal strategies evident., Objectives: The study aims to take stock of current reversal strategies for DOACs, with a particular emphasis on the latest compounds that have been developed or are currently under development., Methods: For obtaining information regarding the ongoing reversal strategies and the compounds under development, we referred to ClinicalTrials website, PubMed, and Google Scholar., Results: In 2024, two specific antidotes to DOACs have already received approval when reversal of anticoagulation is needed owing to life-threatening or uncontrolled bleeding: idarucizumab that reverses the effects of dabigatran, and andexanet alfa, designed to counteract activated factor X inhibitors such as apixaban and rivaroxaban. Furthermore, ciraparantag, a potential universal reversal agent, is currently in advanced stages of clinical development. Concerns remain regarding the safety of specific reversal agents, especially concerning the risk of thrombosis. Additionally, the cost of these antidotes remains high. Consequently, nonspecific strategies to counteract anticoagulant medications, including activated charcoal, hemodialysis, and concentrates of coagulation factors, still have utility., Conclusion: With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Genetic diseases with craniofacial malformations can be associated with anomalies of the craniocervical joint (CCJ). The functions of the CCJ are thus impaired, as mobility may be either limited by abnormal bone fusion causing headaches, or exaggerated in the case of hypermobility, which may cause irreparable damage to the spinal cord. Restoring the balance between mobility and stability requires surgical correction in children. The anatomy and biomechanics of the CCJ are quite unique, yet have been overlooked in the past decades. Pediatric evidence is so scarce, that investigating the adult CCJ is our best shot to disentangle the form-function relationships of this anatomical region. The motivation of the present study was to understand the morphological and functional basis of motion in the CCJ, in the hope to find morphological features accessible from medical imaging able to predict mobility. To do so, we have quantified the in-vitro kinematics of the CCJ in nine cadaveric asymptomatic adults, and estimated a wide range of mobility variables covering the complexity of spinal motion. We compared these variables with the shape of the occipital, the atlas and the axis, obtained using a dense geometric morphometric approach. Morphological joint congruence was also quantified. Our results suggest a strong relationship between bone shape and motion, with the overall geometry predicting best the primary movements, and the joint facets predicting best the secondary movements. We propose a functional hypothesis stating that the musculoligamental system determines movements of great amplitude, while the shape and congruence of joint facets determine the secondary and coupled movements, especially by varying the geometry of bone stops and the way ligaments are tensioned. We believe this work will provide valuable insights in understanding the biomechanics of the CCJ. Furthermore, it should help surgeons treating CCJ anomalies by enabling them to translate objectives of functional and clinical outcome into clear objectives of morphological outcome., (© 2024 The Author(s). Journal of Morphology published by Wiley Periodicals LLC.)

Objective: The disputatio is a pedagogical method existing since the Middle-Ages where students had to debate about a question asked by a "master", exercising their thinking and oratory skills. To move away from traditional vertical teaching methods, the disputatio has been revived by pharmacologists. Thus, for almost three successive years, several groups of young French pharmacologists and therapists confronted their ideas concerning a medical question at a therapeutic impasse. The aim here is to describe the initial feedback received from participants., Methods: An anonymous questionnaire was sent by email in May 2023 to the participants of the different disputationes of 2019, 2022 and 2023. Participants were asked about different aspects of their feelings before, during and after the disputatio, using the 5-point Likert scale. They were also asked to describe the event in 2 to 5 words. Finally, participants could leave their comments in a free-field and were asked to give an overall satisfaction score out of 10., Results: Out of the 39 participants, 27 (69.2%) answered the questionnaire. Although 50% of respondents reported a feeling of anxiety before participating, most enjoyed the expert talks as well as working with people they did not know. Besides, over 66% reported having underestimated the skills they could share with colleagues from different backgrounds. Over 55% of respondents reported progress in methodology, and over 83% in pharmacology and/or therapeutics. Participants reported an overall satisfaction score of 8.6/10, and the main terms used to describe the event were "sharing", "enriching" and "meeting"., Conclusion: The disputatio is an innovative training program whose pedagogical and human values were underlined by most of the participants. Beyond pharmacology and therapeutics, the principle of disputatio could be extended to other disciplines, spanning the centuries., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

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/1.72m 2 , 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., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Trigonocephaly occurs due to the premature fusion of the metopic suture, leading to a triangular forehead and hypotelorism. This condition often requires surgical correction for morphological and functional indications. Metopic ridges also originate from premature metopic closure but are only associated with mid-frontal bulging; their surgical correction is rarely required. Differential diagnosis between these two conditions can be challenging, especially in minor trigonocephaly., Methods: Two hundred seven scans of patients with trigonocephaly (90), metopic rigdes (27), and controls (90) were collected. Geometric morphometrics were used to quantify skull and orbital morphology as well as the interfrontal angle and the cephalic index. An innovative method was developed to automatically compute the frontal curvature along the metopic suture. Different machine-learning algorithms were tested to assess the predictive power of morphological data in terms of classification., Results: We showed that control patients, trigonocephaly and metopic rigdes have distinctive skull and orbital shapes. The 3D frontal curvature enabled a clear discrimination between groups (sensitivity and specificity > 92%). Furthermore, we reached an accuracy of 100% in group discrimination when combining 6 univariate measures., Conclusion: Two diagnostic tools were proposed and demonstrated to be successful in assisting differential diagnosis for patients with trigonocephaly or metopic ridges. Further clinical assessments are required to validate the practical clinical relevance of these tools., (© 2024. The Author(s).)

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., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Pediatric orthopaedic surgeons often communicate with general pediatric providers to facilitate patient care, but little data exist on communication preferences. This study investigates pediatric provider preferences regarding when they would like to receive patient updates from pediatric orthopedists, which communication modalities they prefer, and what information they like to receive., Methods: We developed a 19-question e-mail survey to evaluate provider preferences on communication modality, timing, frequency, and what data they deem important as it relates to musculoskeletal patient care., Results: A total of 111 general pediatric providers in our geographical region completed the survey. Among the providers, 55.9% preferred fax, 40.5% electronic health record inbox message, 19.8% e-mail, 12.6% mail, and 7.2% call/voicemail. The majority (67.9%) preferred information in a traditional note format, whereas 24.8% preferred a summary in paragraph format. Patient diagnosis and treatment plan for shared patients were the most important pieces of information for general pediatric providers to receive from pediatric orthopedists. Of various patient-specific scenarios included in the survey, referrals for osteomyelitis concern, fractures requiring surgery, scoliosis concern, and developmental dysplasia of the hip requiring treatment were considered most important for pediatric orthopedists to send updates. In terms of frequency of communication, over half of the pediatric providers (59.5%) desired updates after the first visit and after care plan changes (50.5%)., Conclusion: Only 43.5% of pediatric providers feel like current communication with pediatric orthopaedic surgeons is "always" or "often" adequate. Most of our surveyed providers preferred occasional SOAP notes through fax as communication from pediatric orthopaedic surgeons. The communication deemed most important to providers related to referrals where the provider makes the initial diagnosis and then refers the patient to orthopaedics for a condition with potential long-term patient impacts. Finally, providers felt communication was most important after the first pediatric orthopaedic office visit., Evidence: Level III, survey based., Competing Interests: The authors declare no conflicts of interest, (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical trials often last several months or even several years. As the trial progresses, it can be tempting to find out whether the data obtained already answers the question posed at the start of the trial in order to stop inclusions or monitoring earlier. However, knowing and taking into account interim results can sometimes compromise the integrity of the results, which is counterproductive. To minimise this risk and ensure that the treatments are assessed reliably, safety and/or efficacy criteria are monitored during the study by a Data Monitoring Committee. After receiving the results confidentially, the Data Monitoring Committee assesses the benefit/risk ratio of the study treatment and recommends that the trial be continued, modified or terminated. Data Monitoring Committee members issuing these recommendations have an important responsibility: a hasty decision to end the trial may lead to inconclusive results unable to answer the initial question and, inversely, delaying the decision to end the trial may expose the subjects to potentially ineffective or even harmful interventions. The Data Monitoring Committee's task is therefore particularly complex. With this in mind, the round table discussion at the Giens workshops was a chance to review the scientific justification for creating Data Monitoring Committees and to recall the need for their members to receive comprehensive training on the complexities of multiple analyses, confidentiality requirements applying to the results and the need for them to be aware that recommendations to end a trial must be based on data that is robust enough to assess the benefit/risk ratio of the treatment studied., (Copyright © 2023. Published by Elsevier Masson SAS.)

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 CAT 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<30mL/min/1.72m 2 , 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 (<50,000 platelets/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., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

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., (© 2023 John Wiley & Sons Ltd.)

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 six months. The patient and treatment should be re-evaluated regularly and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond six months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first six months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: In recent years, knowledge about cancer associated thrombosis has evolved considerably., Methods: Practical guidelines were drafted on the initiative of the INNOVTE FCRIN Network, led by the French Speaking Society of Respiratory Diseases (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of different scientific societies practicing in various settings. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS)., Results: After a literature review, guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease and management from the data of available clinical trials and observational studies : epidemiology, initial treatment, treatment duration, extended treatment, recurrent thrombosis, central venous catheter thrombosis, incidental thrombosis, treatment in case of thrombocytopenia., Conclusion: These evidence-based guidelines are intended to guide the practical management of patients with cancer associated thrombosis., Competing Interests: Declaration of Competing Interest I. Mahé: Grants: BMS, Pfizer; Consulting fees : BMS/Pfizer, Leo-Pharma, Sanofi, Aventis, Astra-Zeneca; Support for attending meeting: BMS/Pfizer, Leo-Pharma. P. Girard: Payment or Honoria for lectures: Leo-Pharma, MBS/Pfizer, Bayer; Support for attending meeting: Leo-Pharma; L. Bertoletti: Grants: MSD, Bayer; Payment or Honoria for lectures: Leo-Pharma, MBS/Pfizer, MSD, Viatris; Support for attending meeting: Leo-Pharma, MBS/Pfizer, MSD, Viatris. S. Laporte: Consulting fees: Ferring; Payment or Honoria for lectures: Pfizer, Lilly. F Couturaud : Grants: Bayer, BMS, Pfizer, GSK, Astra, Leo-Pharma, MSD, Roche; Payment or Honoria for lectures: Bayer, BMS, GSK, Astra, Leo-Pharma, Sanofi, MSD; Support for attending meeting: Astra, MSD. P. Mismetti : None O. Sanchez : Consulting fees: Bayer, BMS/Pfizer, Leo-Pharma, Sanofi/Aventis, Boehringer, Inari, Boston Scientifics, MSD; Payment or Honoria for lectures: Bayer, BMS/Pfizer, Leo-Pharma, Sanofi Aventis, Boehringer, Inari, Boston Scientifics, MSD, Viatris; Support for attending meetings and/or travel: Oxyvie, BMS/Pfizer, (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., Competing Interests: Declaration of competing interest Céline Chapelle, Edouard Ollier, Paul Bonjean, Clara Locher, and Paul Jacques Zufferey: none. Michel Cucherat has received personal fees from Bayer and BMS for consulting. Silvy Laporte has received personal fees from Bayer for consulting, personal fees continuing medical education lectures from Pfizer, and personal fees for continuing medical education lectures from Eli Lilly., (Copyright © 2023 Elsevier Inc. All rights reserved.)

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Pesticides and climate change are both thought to contribute to the global amphibian decline, yet their combined effects are still poorly understood. Metolachlor is a widespread herbicide applied across North America, but little is known about its effects on amphibians. We used a replicated mesocosm experimental design with different levels of drying (i.e., no drying and medium and rapid drying) and metolachlor concentrations (0, 0.8, 8, and 80 µg/L) to assess their respective and combined effects on wood frog (Lithobates sylvaticus) larvae throughout metamorphosis. Metolachlor had no significant effect on survival and development of tadpoles. However, metolachlor significantly interacted with drying levels to reduce the growth of tadpoles, which was mainly due to a difference detected among metolachlor concentrations under the rapid drying treatment. Drying also directly reduced growth and body mass at metamorphosis. Our results suggest that environmental stressors, such as drying, should be considered in toxicological experiments to provide relevant exposure conditions to pesticides for ephemeral pond species in the context of global climate change. Environ Toxicol Chem 2023;42:1772-1781. © 2023 SETAC., (© 2023 SETAC.)

Objective: To systematically review randomised controlled trials (RCTs) using a wearable physical activity monitoring device as an intervention to increase daily walking activity and improve physical capacities in patients with cardiovascular disease (CVD)., Design: Systematic review and meta-analysis of RCTs., Data Sources: PubMed, Embase and Web of Science from inception to June 2022., Eligibility Criteria: Randomised controlled studies including patients with CVD over 18 years of age at the end of a cardiac rehabilitation programme comparing an intervention group using a wearable physical activity monitoring device with feedback with usual care or with a control group receiving no feedback on their physical activity and reporting a change in the daily number of steps and/or a change in the distance covered in the 6-minute walk test (6-MWT) or a change in peak oxygen uptake (V̇O2 peak ) as endpoints., Results: Sixteen RCTs were included. The intervention of wearing a physical activity monitoring device with feedback significantly improved daily number of steps compared with controls (standardised mean difference (SMD) 0.85; 95% CI (0.42; 1.27); p<0.01). The effect was greater when the duration of the intervention was less than 3 months (SMD 1.0; 95% CI (0.18; 1.82); p<0.01) than when the duration of the intervention was 3 months or longer (SMD 0.71; 95% CI (0.27; 1.16); p<0.01), but no significant interaction was found between subgroups (p=0.55). 6-MWT distance and V̇O2 peak showed only small effects (SMD 0.34; 95% CI (-0.11; 0.80); p=0.02 and SMD 0.54; 95% CI (0.03; 1.03); p=0.07, respectively)., Conclusion: The use of wearable physical activity monitoring devices appears to help patients with CVD to increase their daily walking activity and thus their physical activity, particularly in the short term., Prospero Registration Number: CRD42022300423., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients., Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707)., Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034)., Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens., Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole., Competing Interests: Dr. Zuily reports grants from French Ministry of Health, grants from The Grand Est Regional Council, grants from The Grand Nancy Métropole, grants from The Comité ad hoc de pilotage national des essais thérapeutiques et autres recherches sur le COVID-19 (CAPNET, label Priorité Nationale de Recherche–National Research Priority), during the conduct of the study; personal fees from Leo Pharma, personal fees from Bristol Myers Squibb, personal fees from Pfizer, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Viatris, personal fees from Sanofi, grants from Boehringer Ingelheim, grants from Bayer, outside the submitted work; Dr. Lefevre reports grants from Gilead, grants from ViiV, outside the submitted work; Dr. Sanchez reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from Boehringer Ingelheim, personal fees from Inari, personal fees from Boston Scientific, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Chiesi, grants from Oxyvie, outside the submitted work; Dr. Empis De Vendin has nothing to disclose; Dr. De Ciancio has nothing to disclose; Dr. Arlet reports grants from Addmedical, grants and other from Novartis, outside the submitted work; Dr. Khider has nothing to disclose; Dr. Terriat has nothing to disclose; Dr. Greigert has nothing to disclose; Dr. Robert has nothing to disclose; Dr. Louis has nothing to disclose; Dr. Trinh-Duc has nothing to disclose; Dr. Rispal has nothing to disclose; Dr. Accassat reports other from Leo Pharma, other from Janssen, other from MSD, outside the submitted work; Dr. Thiery has nothing to disclose; Dr. Montani reports grants and personal fees from Acceleron, grants and personal fees from Janssen, grants and personal fees from Merck, personal fees from Bayer, outside the submitted work; Dr. Azarian has nothing to disclose; Dr. Meneveau reports grants, personal fees and other from Bayer, grants, personal fees and other from Bristol Myers Squibb, grants, personal fees and other from Pfizer, grants from Medtronic, grants and personal fees from Boston Scientific, grants, personal fees and other from Abbott, personal fees from Inari, personal fees from Terumo, outside the submitted work; Dr. Soudet reports grants and personal fees from Leo Pharma, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, outside the submitted work; Dr. Le Mao has nothing to disclose; Dr. Maurier has nothing to disclose; Dr. Le Moing has nothing to disclose; Dr. Quéré reports other from Leo Pharma, outside the submitted work; Dr. Yelnik has nothing to disclose; Dr. Lefebvre reports personal fees and other from Pfizer, other from Eumedica, outside the submitted work; Dr. Martinot reports other from Menarini, other from Overcome, outside the submitted work; Dr. Delrue has nothing to disclose; Dr. Benhamou has nothing to disclose; Dr. Parent reports grants from Oxyvie, personal fees from MSD, outside the submitted work; Dr. Roy reports personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, personal fees and other from Aspen, personal fees and other from Sanofi, outside the submitted work; Ms. Presles has nothing to disclose; Dr. Goehringer has nothing to disclose; Dr. Mismetti reports personal fees from Bayer Healthcare, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Aspen, personal fees from Pfizer, outside the submitted work; Dr. Bertoletti reports grants from Bayer, grants and personal fees from MSD, personal fees and other from Leo Pharma, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, outside the submitted work; Dr. Rossignol reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Boehringer-Ingelheim, personal fees from Cincor, personal fees from KBP, personal fees from Novartis, personal fees from NovoNordisk, personal fees from Roche, personal fees from Vifor/Relypsa, personal fees from Fresenius, personal fees and other from CardioRenal, personal fees from Idorsia, personal fees from Sequana, personal fees from Vifor, non-financial support from G3P, outside the submitted work; Dr. Couturaud reports grants and personal fees (board memberships, symposia or travel) from Bayer, grants and personal fees (board memberships, symposia or travel) from Bristol-Myers Squibb/Pfizer, personal fees (board memberships, symposia or travel) from Merck Sharp and Dohme, personal fees (board memberships, symposia or travel) from Astra Zeneca, personal fees (board memberships or symposia) from Sanofi, personal fees (board memberships or symposia) from Janssen, personal fees (board memberships, symposia or travel) from Leo Pharma, outside the submitted work; Dr. Wahl has nothing to disclose; Dr. Thilly has nothing to disclose; Dr. Laporte reports personal fees from Lilly/Boehringer Ingelheim, personal fees from Bristol Myers Squibb/Pfizer, personal fees from Merck, personal fees from Leo-Pharma, outside the submitted work., (© 2023 The Authors.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined., Objective: To determine the frequency and predictors for CTEPH after a first unprovoked PE., Patients/methods: In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated., Results: During a median follow-up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95-4.64), and of 1.31% (95% CI 0.01-2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64-667.00, p = .02) and 12.50 (95% CI 2.10-74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11-1310.00, p < .01]and HR 17.2 [95% CI 2.75-108, p < .01])., Conclusion: After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis., (© 2022 International Society on Thrombosis and Haemostasis.)

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., (Copyright © 2022 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Craniosynostoses affect 1/2000 births and their incidence is currently increasing. Without surgery, craniosynostosis can lead to neurological issues due to restrained brain growth and social stigma due to abnormal head shapes. Understanding growth patterns is essential to develop surgical planning approaches and predict short- and long-term post-operative results. Here we provide a systematic review of normal and pathological cranial vault growth models., Material and Methods: The systematic review of the literature identified descriptive and comprehensive skull growth models with the following criteria: full text articles dedicated to the skull vault of children under 2 years of age, without focus on molecular and cellular mechanisms. Models were analysed based on initial geometry, numerical method, age determination method and validation process., Results: A total of 14 articles including 17 models was reviewed. Four descriptive models were assessed, including 3 models using statistical analyses and 1 based on deformational methods. Thirteen comprehensive models were assessed including 7 finite element models and 6 diffusion models. Results from the current literature showed that successful models combined analyses of cranial vault shape and suture bone formation., Discussion: Growth modelling is central when assessing craniofacial architecture in young patients and will be a key factor in the development of future customized treatment strategies. Recurrent technical difficulties were encountered by most authors when generalizing a specific craniosynostosis model to all types of craniosynostoses, when assessing the role of the brain and when attempting to relate the age with different stages of growth., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: -SL reports grants from Leo Pharma and personal fees from Eli Lilly and Bayer Healthcare, outside the submitted work. -PMR reports personal fees and non-financial support from Bayer Health care, from Boehringer Ingelheim France, from Bristol Myers Squibb, from Pfizer, from Aspen, from Daiichi Sankyo, and from Sanofi Aventis France, outside the submitted work.

Clinical pharmacology is the study of drugs in humans, from first-in-human studies to randomized controlled trials (RCTs) and benefit-risk ratio assessment in large populations. The objective of this review is to present the recent innovations that may revolutionize the development of drugs in the future. On behalf of the French Society of Pharmacology and Therapeutics, we provide recommendations to address those future challenges in clinical pharmacology. Whatever the future will be, robust preliminary data on drug mechanism of action and rigorous study design will remain crucial prior to the start of pharmacological studies in human. At the present time, RCTs remain the gold standard to evaluate the efficacy of human drugs, although alternative designs (pragmatic trials, platform trials, etc.) are emerging. Innovations in healthy volunteers' studies and the contribution of new technologies such as artificial intelligence, machine learning, and internet-based trials have the potential to improve drug development. In the field of precision medicine, new disease phenotypes and endotypes will probably help to identify new pharmacological targets, responders to therapies, and patients at risk for drug adverse events. In such a moving landscape, the development of translational research through academic and private partnership, transparent sharing of clinical trial data and enhanced interactions between drug experts, patients, and the general public are priority areas for action., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Understanding the molecular evolution of the SARS-CoV-2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three-dimensional structures of SARS-CoV-2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48 000 viral isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein-protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein-protein and protein-nucleic acid interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance., (© 2021 Wiley Periodicals LLC.)

Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (β = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding., Competing Interests: I.M. reports an independent research grant to the sponsor (AP-HP) from BMS/Pfizer. I.M. has received a research grant from Leo Pharma, has been a speaker for BMS and Leo Pharma, and has participated in advisory boards for BMS and Bayer. G.A.: no disclosure was declared by the author. C.A. has received honoraria for lectures from Bayer, BKS, Pfizer, Sanofi, and Daiichi Sankyo, and has participated in advisory boards for Bayer, BMS, Pfizer, and Sanofi. C.B. has received consulting fees/honoraria from Bayer Healthcare, Daiichi Sankyo, and BMS. A.B. has nothing to disclose. M.C. reports research funding from BMS, Pfizer, and Leo Pharma, and honoraria from BMS, Pfizer, Sanofi, Bayer, Leo Pharma, Servier, and Valeo; all payments were made to the institution. C.C. has received consulting fees from Leo Pharma. A.T.C.: no disclosure was declared by the author. P.G. has received honoraria and support for attending meetings and/or travel from Leo Pharma and Bayer. M.V.H. reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees to the hospital from Boehringer Ingelheim, BMS/Pfizer, Bayer Healthcare, Aspen, and Daiichi Sankyo, all outside the submitted work. F.A.K. reports research grants from Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, MSD, The Netherlands Organization for Health Research and Development, Actelion, the Dutch Heart Foundation, and the Dutch Thrombosis Association, all outside the submitted work. J.J.L.-N. has received honoraria for: lectures from Bayer, Pfizer and Rovi; educational events from Leo Pharma; lectures and support for attending meetings and travel from Bayer, Boehringer Ingelheim, BMS, Pfizer, Leo Pharma, Rovi, and Sanofi; and advisory board participation from Pfizer and Techdow. A.M. has received honoraria from Bayer, BMS, Leo Pharma, Rovi, and Pfizer, and support for attending meetings and/or travel from Bayer and BMS, and has participated in a data safety monitoring board or an advisory board for Bayer, BMS, and Leo Pharma. D.M. has received consulting fees from Leo Pharma, Pfizer, and BMS, and honoraria and support for attending meetings and/or travel from Leo Pharma and Pfizer. O.M. has received consulting fees from AstraZeneca, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck Sharpe & Dohme, Pfizer, Roche, Servier, and Vifor Pharma, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Blueprint Medicines, Eli-Lilly, Pfizer, Roche, and support for attending meetings and/or travel from Amgen and Roche, and has participated on a data safety monitoring board or advisory board for Blueprint Medicines, Boehringer-Ingelheim; and holds stock or stock options in Amplitude Surgical and Ipsen Transgene. M.M. has received an unrestricted grant for research from Sanofi, Leo Pharma, and Rovi, consulting fees from Sanofi and Bristol, and honoraria for lectures from Sanofi and Pfizer. M.R. has received honoraria for lectures from Bayer, Pfizer, and Biomérieux. C.M.S. has participated in a data safety monitoring board for the API-CAT study. K.S. has received personal fees from Roche, BMS, and MSD, and institutional fees from Amgen. S.S. has received honoraria for lectures from Bayer, BMS, Pfizer, Angelini, Janssen-Cilag, and Roche, and support for attending meetings and/or travel from BMS. A.T. has received consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and participated on an advisory board for Bayer and Pfizer. P.V. is co-holder of the Bayer Chair in Cardiovascular Medicine at the University of Leuven. He has received consulting fees from Bayer, Daiichi Sankyo, Portola, and Anthos Pharmaceuticals, and honoraria from Bayer, Daiichi Sankyo, BMS, Pfizer, Boehringer, and Leo Pharma. E.V. has contracts for consulting in statistics with Pfizer, Novartis, Boehringer, Hexacath, Amgen, and Abbott. He has received fees for consulting in statistics from Pfizer, Novartis, Boehringer, Hexacath, Amgen, and Abbott, and honoraria for lectures on statistics from Amgen. T.-F.W. has received a research grant from Leo Pharma, and has participated in advisory boards for Pfizer and Servier. G.M. is deceased. S.L. has received grants from Leo Pharma, grants and consulting fees from Bayer Healthcare, and speaker fees from BMS, Pfizer, Merck Serono. The other authors report no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) are an alternative to low-molecular-weight heparin for treating cancer-associated VTE., Research Question: Is rivaroxaban as efficient and safe as dalteparin to treat patients with cancer-associated VTE?, Study Design and Methods: In a randomized open-label noninferiority trial, patients with active cancer who had proximal DVT, pulmonary embolism (PE), or both were assigned randomly to therapeutic doses of rivaroxaban or dalteparin for 3 months. The primary outcome was the cumulative incidence of recurrent VTE, a composite of symptomatic or incidental DVT or PE, and worsening of pulmonary vascular or venous obstruction at 3 months., Results: Of 158 randomized patients, 74 and 84 patients were assigned to receive rivaroxaban and dalteparin, respectively. Mean age was 69.4 years, and 115 patients (76.2%) had metastatic disease. The primary outcome occurred in 4 and 6 patients in the rivaroxaban and dalteparin groups, respectively (both the intention-to-treat and per-protocol populations: cumulative incidence, 6.4% vs 10.1%; subdistribution hazard ratio [SHR], 0.75; 95% CI, 0.21-2.66). Major bleeding occurred in 1 and 3 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 1.4% vs 3.7%; SHR, 0.36; 95% CI, 0.04-3.43). Major or clinically relevant nonmajor bleeding occurred in 9 and 8 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 12.2% vs 9.8%; SHR, 1.27; 95% CI, 0.49-3.26). Overall, 19 patients (25.7%) and 20 patients (23.8%) died in the rivaroxaban and dalteparin groups, respectively (hazard ratio, 1.05; 95% CI, 0.56-1.97)., Interpretation: In this trial comparing rivaroxaban and dalteparin in the treatment of cancer-associated VTE, the number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs. An updated meta-analysis of randomized trials comparing DOACs with low-molecular-weight heparin in patients with cancer-associated VTE is provided., Trial Registry: ClinicalTrials.gov; No.: NCT02746185; URL: www., Clinicaltrials: gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: As a leading cause of disability with a high societal and economic cost, it is crucial to better understand risk factors of neck pain and surgical complications. Getting subject-specific external loading is essential for quantifying muscle forces and joint loads but it requires exertion trials and load cells which are uncommon in clinical settings., Methods: This paper presents a method to compute the gravitational loading at four levels of the cervical spine (C3C4, C4C5, C5C6, C6C7) in neutral standing position from biplanar radiographs exclusively. The resulting load was decomposed in local disc frames and its components were used to compare different populations: 118 asymptomatic subjects and 46 patients before and after surgery (anterior cervical discectomy and fusion or total disc replacement). Comparisons were performed at C6C7 and the upper level adjacent to surgery., Findings: Significant changes in gravitational loading were observed with age in healthy subjects as well as in patients after surgery and have been associated with changes in posture., Interpretation: This approach quantifies the influence of postural changes on gravitational loading on the cervical spine. It represents a simple way to obtain necessary input for muscle force quantification models in clinical routine and to use them for patient evaluation. The study of the subsequent subject-specific spinal loading could help further the understanding of cervical spine biomechanics, degeneration mechanisms and complications following surgery., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In the context of cochlear implants, which are now widely used, and innovative active devices, the cranial implantation of electronic devices raises new questions about the mechanical interactions between the implant and the skull. The aim of this study was to build a methodology using experimental data and numerical simulations to evaluate the mechanical interactions between the skull and the WIMAGINE® active cranial implant intended for use for tetraplegic patients. A finite element model of the implant housing and a simplified model of the three-layered skull were developed. 2.5 J-hammer impact tests were performed on implant housings and ovine cadaver heads for model calibration. The two models were then combined to analyze the interactions between the skull and the implant and compared against impact tests. The implant dissipates a certain amount of the impact energy which could be a parameter to include in implant design in addition to the implant integrity, tending to increase the implant stiffness. The non-implanted as well as the implanted lamb heads demonstrated an overall good resistance to the impact tests. The models correlated well with the experimental data, and improvements of the model through more realistic geometry (CT-scans) and more complex material behavior could now be implemented. Such a model could then be used with human head geometries and help for future implant design optimizations using numerical models of the implant-skull and even implant-head complex., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients., Methods: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score., Results: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65)., Conclusion: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE., Competing Interests: All participants have received fees from LEO Pharma for this research, either personally and/or to support the local organization of the research. Anne Lamblin is an employee of LEO Pharma., (Thieme. All rights reserved.)

The clinical efficacy of the inhibitors of the renin-angiotensin-aldosterone system (RAAS) as an upstream therapy for atrial fibrillation (AF) prevention is controversial. No study has itemized so far the role of RAAS inhibitors in AF prevention after atrial flutter (AFL) ablation. This trial aims to investigate the effect of ramipril compared with placebo on AF occurrence in patients hospitalized for AFL ablation without structural heart disease. The Prevention of Atrial Fibrillation by Inhibition Conversion Enzyme (ICE) After Radiofrequency Ablation of Atrial Flutter (PREFACE) trial was a prospective, multicenter, randomized, double-blind, double-dummy trial depicting the AF occurrence during a 12-month follow-up as the primary end point. A total of 198 patients hospitalized for AFL ablation were enrolled in the trial and randomized to placebo or ramipril 5 mg/day. Patients were followed up during 1 year after AFL ablation using 1-week Holter electrocardiogram at 3, 6, 9, and 12 months. The intention-to-treat population encompassed 97 patients in the ramipril group and 101 patients in the placebo group. The primary end point, such as AF occurrence during the 1-year follow-up, was not different between the 2 groups (p = 0.96). Secondary end points, including the occurrence of supraventricular arrhythmia (p = 0.50), heart failure, stroke, and death, were not different between the 2 groups. Safety outcome parameters, including serious adverse events leading to treatment disruption (p = 0.10), hypotension, impairment of renal function, and elevated serum potassium level, also were not different between the 2 groups. In conclusion, RAAS inhibition using ramipril does not reduce AF occurrence in patients facing AFL ablation during the 1-year follow-up., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Concomitant anticoagulant and antiplatelet therapy increases bleeding risk, but most data are derived from patients with atrial fibrillation. Patients with venous thromboembolism (VTE) may differ., Objective: To study the management of patients diagnosed with acute VTE while receiving antiplatelet treatment. The primary outcome was the number of patients discharged with concomitant therapy. Secondary outcomes were clinically relevant bleeding, cardiovascular events, recurrent VTE and death during follow-up, according to discharge therapy., Methods: We performed a post-hoc analysis of patients included in two prospective registries, sharing the same case report form, from 2007 to 2017., Results: Among the 1694 identified patients, 254 (15.0%) were receiving antiplatelet treatment at VTE diagnosis, of whom 61 (24.0%) were discharged with concomitant anticoagulant and antiplatelet therapy. In multivariable analysis, age ≥ 80 years-old and the use of Direct Oral Anticoagulants for VTE therapy were associated with the decision to stop the antiplatelet, while having dual anti-platelet therapy at baseline, a history of coronaropathy or peripheral arterial disease were associated with concomitant anticoagulant and antiplatelet therapy. The decision to stop antiplatelet was associated with a non-significant 46% decrease in the risk of bleeding (OR 0.54 (0.16; 1.78)), and a non-significant 68% increase in the risk of cardiovascular events (OR 1.68 (0.44; 6.46))., Conclusion: At acute VTE diagnosis, over 15% of patients were receiving antiplatelet agents, of whom 24% were discharged with concomitant anticoagulant and antiplatelet therapy. This therapeutic decision may be associated with a lower risk of cardiovascular events, but an increased risk of bleeding., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The venous thromboembolism risk is low to moderate in nonmajor orthopedic surgery. The literature is unconclusive. New emerging data are now available. The global patient risk has to be taken into account to determine the need for any prophylaxis., (Copyright © 2020. Published by Elsevier Inc.)

Background and Objectives: Few data are available about anticoagulation management beyond 6 months in patients with cancer associated thrombosis (CAT). Our objective was to describe anticoagulant treatment modalities up to 12 months., Methods: The management of the anticoagulant treatment beyond 6 months was described in this initially retrospective non-interventional French multicenter study in patients treated with low-molecular-weight heparins (LMWH) still alive at the end of an initial 6-month treatment period. Clinical outcomes, including venous thromboembolism, recurrence, bleeding and deaths have been published previously., Results: Among the 432 patients (mean age 66.5±12.7 years) included in the study, 332 were followed up to 12 months while 96 patients deceased before study end and 4 patients were lost-to-follow-up. At 6 months, anticoagulant therapy was stopped in 74 patients, 56 were switched to vitamin K antagonists (VKA) (16.1% [95%CI, 12.4%-20.4]), 30 to direct oral anticoagulants (DOAC) (8.6% [95%CI, 5.9%-12.1]). LMWHs were maintained in 256 patients (73.6% [95%CI, 68.6-78.1]). During the follow-up, LMWHs were definitively discontinued in 86 patients (33.7%), the main reason being a favorable course of the cancer (16 patients, 18.6%), or the thromboembolic disease (11 patients, 12.8%), whereas concern about bleeding risk was low (2 patients, 2.3%)., Conclusion: Anticoagulation beyond 6 months and up to 12 months was in accordance with clinical practice guidelines suggesting that treatment should be continued as long cancer is active or in the absence of bleeding risk. Anticoagulant treatment discontinuation beyond 6 months was influenced by the favorable courses of both malignancy and thromboembolic disease, as well as patient's preference., Competing Interests: Conflict of Interest Disclosures L. Plaisance, B. Planquette, L. Falchero, I.Mahé, S.Djennaoui: nothing to disclose. C. Chapelle: personal fees from LEO-PHARMA. I. Mahé: grants from LEO-PHARMA, during the conduct of the study; grants, personal fees and non-financial support from BMSPfizer, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Leo-Pharma, outside the submitted work. S. Laporte: grants from LeoPharma, grants and personal fees from Bayer HealthCare, personal fees from Pfizer, outside the submitted work. L. Bertoletti: personal fees and other from Bayer, personal fees and other from BMS, personal fees and other from Pfizer, personal fees and other from Léo-Pharma, non-financial support from Sanofi, outside the submitted work. F. Couturaud: grants from Pfizer, personal fees from Bayer, other from Boeringher, grants, personal fees and other from BMS, other from Daiichi, personal fees and other from Aztra zeneca, other from GSK, personal fees from leopharma, other from actelion, outside the submitted work. N. Falvo: personal fees from BMS, personal fees from Bayer, personal fees from Leo-Pharma, outside the submitted work.

The tearing of a muscle-tendon complex (MTC) is caused by an eccentric contraction; however, the structures involved and the mechanisms of rupture are not clearly identified. The passive mechanical behavior the MTC has already been modeled and validated with the discrete element method. The muscular activation is the next needed step. The aim of this study is to model the muscle fiber activation and the muscular activation of the MTC to validate their active mechanical behaviors. Each point of the force/length relationship of the MTC (using a parabolic law for the force/length relationship of muscle fibers) is obtained with two steps: 1) a passive tensile (or contractile) test until the desired elongation is reached and 2) fiber activation during a position holding that can be managed thanks to the Discrete Element model. The muscular activation is controlled by the activation of muscle fiber. The global force/length relationship of a single fiber and of the complete MTC during muscular activation is in agreement with literature. The influence of the external shape of the structure and the pennation angle are also investigated. Results show that the different constituents of the MTC (extracellular matrix, tendon), and the geometry, play an important role during the muscular activation and enable to decrease the maximal isometric force of the MTC. Moreover, the maximal isometric force decreases when the pennation angle increases. Further studies will combine muscular activation with a stretching of the MTC, until rupture, in order to numerically reproduce the tearing of the MTC.

This study aimed to explore the validity of the use of the net clinical benefit (NCB), i.e. the sum of major bleeding and thrombotic events, as a potential surrogate for all-cause mortality in clinical trials assessing antithrombotics. Published randomized controlled trials testing anticoagulants in the prevention or treatment of venous thromboembolism (VTE) and non-valvular atrial fibrillation (NVAF) were systematically reviewed. The validity of NCB as a surrogate endpoint was estimated by calculating the strength of correlation of determination (R 2 ) and its 95% confidence interval (CI) between the relative risks of NCB and all-cause mortality. Amongst the 125 trials retrieved, the highest R 2 trial values were estimated for NVAF (R 2 trial  = 0.41, 95% CI [0.03; 0.48]), and acute VTE (R 2 trial  = 0.30, 95% CI [0.04; 0.84]). Conversely, the NCB did not correlate with all-cause mortality in prevention studies with medical (R 2 trial  = 0.12, 95% CI [0.00; 0.36]), surgical (R 2 trial  = 0.05, 95% CI [0.00; 0.23]), and cancer patients (R 2 trial  = 0.006, 95% CI [0.00; 1.00]). A weak correlation between NCB and all cause-mortality was found in NVAF and acute VTE, whereas no correlation was observed in clinical situations where the mortality rate was low. Consequently, NCB should not be considered a surrogate outcome for all cause-mortality in anticoagulation trials., (© 2021. The Author(s).)

Background: To simulate mechanical shocks on an intracranial implant called WIMAGINE ® , Clinatec chose a Johnson-Cook model to account for the viscoplastic behavior of grade 2 titanium in a dynamic study using Radioss © ., Methods: Thirty tensile specimens were subjected to tensile tests at room temperature, and the influence of the strain rate (8 × 10 -3 and 8 × 10 -2 s -1 ) and sandblasting was analyzed. Relaxations were included in the tests to analyze viscosity phenomena., Results: A whole set of parameters was identified for the elastic and plastic parts. Strain rate influence on stress was negligible at these strain rates. As expected, the sandblasting hardened the material during the tests by decreasing the hardening parameters, while local necking occurred at an earlier strain., Conclusions: This article provides the parameters of a Johnson-Cook model to simulate the elastoplastic behavior of pure titanium (T40, grade 2) in Finite Element Model (FEM) software.

Glioblastoma (GBM) is the most common and lethal brain tumor. GBM has a remarkable degree of motility and is able to infiltrate the healthy brain. In order to perform a rationale-based drug-repositioning study, we have used known inhibitors of two small Rho GTPases, Rac1 and Cdc42, which are upregulated in GBM and are involved in the signaling processes underlying the orchestration of the cytoskeleton and cellular motility. The selected inhibitors (R-ketorolac and ML141 for Cdc42 and R-ketorolac and EHT 1864 for Rac1) have been successfully employed to reduce the infiltration propensity of GBM in live cell imaging studies. Complementarily, all-atom simulations have elucidated the molecular basis of their inhibition mechanism, identifying the binding sites targeted by the inhibitors and dissecting their impact on the small Rho GTPases' function. Our results demonstrate the potential of targeting the Rac1 and Cdc42 proteins with small molecules to contrast GBM infiltration growth and supply precious information for future drug discovery studies aiming to fight GBM and other infiltrative cancer types.

We present the case of a 69-year-old male patient who presented with progressive neck swelling causing symptoms of dysphonia and dysphagia. Flexible nasendoscopy revealed bruising of the right hemilarynx, hypopharynx and parapharyngeal mucosal consistent with a spontaneous cervical haematoma. After conservative management, the haematoma self-resolved and the source of the haematoma was thought to be a parathyroid adenoma. Surgical excision was completed, and histopathological assessment revealed a parathyroid carcinoma. Spontaneous cervical haematoma can progress to airway obstruction and the initial focus is to observe for any signs of progression and establish a secure airway if required. The subsequent challenge is to establish the origin of the haematoma and as in this case this can be a diagnostic challenge. This case highlights the diagnostic difficulties of spontaneous cervical haematoma, the importance of comprehensive investigation and the possibility of malignancy preoperatively, especially important when complete excision gives the best opportunity for cure., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The Arp2/3 molecular machine stimulates the generation of branched actin networks at the cytosolic surface of cellular membranes. Arp2/3 is thus pivotal for cell motility and migration, and its aberrant function is implicated in cancer invasion and metastasis. Here, all-atom multi μs-long molecular dynamics simulations and dynamical NetWork Analysis (NWA) unprecedentedly disclose the molecular terms of Arp2/3 regulation (activation/inhibition) by positive/negative allosteric modulators. After identifying the crucial structural elements underlying Arp2/3's conformational transition toward its active actin-polymerization-competent state, we decrypt the activating signaling paths heading from the allosteric effector (ATP) binding sites to these pivotal regions, also elucidating how small-molecule inhibitors scramble this signal-exchange. As a result, while ATP-induced signaling triggers a harmonious conformational transition toward active Arp2/3, the inhibitors disturb these information channels, desynchronizing Arp2/3 functional movements, thus hindering its activation. Our outcomes supply a conceptual basis for devising small-molecule inhibitors to block infiltrative cancer migration.

Aims: Although alirocumab and evolocumab have both been associated with improved outcomes in patients with dyslipidaemia or established atherosclerotic cardiovascular disease, data on their respective performances are scarce. This study aimed at providing an indirect comparison of the efficacy and safety of alirocumab vs. evolocumab., Methods and Results: We conducted a systematic review and network meta-analysis of randomized trials comparing alirocumab or evolocumab to placebo with consistent background lipid-lowering therapy up to November 2018. We estimated the relative risk (RR) and the 95% confidence intervals (CIs) using fixed-effect model in a frequentist pairwise and network meta-analytic approach. A total of 30 trials, enrolling 59 026 patients were included. Eligibility criteria varied significantly across trials evaluating alirocumab and evolocumab. Compared with evolocumab, alirocumab was associated with a significant reduction in all-cause death (RR 0.80, 95% CI 0.66-0.97) but not in cardiovascular death (RR 0.83, 95% CI 0.65-1.05). This study did not find any significant differences in myocardial infarction (RR 1.15, 95% CI 0.99-1.34), stroke (RR 0.96, 95% CI 0.71-1.28), or coronary revascularization (RR 1.13, 95% CI 0.99-1.29) between the two agents. Alirocumab was associated with a 27% increased risk of injection site reaction compared to evolocumab; however, no significant differences were found in terms of treatment discontinuations, systemic allergic reaction, neurocognitive events, ophthalmologic events, or new-onset of or worsening of pre-existing diabetes., Conclusion: Alirocumab and evolocumab share a similar safety profile except for injection site reaction. No significant differences were observed across the efficacy endpoints, except for all-cause death, which may be related to the heterogeneity of the studied populations treated with the two drugs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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., (© 2021 International Society on Thrombosis and Haemostasis.)