Publications by authors named "Eric Vicaut"

393 Publications

Efficacy of Severe Acute Respiratory Syndrome Coronavirus-2 Vaccine in Patients With Thoracic Cancer: A Prospective Study Supporting a Third Dose in Patients With Minimal Serologic Response After Two Vaccine Doses.

J Thorac Oncol 2021 Nov 16. Epub 2021 Nov 16.

Thoracic Oncology Department, Université de Paris, North-Paris Cancer University Institute, Bichat-Claude Bernard Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP.Nord), Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1425, Bichat-Claude Bernard Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP.Nord), Paris, France; INSERM U830 Cancer, Heterogeneity Plasticity, Curie Institute Research Centre, Paris, France. Electronic address:

Introduction: Coronavirus disease 2019 resulted in a 30% mortality rate in patients with thoracic cancer. Given that patients with cancer were excluded from serum antisevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine registration trials, it is still unknown whether they would develop a protective antispike antibody response after vaccination. This prospective vaccine monitoring study primarily aimed to assess humoral responses to the SARS-CoV-2 vaccine in patients with thoracic cancer.

Methods: SARS-CoV-2-spike antibodies were measured using the Abbot Architect SARS-CoV-2 immunoglobulin G immunoassay before the first injection of BNT162b2 mRNA vaccine, at week 4, and 2 to 16 weeks after the second vaccine dose administration. The factors associated with antibody response were analyzed.

Results: Overall, 306 patients, with a median age of 67.0 years (interquartile range: 58-74), were vaccinated. Of these, 283 patients received two vaccine doses at 28-day intervals. After a 6.7-month median follow-up, eight patients (2.6%) contracted proven symptomatic SARS-CoV-2 infection, with rapid favorable evolution. Of the 269 serologic results available beyond day 14 after the second vaccine dose administration, 17 patients (6.3%) were still negative (<50 arbitrary units/mL, whereas 34 (11%) were less than 300 arbitrary units/mL (12.5th percentile). In multivariate analysis, only age (p < 0.01) and long-term corticosteroid treatment (p = 0.01) were significantly associated with a lack of immunization. A total of 30 patients received a third vaccine dose, with only three patients showing persistently negative serology thereafter, whereas the others exhibited clear seroconversion.

Conclusions: SARS-CoV2 vaccines were found to be efficient in patients with thoracic cancer, most of them being immunized after two doses. A third shot given to 1% of patients with persistent low antibody titers resulted in an 88% immunization rate.
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http://dx.doi.org/10.1016/j.jtho.2021.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593625PMC
November 2021

Evaluating the Effectiveness of Yttrium-90 Glass Microspheres in the Treatment of Hepatocellular Carcinoma, Intrahepatic Cholangiocarcinoma, and Metastatic Colorectal Cancer in Practice: Protocol for the Prospective PROACTIF Phase IV Registry Study in France.

Cardiovasc Intervent Radiol 2021 Nov 18. Epub 2021 Nov 18.

Department of Radiology, St. Eloi University Hospital - Montpellier School of Medicine, 80 avenue Augustin Fliche, 34295, Montpellier, France.

Primary Objective: Recently, selective internal radiation therapy using yttrium-90 (Y90) glass microspheres (TheraSphere™) was approved for reimbursement by health authorities in France. The PROACTIF study aims to gather data on effectiveness, patient quality of life, and safety with use of Y90 glass microspheres in real-world clinical settings in France.

Inclusion Criteria: Patient with a diagnosis of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCC), and/or metastatic colorectal cancer (mCRC) who was treated with a dose of Y90 glass microspheres that has been reimbursed in France and who do not oppose use of their personal medical data.

Exclusion Criteria: If data collection is opposed, treatment is reimbursed but not administered, or treatment is administered but not reimbursed.

Outcome Measures: Primary outcome measures include overall survival from time of Y90 glass microsphere treatment and quality of life, as assessed using the Functional Assessment of Cancer Therapy- Hepatobiliary questionnaire.

Estimated Number Of Patients To Be Included: This is an open study and there is no set number of patients; 115 have already been enrolled.

Planned Subgroup Analyses: Analyses will be stratified by disease state (HCC, iCC, or mCRC). Subgroups to be analyzed include age group, unilobar/bilobar disease at baseline, Eastern Cooperative Oncology Group (ECOG) status at baseline, liver tumor burden at baseline, target lesion size, and standard versus multi-compartment personalized dosimetry treatment.

Planned Recruitment And Observation Period: Recruitment includes patients who are prescribed and treated with a commercial vial of Y90 glass microspheres between 01 January 2019 and 31 December 2024.

Trial Registration: ClinicalTrials.gov Identifier: NCT04069468.
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http://dx.doi.org/10.1007/s00270-021-03002-0DOI Listing
November 2021

Distribution of bony erosions in feet and performance of two bone erosion scores: A dual-energy computed tomography study of 61 patients with gout.

PLoS One 2021 2;16(11):e0259194. Epub 2021 Nov 2.

Service de Radiologie, Hôpital Lariboisière, AP-HP.Nord-Université de Paris, Paris, France.

Objectives: To assess the distribution of bone erosions and two erosion scores in the feet of patients with gout and analyze the association between erosion scores and monosodium urate (MSU) crystal deposition using dual-energy computed tomography (DECT).

Materials And Methods: We included all patients who underwent DECT of both feet between 2016 and 2019 in our radiology department, with positive detection of MSU deposits. Data on sex, age, treatment, serum urate, and DECT urate volumes were obtained. CT images were analyzed to score bone erosions in 31 sites per foot by using the semi-quantitative method based on the Rheumatoid Arthritis MRI Scoring (RAMRIS) system and the Dalbeth-simplified score. Reproducibility for the two scores was calculated with intraclass correlation coefficients (ICCs). Correlations between clinical features, erosion scores and urate crystal volume were analyzed by the Spearman correlation coefficient (r).

Results: We studied 61 patients (mean age 62.0 years); 3,751 bones were scored. The first metatarsophalangeal joint and the midfoot were the most involved in terms of frequency and severity of bone erosions. The distribution of bone erosions was not asymmetrical. The intra- and inter-observer reproducibility was similar for the RAMRIS and Dalbeth-simplified scores (ICC 0.93 vs 0.94 and 0.96 vs 0.90). DECT urate volume was significantly correlated with each of the two erosion scores (r = 0.58-0.63, p < 0.001). There was a high correlation between the two scores (r = 0.96, p < 0.001).

Conclusions: DECT demonstrates that foot erosions are not asymmetric in distribution and predominate at the first ray and midfoot. The two erosion scores are significantly correlated with DECT urate volume. An almost perfect correlation between the RAMRIS and Dalbeth-simplified scores is observed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562819PMC
November 2021

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock.

Front Immunol 2021 29;12:749659. Epub 2021 Sep 29.

Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France.

Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune-inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.
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http://dx.doi.org/10.3389/fimmu.2021.749659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511792PMC
September 2021

Early and short-term intensive management after discharge for patients hospitalized with acute heart failure: a randomized study (ECAD-HF).

Eur J Heart Fail 2021 Oct 9. Epub 2021 Oct 9.

Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Aims: Hospitalization for acute heart failure (HF) is followed by a vulnerable time with increased risk of readmission or death, thus requiring particular attention after discharge. In this study, we examined the impact of intensive, early follow-up among patients at high readmission risk at discharge after treatment for acute HF.

Methods And Results: Hospitalized acute HF patients were included with at least one of the following: previous acute HF < 6 months, systolic blood pressure ≤ 110 mmHg, creatininaemia ≥ 180 µmol/L, or B-type natriuretic peptide ≥ 350 pg/mL or N-terminal pro B-type natriuretic peptide ≥ 2200 pg/mL. Patients were randomized to either optimized care and education with serial consultations with HF specialist and dietician during the first 2-3 weeks, or to standard post-discharge care according to guidelines. The primary endpoint was all-cause death or first unplanned hospitalization during 6-month follow-up. Among 482 randomized patients (median age 77 and median left ventricular ejection fraction 35%), 224 were hospitalized or died. In the intensive group, loop diuretics (46%), beta-blockers (49%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (39%) and mineralocorticoid receptor antagonists (47%) were titrated. No difference was observed between groups for the primary endpoint (hazard ratio 0.97; 95% confidence interval 0.74-1.26), nor for mortality at 6 or 12 months or unplanned HF rehospitalization. Additionally, no difference between groups according to age, previous HF and left ventricular ejection fraction was found.

Conclusions: In high-risk HF, intensive follow-up early post-discharge did not improve outcomes. This vulnerable post-discharge time requires further studies to clarify useful transitional care services.
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http://dx.doi.org/10.1002/ejhf.2357DOI Listing
October 2021

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Thromb Haemost 2021 Sep 24. Epub 2021 Sep 24.

AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
September 2021

Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study.

Thromb Haemost 2021 Sep 17. Epub 2021 Sep 17.

INNOVTE-FCRIN, Saint-Etienne, France.

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.
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http://dx.doi.org/10.1055/a-1647-9896DOI Listing
September 2021

Prognosis Associated with Sub-Types of Hyperglycaemia in Pregnancy.

J Clin Med 2021 Aug 30;10(17). Epub 2021 Aug 30.

AP-HP, Clinical Research Unit St-Louis-Lariboisière, Denis Diderot University, 75010 Paris, France.

We aimed to compare pregnancy outcomes in 4665 women according to the following types of hyperglycaemia in pregnancy sub-types: (i) normoglycaemia, (ii) gestational diabetes mellitus (GDM), (iii) diabetes in pregnancy (DIP), (iv) early-diagnosed (i.e., <22 weeks of gestation) GDM (eGDM), and (v) early-diagnosed DIP (eDIP). The prevalence of normoglycaemia, eGDM, eDIP, GDM, and DIP was 76.4%, 10.8%, 0.6%, 11.7%, and 0.6%, respectively. With regard to pregnancy outcomes, gestational weight gain (11.5 ± 5.5, 9.0 ± 5.4, 8.3 ± 4.7, 10.4 ± 5.3, and 10.1 ± 5.0 kg, < 0.0001) and insulin requirement (none, 46.0%, 88.5%, 25.5%, and 51.7%; < 0.001) differed according to the glycaemic sub-types. eGDM and eDIP were associated with higher rates of infant malformation. After adjustment for confounders, with normoglycaemia as the reference, only GDM was associated with large-for-gestational-age infant (odds ratio 1.34 (95% interval confidence 1.01-1.78) and only DIP was associated with hypertensive disorders (OR 3.48 (1.26-9.57)). To conclude, early-diagnosed hyperglycaemia was associated with an increased risk of malformation, suggesting that it was sometimes present at conception. Women with GDM, but not those with eGDM, had an increased risk of having a large-for-gestational-age infant, possibly because those with eGDM were treated early and therefore had less gestational weight gain. Women with DIP might benefit from specific surveillance for hypertensive disorders.
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http://dx.doi.org/10.3390/jcm10173904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432067PMC
August 2021

Acute and long-term effects of saxagliptin on a set of cardiovascular targets measured at fasting and post-prandially in obese patients with impaired glucose tolerance: A placebo-controlled study.

Nutr Metab Cardiovasc Dis 2021 09 1;31(10):2945-2958. Epub 2021 Jul 1.

AP-HP, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Paris 13 University, Jean Verdier Hospital, Bondy, France. Electronic address:

Background And Aims: Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state.

Methods And Results: In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016).

Conclusion: In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity.

Clinical Trial Registration Number: NCT01521312.
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http://dx.doi.org/10.1016/j.numecd.2021.06.017DOI Listing
September 2021

IL-1β primed mesenchymal stromal cells moderate hemorrhagic shock-induced organ injuries.

Stem Cell Res Ther 2021 08 5;12(1):438. Epub 2021 Aug 5.

Institut de Recherche Biomédicale des Armées (IRBA), 1 rue du Lieutenant Raoul Batany, 92141, Clamart, France.

Background: Organ damages following hemorrhagic shock (HS) have been partly attributed to an immunological dysfunction. The current challenge in the management of HS patients is to prevent organ injury-induced morbidity and mortality which currently has not etiological treatment available. Mesenchymal stromal cells (MSC) are used in clinical cell therapy for immunomodulation and tissue repair. In vitro priming is often used to improve the immunomodulation efficiency of MSC before administration.

Objective: Assess the effect of naive MSC (MSCn) or interleukin (IL)-1β primed (MSCp) treatment in a context of HS-induced organ injury.

Methods: Rats underwent fixed pressure HS and were treated with allogenic MSCn or MSCp. Liver and kidney injuries were evaluated 6h later by histological and biochemical analysis. Whole blood was collected to measure leukocytes phenotypes. Then, in vitro characterization of MSCn or MSCp was carried out.

Results: Plasma creatinine, blood urea nitrogen, and cystatin C were decrease by MSCp infusion as well as kidney injury molecule (KIM)-1 on histological kidney sections. Transaminases, GGT, and liver histology were normalized by MSCp. Systemic cytokines (IL-1α, IL-6, and IL-10) as well as CD80, 86, and PD-1/PDL-1 axis were decreased by MSCp on monocytes and granulocytes. In vitro, MSCp showed higher level of secreted immunomodulatory molecules than MSCn.

Conclusion: An early administration of MSCp moderates HS-induced kidney and liver injury. IL-1β priming improves MSC efficiency by promoting their immunomodulatory activity. These data provide proof of concept that MSCp could be a therapeutic tool to prevent the appearance of organs injury following HS.
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http://dx.doi.org/10.1186/s13287-021-02505-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340459PMC
August 2021

F-18 Fluorodeoxyglucose PET/CT as a Diagnostic Tool in Orbital Inflammatory Disorders.

Ocul Immunol Inflamm 2021 Jul 28:1-7. Epub 2021 Jul 28.

Service de Médecine Interne, AP-HP, Hôpital Avicenne, Bobigny, France.

Purpose: To assess the usefulness of FDG-PET/CT as a potential diagnostic tool for detecting underlying systemic diseases (SD) in patients with orbital inflammatory disorders (OID).

Methods: All consecutive patients managed for new-onset OID between 2011 and 2018 in a tertiary referral center, who underwent FDG-PET/CT as part of the etiological diagnostic workup were evaluated. To quantify the incremental value of FDG-PET/CT over standard diagnostic workup, the Net Reclassification Index (NRI) and Integrated Discrimination Index (IDI) were used.

Results: Among the 22 patients enrolled, 11 (50%) had a positive FDG-PET/CT. After clinicobiological evaluation, FDG-PET/CT correctly reclassified 4(29%) of 14 patients with SD ( = .04) and 1(13%) of 8 with idiopathic orbital inflammation syndrome ( = .32). NRI and IDI were 0.41 ± 0.17 ( = .03) and 0.38 ± 0.08 ( < .001), respectively. FDG-PET/CT successfully detected asymptomatic lesions in all (n = 4) patients with lymphoma.

Conclusion: FDG-PET/CT enabled accurate reclassification of more than one-quarter of patients with SD, especially extraorbital lymphomas.
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http://dx.doi.org/10.1080/09273948.2021.1957943DOI Listing
July 2021

Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS).

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, H. Sienkiewicza 112, 90-363 Lodz, Poland.

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.
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http://dx.doi.org/10.3390/ijms22147486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303821PMC
July 2021

Efficacy of emergency medical center use of a protocol during telephone calls to give medical advice related to fever or gastroenteritis: a cluster randomized controlled trial.

Emergencias 2021 08;33(4):292-298

AP-HP, Service des Urgences et Service d'Aide Médicale Urgente, Centre Hospitalier Universitaire Avicenne, Bobigny Cedex, Francia. Université Paris 13, Sorbonne Paris Cité, Bobigny, Francia.

Objectives: To determine the efficacy of emergency medical center physicians' use of a protocol to guide their management of telephone consultations for fever and gastroenteritis.

Material And Methods: Cluster randomized controlled trial. Participating centers were randomized to use the telephone protocol or provide usual telephone assistance. Six emergency centers in France included calls from patients needing advice on fever or gastroenteritis. Centers assigned to the protocol followed specific guidelines on managing the call and giving advice on treatment. Primary endpoints were the number of in-person visits and hospital admissions required within 15 days of the call. Secondary endpoints were patient satisfaction and costs.

Results: A total of 2498 calls were included. Use of the assigned protocol while attending 1234 calls was associated with a relative risk for hospitalization or an unscheduled in-person visit for care of 0.70 (95% CI, 0.58-0.85) versus usual practice. Ambulance use, admission to an intensive care unit, mortality, morbidity, and symptom improvement did not differ significantly between centers using the protocol and those following usual practice. Ninety percent of the patients were satisfied. The cost of care was €91 in centers applying the protocol and €150 in the other centers (P .01).

Conclusion: Use of the protocol was associated with fewer unscheduled in-person visits for care and fewer hospital admissions. The protocol is safe and less costly than the centers' usual approaches to giving telephone advice.
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August 2021

Bleeding in the Elderly: Risk Factors and Impact on Clinical Outcomes After an Acute Coronary Syndrome, a Sub-study of the Randomized ANTARCTIC Trial.

Am J Cardiovasc Drugs 2021 Nov 30;21(6):681-691. Epub 2021 Jun 30.

ACTION Study Group, INSERM UMRS 1166, Cardiology Institute, Pitié-Salpêtrière (AP-HP) University Hospital, Sorbonne University, 47-83 bld de l'Hôpital, 75013, Paris, France.

Background: Elderly patients are at high-risk of bleeding, but are under-represented in clinical trials.

Objectives: The aims were to determine the incidence and the predictive factors of bleeding and to assess the impact of bleeding on further ischemic outcomes in elderly patients after acute coronary syndrome (ACS) treated with percutaneous coronary intervention.

Methods: From the 877 patients aged ≥ 75 years included in the ANTARCTIC randomized trial, data on Bleeding Academic Research Consortium (BARC) bleeding complications and major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, and stroke, were collected over 1 year.

Results: Clinically relevant bleeding events (BARC types 2, 3, or 5) were observed in 20.6% of patients (n = 181) at 1 year, of which, one third occurred in the first month. Anemia (adjusted hazard ratio [adj.HR] 3.98, 95% confidence interval [CI] 1.41-11.22; p = 0.009), severe chronic renal failure (adj.HR 1.83, 95% CI 1.12-2.98; p = 0.015), and femoral access (adj.HR 2.54, 95% CI 1.71-3.77; p < 0.001) were independently associated with clinically relevant bleeding events, while age > 85 years (adj.HR 2.22, 95% CI 1.14-4.30; p = 0.018) was independently associated with major bleeding events (BARC types 3 or 5). Patients with a clinically relevant bleeding event had a higher rate of MACE at 1 year (adj.HR 2.04, 95% CI 1.24-3.38; p = 0.005), with a particularly strong effect on stroke (adj.HR 5.55, 95% CI 2.04-15.06; p < 0.001).

Conclusions: Clinically relevant bleeding events were observed in one out of five elderly patients undergoing stenting for an ACS and were strongly associated with further stroke occurrence. Rather than the antiplatelet therapy, comorbidities and an age > 85 years predicted bleeding outcomes in this elderly population.

Clinical Trial Registration: Clinicaltrials.gov identifier: NCT01538446. https://www.clinicaltrials.gov .
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http://dx.doi.org/10.1007/s40256-021-00468-8DOI Listing
November 2021

Plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study.

United European Gastroenterol J 2021 06;9(5):571-580

Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.

Background And Aims: Acetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen-poisoned patients likely to develop liver injury.

Methods: We conducted a prospective observational cohort study including all acetaminophen-poisoned patients requiring N-acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L.

Results: One hundred seventeen patients (age, 32 years (21-53), median [25th-75th percentiles]) were included after self-ingesting 16 g (9-30) acetaminophen and received N-acetylcysteine infusion administered within a median 6 h-delay (4-12) from exposure. Co-ingestions were reported in 77% of patients. Rumack-Matthew nomogram was non-interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577-4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2-44.9) versus 0.1 ng/ml (0-0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10-74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3-22.6; p < 0.001]). PCT (area under the receiver-operating characteristics curve, 0.91 [95%CI: 0.84-0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively.

Conclusion: PCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision-making.
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http://dx.doi.org/10.1002/ueg2.12093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259278PMC
June 2021

HbA and fasting plasma glucose cannot replace oral glucose tolerance test in order to screen for hyperglycaemia in pregnancy.

Diabet Med 2021 Sep 8;38(9):e14604. Epub 2021 Jun 8.

Department of Endocrinology-Diabetology-Nutrition, AP-HP, Avicenne Hospital, Paris 13 University, Sorbonne Paris Cité, CRNH-IdF, CINFO, Bobigny, France.

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http://dx.doi.org/10.1111/dme.14604DOI Listing
September 2021

Impact of Lower Versus Higher LDL Cholesterol Targets on Cardiovascular Events After Ischemic Stroke in Patients With Diabetes.

Diabetes 2021 08 12;70(8):1807-1815. Epub 2021 May 12.

Department of Biostatistics, Fernand Widal Hospital, APHP, Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France.

After an ischemic stroke with evidence of atherosclerosis, lipid-lowering treatment with a target LDL cholesterol of <70 mg/dL compared with 100 ± 10 mg/dL reduced the risk of subsequent cardiovascular events. In this analysis, we explored the effect in the subgroup of patients with diabetes compared with the subgroup without, as well as in those with newly diagnosed diabetes. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned at a 1:1 ratio to a target LDL cholesterol of <70 mg/dL or 100 ± 10 mg/dL using statin or ezetimibe. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and death resulting from vascular disease. We performed a prespecified analysis to evaluate the effect in patients with diabetes. Of 2,860 patients enrolled, 643 had diabetes at baseline, with a mean age of 66.2 years and baseline LDL cholesterol of 127 mg/dL, and were followed for a median of 3 years. The primary composite end point occurred in 27 (8.2%) of 328 patients in the lower-target group and in 44 (14.0%) of 315 patients in the higher-target group (adjusted hazard ratio [HR] 0.56; 95% CI 0.34-0.89; = 0.016). In patients without diabetes, the HR was 0.87 (95% CI 0.66-1.14; = 0.31; interaction = 0.15). In those with diabetes, there were three intracranial hemorrhages in both randomization groups (0.9% vs. 1.0%, respectively). Newly diagnosed diabetes occurred in 98 (9.2%) of 1,070 and in 80 (7.4%) of 1,085 patients in the lower- and higher-target groups, respectively (HR 1.27; 95% CI 0.94-1.71; = 0.11), and baseline higher HbA was the unique multivariable predictor. In conclusion, after an ischemic stroke with evidence of atherosclerosis, targeting an LDL cholesterol of <70 mg/dL compared with 100 ± 10 mg/dL consistently reduced the risk of subsequent stroke and other major vascular events in patients with and without diabetes, but the higher risk in those with diabetes yielded a higher absolute risk reduction, with number needed to treat of 17.
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http://dx.doi.org/10.2337/db21-0302DOI Listing
August 2021

Computer-assisted Individualized Hemodynamic Management Reduces Intraoperative Hypotension in Intermediate- and High-risk Surgery: A Randomized Controlled Trial.

Anesthesiology 2021 08;135(2):258-272

Background: Individualized hemodynamic management during surgery relies on accurate titration of vasopressors and fluids. In this context, computer systems have been developed to assist anesthesia providers in delivering these interventions. This study tested the hypothesis that computer-assisted individualized hemodynamic management could reduce intraoperative hypotension in patients undergoing intermediate- to high-risk surgery.

Methods: This single-center, parallel, two-arm, prospective randomized controlled single blinded superiority study included 38 patients undergoing abdominal or orthopedic surgery. All included patients had a radial arterial catheter inserted after anesthesia induction and connected to an uncalibrated pulse contour monitoring device. In the manually adjusted goal-directed therapy group (N = 19), the individualized hemodynamic management consisted of manual titration of norepinephrine infusion to maintain mean arterial pressure within 10% of the patient's baseline value, and mini-fluid challenges to maximize the stroke volume index. In the computer-assisted group (N = 19), the same approach was applied using a closed-loop system for norepinephrine adjustments and a decision-support system for the infusion of mini-fluid challenges (100 ml). The primary outcome was intraoperative hypotension defined as the percentage of intraoperative case time patients spent with a mean arterial pressure of less than 90% of the patient's baseline value, measured during the preoperative screening. Secondary outcome was the incidence of minor postoperative complications.

Results: All patients were included in the analysis. Intraoperative hypotension was 1.2% [0.4 to 2.0%] (median [25th to 75th] percentiles) in the computer-assisted group compared to 21.5% [14.5 to 31.8%] in the manually adjusted goal-directed therapy group (difference, -21.1 [95% CI, -15.9 to -27.6%]; P < 0.001). The incidence of minor postoperative complications was not different between groups (42 vs. 58%; P = 0.330). Mean stroke volume index and cardiac index were both significantly higher in the computer-assisted group than in the manually adjusted goal-directed therapy group (P < 0.001).

Conclusions: In patients having intermediate- to high-risk surgery, computer-assisted individualized hemodynamic management significantly reduces intraoperative hypotension compared to a manually controlled goal-directed approach.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000003807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277754PMC
August 2021

Important Drop in Rate of Acute Diabetes Complications in People With Type 1 or Type 2 Diabetes After Initiation of Flash Glucose Monitoring in France: The RELIEF Study.

Diabetes Care 2021 06 20;44(6):1368-1376. Epub 2021 Apr 20.

Department of Endocrinology, Diabetology, and Nutrition, Brabois Adult Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France.

Objective: The RELIEF study assessed rates of hospitalization for acute diabetes complications in France before and after initiation of the FreeStyle Libre system.

Research Design And Methods: A total of 74,011 patients with type 1 diabetes or type 2 diabetes who initiated the FreeStyle Libre system were identified from the French national claims database with use of ICD-10 codes, from hospitalizations with diabetes as a contributing diagnosis, or the prescription of insulin. Patients were subclassified based on self-monitoring of blood glucose (SMBG) strip acquisition prior to starting FreeStyle Libre. Hospitalizations for diabetic ketoacidosis (DKA), severe hypoglycemia, diabetes-related coma, and hyperglycemia were recorded for the 12 months before and after initiation.

Results: Hospitalizations for acute diabetes complications fell in type 1 diabetes (-49.0%) and in type 2 diabetes (-39.4%) following FreeStyle Libre initiation. DKA fell in type 1 diabetes (-56.2%) and in type 2 diabetes (-52.1%), as did diabetes-related comas in type 1 diabetes (-39.6%) and in type 2 diabetes (-31.9%). Hospitalizations for hypoglycemia and hyperglycemia decreased in type 2 diabetes (-10.8% and -26.5%, respectively). Before initiation, hospitalizations were most marked for people noncompliant with SMBG and for those with highest acquisition of SMBG, which fell by 54.0% and 51.2%, respectively, following FreeStyle Libre initiation. Persistence with FreeStyle Libre at 12 months was at 98.1%.

Conclusions: This large retrospective study on hospitalizations for acute diabetes complications shows that a significantly lower incidence of admissions for DKA and for diabetes-related coma is associated with use of flash glucose monitoring. This study has significant implications for patient-centered diabetes care and potentially for long-term health economic outcomes.
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http://dx.doi.org/10.2337/dc20-1690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247513PMC
June 2021

Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial.

Trials 2021 Mar 9;22(1):199. Epub 2021 Mar 9.

CHU Nantes, Department of Infectious Disease, Clinical Investigation, Nantes, France.

Background: Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2.

Methods: Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population.

Discussion: This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis.

Trial Registration: ClinicalTrials.gov NCT04453384 , registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.
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http://dx.doi.org/10.1186/s13063-021-05132-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942514PMC
March 2021

Prevention of hypothermia in trauma victims - the HYPOTRAUM 2 study.

J Adv Nurs 2021 Jun 19;77(6):2908-2915. Epub 2021 Mar 19.

URC F-Widal/Lariboisière-Saint Louis, Paris, France.

Introduction: Hypothermia is common in trauma patients. It contributes to increasing mortality rate. Hypothermia is multifactorial, favoured by exposure to cold, severity of the patient's state and interventions such as infusion of fluids at room temperature.

Aim: To demonstrate that specific management of hypothermia (or of the risk of hypothermia) increases the number of trauma patients arriving at the hospital with a temperature >35°C.

Design: This is a prospective, multicentre, open-label, pragmatic, cluster randomized clinical trial of an expected 1,200 trauma patients included by 12 out-of-hospital mobile intensive care units (MICU). Trauma patients are included in a prehospital setting if they present at least one of the following criteria known to be associated with an increased incidence of hypothermia: ambient temperature <18°C, Glasgow coma scale <15, systolic arterial blood pressure <100 mm Hg or body temperature <35°C. Patients are randomized, by cluster, to receive a conventional management or 'interventional' nursing management associating: continuous epitympanic temperature monitoring, early installation in the heated ambulance (temperature target >30°C controlled by infrared thermometer), protection by a survival blanket, and use of heated solutes (temperature objective >35°C controlled by infrared thermometer). The primary end point is the prevalence of hypothermia on arrival at the hospital. The hypothesis tested is a reduction from 20% to 13% in the prevalence of hypothermia. Secondary end points are to evaluate the interaction between the effectiveness of the measures taken and: (1) the severity of the patients assessed by the Revised Trauma Score; (2) the meteorological conditions when they are managed; (3) the time of care; and (4) therapeutic interventions.

Discussion: This trial will assess the effectiveness of an invasive, out-of-hospital, temperature management on the onset of hypothermia in moderate to severe trauma patients.

Impact: Specific management of hypothermia is expected to decrease hypothermia in trauma patients.
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http://dx.doi.org/10.1111/jan.14818DOI Listing
June 2021

Impact of preoperative enteral nutritional support on postoperative outcome in patients with Crohn's disease complicated by malnutrition: Results of a subgroup analysis of the nationwide cohort registry from the GETAID Chirurgie group.

Colorectal Dis 2021 06 12;23(6):1451-1462. Epub 2021 Mar 12.

Department of Digestive Surgery and Surgical Oncology, Hôpital Bicêtre, Université Paris Saclay, APHP, Le Kremlin Bicêtre, France.

Aim: Postoperative morbidity is high in patients operated on for Crohn's disease (CD) complicated by malnutrition. This study aimed to evaluate the impact of preoperative enteral nutritional support (PENS) on postoperative outcome in patients with CD complicated by malnutrition included in a prospective nationwide cohort.

Method: Malnutrition was defined as body mass index <18 kg/m and/or albuminaemia <30 g/L and/or weight loss >10%. Failure of PENS was defined as the requirement for additional preoperative parenteral nutrition to PENS. Univariate analysis of the risk factors for PENS failure was performed. Propensity score matching (PSM) was used to compare the outcomes between 'upfront surgery' and 'PENS' groups. The primary endpoint was the rate of intra-abdominal septic morbidity and/or temporary defunctioning stoma.

Results: Among 592 patients included, 149 were selected. In the intention-to-treat population including 20 (13.4%) patients with PENS failure after PSM, 78 'upfront surgery' and 71 'PENS'-matched patients were compared, with no significant difference in the primary endpoint. Perforating CD and preoperative intra-abdominal fistula were associated with PENS failure [37.5 vs 16.1% (P = 0.047) and 41.2% vs 16.2% (P = 0.020), respectively]. After exclusion of these 20 patients, PSM was used to compare 45 'upfront surgery' and 51 'PENS'-matched patients, with a significantly decreased rate of intra-abdominal septic complications and/or temporary defunctioning stoma in the PENS group (19.6 vs 42.2%, P = 0.016).

Conclusion: Preoperative enteral nutritional support is associated with a trend but no conclusive evidence of a reduction in intra-abdominal septic complications and/or requirement for defunctioning stoma. Patients with perforating CD complicated with malnutrition are at risk of PENS failure.
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http://dx.doi.org/10.1111/codi.15600DOI Listing
June 2021

Acute and long-term effects of saxagliptin on post-prandial glycemic response in obese patients with impaired glucose tolerance.

Nutr Metab Cardiovasc Dis 2021 04 31;31(4):1257-1266. Epub 2020 Dec 31.

Department of Endocrinology, Diabetology, Nutrition, Jean Verdier Hospital, AP-HP, CRNH-IdF, CINFO, Paris Nord University, Sorbonne Paris Cité, Bondy, France. Electronic address:

Background And Aims: Dipeptidyl-peptidase inhibitors might be useful in type 2 diabetes prevention. ACCES (ACute and Chronic Effects of Saxagliptin) was a randomized, placebo-controlled, double-blind, controlled phase 2, pilot study aiming to examine in obese patients with impaired glucose tolerance (IGT) the acute effects and the effects after 12 weeks of treatment by saxagliptin on glucose levels at fasting and postprandially after a standard breakfast, and on glucose tolerance.

Methods And Results: We included 24 obese patients with IGT. Patients were randomized to receive saxagliptin 5 mg or placebo in the morning. The treatment was taken on Visit 1 before breakfast, then continued for 12 weeks. Biochemical measurements were performed before, one, two and three hours after a standard breakfast including 75 g of carbohydrates, during Visit 1 and Visit 2 (12 weeks). Glucose variability (GV) was evaluated at Visit 1 from 24-h continuous glucose monitoring including the breakfast. A second OGTT was performed at Visit 3 (3-5 days after Visit 2). Compared with placebo-treated patients, saxagliptin-treated patients had lower 1 h and 2 h post-meal plasma glucose levels at Visit 1 and similar changes at Visit 2 (p < 0.01 to p < 0.004), with lower GV indexes after breakfast at Visit 1. At Visit 3, all patients but one in saxagliptin group and only 4 patients in placebo group turned to normal glucose tolerance. Lower glucose response to breakfast at Visit 1 was predictive of recovery of glucose tolerance.

Conclusion: Saxagliptin has metabolically beneficial effects in glucose-intolerant obese patients by significantly lowering postprandial blood glucose levels.

Clinical Trial Registration Number: NCT01521312: https://clinicaltrials.gov/ct2/show/NCT01521312.
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http://dx.doi.org/10.1016/j.numecd.2020.12.025DOI Listing
April 2021

Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial.

JAMA 2021 02;325(6):552-560

Université de Paris, AP-HP, French Alliance for Cardiovascular Trials (FACT), INSERM U1148, Paris, France.

Importance: The optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear.

Objective: To determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy.

Design, Setting, And Participants: Open-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019.

Interventions: Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy.

Main Outcomes And Measures: The primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome.

Results: Among 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups.

Conclusions And Relevance: Among patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm.

Trial Registration: ClinicalTrials.gov Identifier: NCT02648113.
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http://dx.doi.org/10.1001/jama.2021.0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873781PMC
February 2021

Limiting the Use of Oral Glucose Tolerance Tests to Screen for Hyperglycemia in Pregnancy during Pandemics.

J Clin Med 2021 Jan 21;10(3). Epub 2021 Jan 21.

AP-HP, Department of Endocrinology-Diabetology-Nutrition, Avicenne Hospital, Paris 13 University, Sorbonne Paris Cité, CRNH-IdF, CINFO, 93 000 Bobigny, France.

We aimed to evaluate each proposal of Australian-New Zealand Societies to limit the number of oral glucose tolerance tests (OGTTs) to diagnose hyperglycemia in pregnancy (HIP) during the coronavirus disease 2019 (COVID-19) pandemic. At our university hospital (2012-2016), we retrospectively applied in 4245 women who had OGTT between 22 and 30 weeks of gestation (reference standard: WHO criteria) the proposals in which OGTT is performed only in high-risk women; in all (Option 1) or high-risk (Option 1-Sel) women with fasting plasma glucose (FPG) 4.7-5.0 mmol/L; in all (Option 2) or high-risk (Option 2-Sel) women without history of HIP and with FPG 4.7-5.0 mmol/L. We also tested FPG measurement alone in all high-risk women. Measuring FPG alone had a sensitivity of 49% (95% confidence interval 45-54) applying universal screening. Option 2 appeared to have the best balance considering the needed OGTT (17.3%), sensitivity (72% (67-76)) and rates of a composite outcome (true negative cases: 10.6%, false positive cases: 24.4%; true positive cases: 19.5%; false negative cases: 10.2%). Consideration of a history of HIP and measuring first FPG can avoid more than 80% of OGTTs and identify women with the highest risk of adverse HIP-related events.
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http://dx.doi.org/10.3390/jcm10030397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864504PMC
January 2021

Predictive Value of the Residual SYNTAX Score in Patients With Cardiogenic Shock.

J Am Coll Cardiol 2021 01;77(2):144-155

ACTION Study Group, INSERM UMRS_1166 Cardiology Institute, University of the Sorbonne, Paris, France. Electronic address:

Background: In hemodynamically stable patients, complete revascularization (CR) following percutaneous coronary intervention (PCI) is associated with a better prognosis in chronic and acute coronary syndromes.

Objectives: This study sought to assess the extent, severity, and prognostic value of remaining coronary stenoses following PCI, by using the residual SYNTAX score (rSS), in patients with cardiogenic shock (CS) related to myocardial infarction (MI).

Methods: The CULPRIT-SHOCK (Culprit Lesion Only Percutaneous Coronary Intervention [PCI] Versus Multivessel PCI in Cardiogenic Shock) trial compared a multivessel PCI (MV-PCI) strategy with a culprit lesion-only PCI (CLO-PCI) strategy in patients with multivessel coronary artery disease who presented with MI-related CS. The rSS was assessed by a central core laboratory. The study group was divided in 4 subgroups according to tertiles of rSS of the participants, thereby isolating patients with an rSS of 0 (CR). The predictive value of rSS for the 30-day primary endpoint (mortality or severe renal failure) and for 30-day and 1-year mortality was assessed using multivariate logistic regression.

Results: Among the 587 patients with an rSS available, the median rSS was 9.0 (interquartile range: 3.0 to 17.0); 102 (17.4%), 100 (17.0%), 196 (33.4%), and 189 (32.2%) patients had rSS = 0, 0 < rSS ≤5, 5 < rSS ≤14, and rSS >14, respectively. CR was achieved in 75 (25.2%; 95% confidence interval [CI]: 20.3% to 30.5%) and 27 (9.3%; 95% CI: 6.2% to 13.3%) of patients treated using the MV-PCI and CLO-PCI strategies, respectively. After multiple adjustments, rSS was independently associated with 30-day mortality (adjusted odds ratio per 10 units: 1.49; 95% CI: 1.11 to 2.01) and 1-year mortality (adjusted odds ratio per 10 units: 1.52; 95% CI: 1.11 to 2.07).

Conclusions: Among patients with multivessel disease and MI-related CS, CR is achieved only in one-fourth of the patients treated using an MV-PCI strategy. and the residual SYNTAX score is independently associated with early and late mortality.
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http://dx.doi.org/10.1016/j.jacc.2020.11.025DOI Listing
January 2021

Restrictive vs liberal red blood cell transfusion strategies in patients with acute myocardial infarction and anemia: Rationale and design of the REALITY trial.

Clin Cardiol 2021 Feb 6;44(2):143-150. Epub 2021 Jan 6.

Université de Paris, AP-HP, French Alliance for Cardiovascular Trials (FACT), INSERM U1148, Paris, France.

Background: Anemia is common in patients with acute myocardial infarction (AMI), and is an independent predictor of mortality. The optimal transfusion strategy in these patients is unclear.

Hypothesis: We hypothesized that a "restrictive" transfusion strategy (triggered by hemoglobin ≤8 g/dL) is clinically noninferior to a "liberal" transfusion strategy (triggered by hemoglobin ≤10 g/dL), but is less costly.

Methods: REALITY is an international, randomized, multicenter, open-label trial comparing a restrictive vs a liberal transfusion strategy in patients with AMI and anemia. The primary outcome is the incremental cost-effectiveness ratio (ICER) at 30 days, using the primary composite clinical outcome of major adverse cardiovascular events (MACE; comprising all-cause death, nonfatal stroke, nonfatal recurrent myocardial infarction, or emergency revascularization prompted by ischemia) as the effectiveness criterion. Secondary outcomes include the ICER at 1 year, and MACE (and its components) at 30 days and at 1 year.

Results: The trial aimed to enroll 630 patients. Based on estimated event rates of 11% in the restrictive group and 15% in the liberal group, this number will provide 80% power to demonstrate clinical noninferiority of the restrictive group, with a noninferiority margin corresponding to a relative risk equal to 1.25. The sample size will also provide 80% power to show the cost-effectiveness of the restrictive strategy at a threshold of €50 000 per quality-adjusted life year.

Conclusions: REALITY will provide important guidance on the management of patients with AMI and anemia.
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http://dx.doi.org/10.1002/clc.23453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852166PMC
February 2021

COVID-19 pandemic: Can fasting plasma glucose and HbA1c replace the oral glucose tolerance test to screen for hyperglycaemia in pregnancy?

Diabetes Res Clin Pract 2021 Feb 13;172:108640. Epub 2021 Jan 13.

AP-HP, Avicenne Hospital, Paris 13 University, Sorbonne Paris Cité, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Bobigny, France; Paris 13 University, Sorbonne Paris Cité, UMR U557 INSERM/U11125 INRAE/CNAM/Université Paris13, Unité de Recherche Epidémiologique Nutritionnelle, Bobigny, France. Electronic address:

Aims: To evaluate proposals considering HbA1c and fasting plasma glucose (FPG) measurement as a substitute for oral glucose tolerance test (OGTT) to diagnose hyperglycaemia in pregnancy (HIP) during COVID-19 pandemic.

Methods: Of the 7,334 women who underwent the OGTT between 22 and 30 weeks gestation, 966 had HIP (WHO diagnostic criteria, reference standard). The 467 women who had an available HbA1c were used for analysis. French-speaking Society of Diabetes (SFD) proposal to diagnose HIP during COVID-19 pandemic was retrospectively applied: HbA1c ≥5.7% (39 mmol/mol) and/or FPG level ≥5.1 mmol/l. SFD proposal sensitivity for HIP diagnosis and the occurrence of HIP-related events (preeclampsia, large for gestational age infant, shoulder dystocia or neonatal hypoglycaemia) in women with false negative (FN) and true positive (TP) HIP-diagnoses were evaluated.

Results: The sensitivity was 57% [95% confidence interval 52-62]. FN women had globally lower plasma glucose levels during OGTT, lower HbA1c and body mass index than those TP. The percentage of HIP-related events was similar in FN (who were cared) and TP cases, respectively 19.5 and 16.9% (p = 0.48). We observed similar results when women at high risk for HIP only were considered.

Conclusion: The SFD proposal has a poor sensitivity to detect HIP. Furthermore, it fails to have any advantages in predicting adverse outcomes.
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http://dx.doi.org/10.1016/j.diabres.2020.108640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834431PMC
February 2021

Glucocorticoids with low-dose anti-IL1 anakinra rescue in severe non-ICU COVID-19 infection: A cohort study.

PLoS One 2020 16;15(12):e0243961. Epub 2020 Dec 16.

Pulmonology Department, Kremlin-Bicêtre University Hospital, AP-HP, Paris-Saclay University, Kremlin-Bicêtre, France.

Background: The optimal treatment for patients with severe coronavirus-19 disease (COVID-19) and hyper-inflammation remains debated.

Material And Methods: A cohort study was designed to evaluate whether a therapeutic algorithm using steroids with or without interleukin-1 antagonist (anakinra) could prevent death/invasive ventilation. Patients with a ≥5-day evolution since symptoms onset, with hyper-inflammation (CRP≥50mg/L), requiring 3-5 L/min oxygen, received methylprednisolone alone. Patients needing ≥6 L/min received methylprednisolone + subcutaneous anakinra daily either frontline or in case clinical deterioration upon corticosteroids alone. Death rate and death or intensive care unit (ICU) invasive ventilation rate at Day 15, with Odds Ratio (OR) and 95% CIs, were determined according to logistic regression and propensity scores. A Bayesian analysis estimated the treatment effects.

Results: Of 108 consecutive patients, 70 patients received glucocorticoids alone. The control group comprised 63 patients receiving standard of care. In the corticosteroid±stanakinra group (n = 108), death rate was 20.4%, versus 30.2% in the controls, indicating a 30% relative decrease in death risk and a number of 10 patients to treat to avoid a death (p = 0.15). Using propensity scores a per-protocol analysis showed an OR for COVID-19-related death of 0.9 (95%CI [0.80-1.01], p = 0.067). On Bayesian analysis, the posterior probability of any mortality benefit with corticosteroids+/-anakinra was 87.5%, with a 7.8% probability of treatment-related harm. Pre-existing diabetes exacerbation occurred in 29 of 108 patients (26.9%).

Conclusion: In COVID-19 non-ICU inpatients at the cytokine release phase, corticosteroids with or without anakinra were associated with a 30% decrease of death risk on Day 15.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743937PMC
December 2020

Clinical Outcomes According to ECG Presentations in Infarct-Related Cardiogenic Shock in the Culprit Lesion Only PCI vs Multivessel PCI in Cardiogenic Shock Trial.

Chest 2021 04 26;159(4):1415-1425. Epub 2020 Nov 26.

ACTION Study Group, Institut de Cardiologie (AP-HP), INSERM UMRS_1166, Sorbonne Université, Paris. Electronic address:

Background: The impact of ECG presentations of acute myocardial infarction (AMI) in cardiogenic shock is unknown.

Research Question: In myocardial infarction with cardiogenic shock, is there a difference in the outcomes and effect of revascularization strategies between non-ST-segment elevation myocardial infarction (NSTEMI) and left bundle branch block myocardial infarction (LBBBMI) vs ST-segment elevation myocardial infarction (STEMI)?

Study Design And Methods: Cardiogenic shock patients from the CULPRIT-SHOCK trial with NSTEMI or LBBBMI were compared with STEMI patients for 30-day and 1-year all-cause mortality. The interaction between ECG presentation and the effect of revascularization strategies on outcomes was evaluated.

Results: Of 665 cardiogenic shock patients analyzed, 55.9% demonstrated STEMI, 29.3% demonstrated NSTEMI, and 14.7% demonstrated LBBBMI. Patients differed in mean age (68.0 years in STEMI patients, 71.0 years in NSTEMI patients, and 73.5 years in LBBBMI patients; P = .015), cardiovascular risk factors, and angiographic severity. No difference was found in the 30-day risk of death between NSTEMI and STEMI patients (48.7% vs 43.0%; adjusted OR [aOR], 1.05; 95% CI, 0.66-1.67; P = .85), nor between LBBBMI and STEMI patients (59.2% vs 43.0%; aOR, 1.31; 95% CI, 0.73-2.34; P = .36). Although the univariate risk of death by 1 year was higher in NSTEMI and LBBBMI patients compared with STEMI patients, ECG presentation was not an independent risk factor of mortality after adjustment (NSTEMI vs STEMI: 56.4% vs 46.8%; aOR, 1.21; 95% CI, 0.76-1.92; P = .42; LBBBMI vs STEMI: 69.4% vs 46.8%; aOR, 1.59; 95% CI, 0.89-2.84; P = .12). ECG presentation did not modify the effect of the revascularization strategy on 30-day and 1-year mortality (P = .91 and P = .97 for interaction).

Interpretation: In patients with cardiogenic shock, NSTEMI and LBBBMI presentations reflect higher-risk profiles than STEMI presentations, but are not independent risk factors of mortality. ECG presentations did not modify the treatment effect, supporting culprit-lesion-only percutaneous coronary intervention as the preferred strategy across the AMI spectrum.
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http://dx.doi.org/10.1016/j.chest.2020.10.089DOI Listing
April 2021
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