Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Lésions méniscales

- Save the Meniscus - Important de distinguer les lésions traumatiques sur ménisque sain des lésions dégénératives. - Distinguer la stabilité du genou de la stabilité de la lésion méniscale. - Priorité à la conservation méniscale par réparation ou abstention chirurgicale

Fracture of the polyethylene component in an ankle arthroplasty: a case report

A 57-year-old female underwent total ankle arthroplasty for post-traumatic arthrosis using the Agility Total Ankle System. The talar component was placed in varus malalignment. Her postoperative course was remarkable for 19 months of satisfactory function followed by the acute onset of intense pain and decreased range of motion. There was no history of trauma. After failing a short course of observation, revision surgery of the arthroplasty was performed. Operative findings revealed a complete fracture of the polyethylene. This report details the first case of such a complication and discusses the importance of component alignment in the prevention of polyethylene insert failure

Patient-Specific Instruments for Forearm Sarcoma Resection and Allograft Reconstruction in Children: Results in 4 Cases.

For pediatric malignant bone tumors located in the limbs, limb salvage surgery is the gold standard, but it requires adequate resection margins to avoid local recurrence. Primitive bone sarcomas of the forearm (radius or ulna) are very rare and the reconstruction remains challenging. We describe a method to ensure minimal but adequate resection bone margins with precision in four consecutive patients with primitive bone sarcomas of the forearm. During the preoperative planning, magnetic resonance imaging (MRI) was used to delineate the tumor and the tumor volume was transferred to computerized tomography (CT) by image fusion. A patient-specific instrument (PSI) was manufactured by 3D printing to allow the surgeon to perform the surgical cuts precisely according to the preoperative planning. The first PSI was used for the resection of the tumor, which adopted a unique position at the bony surface. A second PSI was intended for the cutting of the bone allograft so that it fitted perfectly with the bone defect. In all four cases, the safe margin obtained into the bone was free of tumor (R0: microscopically margin-negative resection). The functional result was very good in all four patients. This limb salvage surgical technique can be applied in forearm bone sarcoma and improves surgical precision while maintaining satisfactory local tumor control. It can also reduce the surgical time and allow a stable osteosynthesis

Tumeurs frontières de l’ovaire. Recommandations pour la pratique clinique du CNGOF – Fertilité

International audienceObjectivesBorderline ovarian tumors (BOT) represent around 15% of all ovarian neoplasms and are more likely tobe diagnosed in women of reproductive age. Overall, given the epidemiological profile of BOT and theirfavourable prognosis, ovarian function and fertility preservation should be systematically considered in patientspresenting these lesions.MethodsThe research strategy was based on the following terms: borderline ovarian tumor, fertility, fertility preservation,infertility, fertility-sparing surgery, in vitro fertilization, ovarian stimulation, oocyte cryopreservation,using PubMed, in English and French.Results and conclusionsFertility counselling should become an integral part of the clinical management of women with BOT. Patientswith BOT should be informed that surgical management of BOT may cause damage ovarian reserveand/or peritoneal adhesions. Nomogram to predict recurrence, ovarian reserve markers and fertility explorationsshould be used to provide a clear and relevant information about the risk of infertility in patients withBOT. Fertility-sparing surgery should be considered for young women who wish preserving their fertilitywhen possible. There is insufficient evidence to claim a causal relation between controlled ovarian stimulation(COS) and BOT. However, in case of poor prognosis factors, the use of COS should be consideredcautiously through a multidisciplinary approach. In case of infertility after surgery for BOT, COS can be performedwithout delay, once histopathological diagnosis of BOT is confirmed. There is insufficient consistentevidence that fertility drugs and COS increase the risk of recurrence of BOT after conservative management.The conservative surgical treatment can be associated to oocyte cryopreservation considering the high riskof recurrence of the disease. In women with BOT recurrence in a single ovary and in women with bilateralovarian involvement when the conservative management is not possible, other fertility preservation strategiesare available, but still experimental.ObjectifsLes tumeurs frontières de l’ovaire (TFO) représentent 10 à 20 % des tumeurs séreuses de l’ovaire et surviennentdans près d’un tiers des cas chez des femmes âgées de moins de 40 ans, n’ayant pas toujours accomplileur projet conceptionnel. Ainsi, la problématique de la fertilité dans la prise en charge des TFO doit être miseau premier plan.MéthodesUne sélection bibliographique a été réalisée dans PubMed de 1988 à mai 2019 inclus, sur les thématiques :infertilité et TFO, préservation de la fertilité et TFO.Résultats et conclusionsIl est recommandé de proposer une consultation spécialisée de Médecine de la reproduction lors du diagnosticde TFO chez une patiente en âge de procréer. Il est recommandé de délivrer une information complèteaux patientes, sur le risque de baisse de réserve ovarienne faisant suite à un traitement chirurgical de TFO. Ilest recommandé de s’appuyer sur les scores d’évaluation du risque de récidive, l’étude des paramètres d’infertilitéet de réserve ovarienne pour délivrer une information complète quant au risque d’infertilité des patientesprésentant une TFO (grade C). Lorsqu’elle est possible, une stratégie chirurgicale conservatrice est recommandéepour préserver la fertilité des femmes en âge de procréer en cas de TFO (grade C). Après traitementoptimal d’une TFO, il n’existe pas dans la littérature de donnée contre-indiquant formellement le recours àune stimulation ovarienne. Néanmoins, en cas de facteurs pronostics histologiques péjoratifs (implants), lerecours à une stimulation ovarienne sera discuté au cas par cas dans le cadre d’une RCP. En cas d’infertilitéaprès traitement conservateur d’une TFO, il n’existe pas de données justifiant un délai entre le traitementchirurgical et la prise en charge en assistance médicale à la procréation. La stimulation ovarienne dans le cadred’une AMP chez les femmes ayant été traitées de façon conservatrice pour TFO ne semble pas augmenter lerisque de récidive (grade C). En cas de traitement conservateur (chirurgie complète et stadification), il n’existepas de contre-indication dans la littérature à réaliser une stimulation ovarienne en vue d’une vitrificationovocytaire pour préservation de fertilité (PF). En présence de critères histologiques péjoratifs (implants), lapossibilité d’une stimulation ovarienne sera à discuter au cas par cas en RCP avant PF. Pour les femmes dontle traitement chirurgical ne peut être conservateur sur les annexes ou pour les patientes présentant une récidivede TFO sur ovaire unique, plusieurs techniques de préservation de la fertilité sont décrites dans la littératuremais avec des niveaux de preuves insuffisants pour pouvoir les recommander

Cardiovascular complications in patients with Zika virus-induced Guillain-Barré syndrome

International audienc

Vers une cosimulation multi-physique interactive – le projet COSIMPHI

International audienceThe project COSIMPHI, supported by the French National Research Agency (ANR) has been dedicated to multi-physics simulation to simultaneously consider acoustics, lighting and thermal comforts and energetic, environmental and economic performances in building design process. The development in this project brings a prototype of a multi-physics simulation tool linked to an optimization and decision-making support system. The works have been revolved around three axes: data structuration, multi-physics simulation and decision-making support and multicriteria optimization. This paper presents the methodology applied and the results obtained. Firstly, discussions between each expertise (acoustics, lighting, energetic, environment, economic) lead to a common dataset considering data of each tool. Then, efforts have been focused on co-simulation to correctly orchestrate each thematic tool. This orchestrator assumes the link between component and equipment database and thematic tools, and then provide the results to the optimization and decision-making support system.Cet article présente les travaux réalisés dans le cadre du projet ANR COSIMPHI visant à développer un outil de co-simulation multi-physique (acoustique, coût, éclairage, énergie-confort d’été, environnement) interactive, cohérent scientifiquement et techniquement, pour améliorer le processus de conception. Dans les travaux réalisés, la mise en cohérence de la description du bâtiment a été réalisée à travers un Modèle de Données Pivot, description commune aux cinq outils métiers du projet, compatible à la fois avec les maquettes numériques et avec une base de données (BDD) multi-physiques. Ces entrées alimentent une plate-forme de co-simulation. Un orchestrateur, également développé en Web Service (WS), gère les appels des outils métier et transmet les informations d’un outil à l’autre. Enfin, un module d’optimisation basé sur les algorithmes génétiques, un module de règles expertes basé sur la logique floue et un module d’aide à la décision multicritères sont capables de fournir au concepteur des informations quantitatives et qualitatives sur ses choix de conception

Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact

Aims: A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus-9 (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and results: Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3 ± 1.2 Hz in hPLN-R14del vs. 25.7 ± 1.3 Hz in WT, P < 0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital polymerase chain reaction and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end-diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9 ± 2.3 Hz vs. 21.3 ± 1.5 Hz; P < 0.01). Conclusions: This study is the first to show that disruption of hPLN-R14del allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease