[Balancing drug regulation and health democracy: The role of patient and healthcare professional advisors at the ANSM]. / Concilier régulation du médicament et démocratie sanitaire : rôle des conseillers patient ou professionnel de santé à l'ANSM.

The French National Agency for Health Products (ANSM) is a regulatory and public health agency. Its regulatory, health policing and public health protection activities require a perfect fit with the field and the various people involved in the use of health products. Since 2019, the ANSM has adapted its organisation, procedures and processes to encourage and improve interaction with its stakeholders, as part of its policy of openness towards civil society. To accompany this ambitious change and to support its staff, the Agency has recruited advisors corresponding to the main users of health products: prescribers (doctor's hospital and outpatient), pharmacists and patients. Working as a group or individually, they provide a "lived" user perspective on health products at each stage of the evaluation process. They may be involved in the assessment of dossiers, signals or applications received by the Agency, in the internal validation of reports or in discussions with stakeholders. They are particularly involved when the analysis requires expertise that goes beyond the technical, scientific or regulatory aspects. They may also work with ANSM staff to explain certain processes and difficulties in the field. Advisors help to ensure that regulatory and/or scientific expertise is clear and consistent with user experience. In addition to their scientific and therapeutic aspects, medicines are also economic, social and political issues. Their regulation is therefore particularly affected by the need for health democracy. This requires the active participation of health professionals, patients and, more broadly, civil society in the decision-making process. Civil society is a space occupied by a wide range of actors who exert pressure from different ideological positions to influence the regulation of health products. In this context, taking into account a plurality of viewpoints in the regulation of health products is necessary and complex, but its operation can be facilitated by the collective efforts of the actors and the adaptation of organisations, such as the integration of advisors.

Early hyperoxia and 28-day mortality in patients on venoarterial ECMO support for refractory cardiogenic shock: a bicenter retrospective propensity score-weighted analysis.

BACKGROUND: The mortality rate for a patient with a refractory cardiogenic shock on venoarterial (VA) extracorporeal membrane oxygenation (ECMO) remains high, and hyperoxia might worsen this prognosis. The objective of the present study was to evaluate the association between hyperoxia and 28-day mortality in this setting. METHODS: We conducted a retrospective bicenter study in two French academic centers. The study population comprised adult patients admitted for refractory cardiogenic shock. The following arterial partial pressure of oxygen (PaO2) variables were recorded for 48 h following admission: the absolute peak PaO2 (the single highest value measured during the 48 h), the mean daily peak PaO2 (the mean of each day's peak values), the overall mean PaO2 (the mean of all values over 48 h), and the severity of hyperoxia (mild: PaO2 < 200 mmHg, moderate: PaO2 = 200-299 mmHg, severe: PaO2 ≥ 300 mmHg). The main outcome was the 28-day all-cause mortality. Inverse probability weighting (IPW) derived from propensity scores was used to reduce imbalances in baseline characteristics. RESULTS: From January 2013 to January 2020, 430 patients were included and assessed. The 28-day mortality rate was 43%. The mean daily peak, absolute peak, and overall mean PaO2 values were significantly higher in non-survivors than in survivors. In a multivariate logistic regression analysis, the mean daily peak PaO2, absolute peak PaO2, and overall mean PaO2 were independent predictors of 28-day mortality (adjusted odds ratio [95% confidence interval per 10 mmHg increment: 2.65 [1.79-6.07], 2.36 [1.67-4.82], and 2.85 [1.12-7.37], respectively). After IPW, high level of oxygen remained significantly associated with 28-day mortality (OR = 1.41 [1.01-2.08]; P = 0.041). CONCLUSIONS: High oxygen levels were associated with 28-day mortality in patients on VA-ECMO support for refractory cardiogenic shock. Our results confirm the need for large randomized controlled trials on this topic.

Neopulmonary Venous Confluence for Heart Transplantation With Giant Left Atrium.

Heart transplantation in a recipient with giant left atrium is rare. To correct the mismatch between recipient and donor at the level of the left atrium, plication of the left atrium has been proposed. We report a case in which plication was not feasible owing to significant calcification of the left atrial wall and tight pericardial adhesions resulting from two previous sternotomies. Creating a pulmonary venous confluence allows orthotopic heart transplantation with any size of left atrium and conformation of pulmonary veins in cases of significant calcification or redo sternotomy.

Central venous-to-arterial PCO2 difference, arteriovenous oxygen content and outcome after adult cardiac surgery with cardiopulmonary bypass: A prospective observational study.

BACKGROUND: Rapid identification and treatment of tissue hypoxia reaching anaerobiosis (dysoxia) may reduce organ failure and the occurrence of major postoperative complications (MPC) after cardiac surgery. The predictive ability of PCO2-based dysoxia biomarkers, central venous-to-arterial PCO2 difference (ΔPCO2) and ΔPCO2 to arteriovenous oxygen content difference ratio, is poorly studied in this setting. OBJECTIVES: We evaluated the ability of PCO2-based tissue dysoxia biomarkers, blood lactate concentration and central venous oxygen saturation measured 2 h after admission to the ICU as predictors of MPC. DESIGN: A prospective, observational cohort study. SETTING: Single-centre, academic hospital cardiovascular ICU. PATIENTS: We included adult patients undergoing cardiac surgery with cardiopulmonary bypass and measured dysoxia biomarkers at ICU admission, and after 2, 6 and 24 h. MAIN OUTCOME MEASURES: The primary endpoint was MPC, a composite of cardiac and noncardiac MPC evaluated in the 48 h following surgery. After univariate analysis of MPC covariates including dysoxia biomarkers measured at 2 h, multivariate logistic regression analyses were performed to identify the association of these biomarkers with MPC for confounders. Areas under the receiver operating characteristic curves were determined for biomarkers which remained independently associated with MPC. RESULTS: MPC occurred in 56.5% of the 308 patients analysed. ΔPCO2, blood lactate concentration and central venous oxygen saturation measured at 2 h, but not ΔPCO2 to arteriovenous oxygen content difference ratio, were significantly associated with MPC. However, only ΔPCO2 was independently associated with MPC after multivariate analysis. The areas under the receiver operating characteristic curves of ΔPCO2 measured at 2 h for MPC prediction was 0.64 (95% CI 0.57 to 0.70, P < 0.001). CONCLUSION: After cardiac surgery with cardiopulmonary bypass, ΔPCO2 measured 2 h after ICU admission was the only dysoxia biomarker independently associated with MPC, but with limited performance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03107572.

PCR-electrospray ionization time-of-flight mass spectrometry: a new tool for the diagnosis of infective endocarditis from heart valves.

A polymerase chain reaction with an injection of the amplicons in an electrospray ionization mass spectrometry (PCR-ESI-MS) technique was evaluated for the diagnosis of bacterial and yeast pathogens on 13 cardiac valves with suspected endocarditis. At the moment of surgery, 3/13 PCR-ESI-MS results matched with microbiological documentation. Nine PCR-ESI-MS results correlated with Duke's criteria, leukocytes, C-reactive protein and blood cultures before surgery. The PCR-ESI-MS result of the last valve failed to confirm the blood culture result obtained fifteen days before. With speed and accuracy, this method may be useful to assert microbiological identification and adapt treatment.

An unusual case of fatal pericarditis due to Listeria monocytogenes.

Pericarditis due to Listeria monocytogenes is a very uncommon and serious disease. We describe a case of fatal subacute pericarditis that was caused by L. monocytogenes in a 61-year-old woman with Hodgkin's disease who was diagnosed in 1975 and considered cured. In addition, we review the literature on this condition.

Rapid identification of Cardiobacterium hominis by MALDI-TOF mass spectrometry during infective endocarditis.

We report a new case of Cardiobacterium hominis endocarditis identified during an acute coronary syndrome. The positivity of the blood cultures was confirmed rapidly (50 h) as a result of improvements to the automated detection system, whereby it is no longer necessary to incubate the vials for long periods of time when Aggregatibacter-Cardiobacterium-Eikenella-Kingella infections is suspected. The phenotype-based VITEK 2 NH identification system is not able to distinguish between the two species of Cardiobacterium, as it does not contain C. valvarum in its library. The method for 16S rRNA gene sequence analysis is able to separate the two species but is not available in all laboratories. We used MALDI-TOF mass spectrometry, as an alternative, to rapidly distinguish between C. hominis and C. valvarum, because both species are contained in the system library.

First case of postaneurysmal prosthetic vascular infection due to a nonsuperantigenic Yersinia pseudotuberculosis strain.

Among Yersinia spp., Y. enterocolitica is the species most frequently isolated from infected aneurysms. This report describes the first case of postaneurysmal prosthetic vascular infection due to a superantigen-negative Yersinia pseudotuberculosis strain, showing a potential affinity of this species for endovascular tissue.

TEVAR in patients with late complications of aortic coarctation repair.

PURPOSE: To review the use of thoracic endovascular aortic repair (TEVAR) for late pseudoaneurysm formation after surgical repair of aortic coarctation. METHODS: From May 2001 to May 2005, 8 patients (5 men; mean age 47.6 years, range 18-73) with a history of aortic coarctation repairs 17 to 40 years prior were referred to our institution for an anastomotic thoracic pseudoaneurysm. TEVAR was performed successfully in 7 patients; 1 died of suspected aneurysm rupture before the scheduled procedure. A carotid-subclavian bypass was performed in 3 patients. RESULTS: All the procedures were immediately successful. No type I endoleaks were seen on the final control angiogram, but 2 of the patients with carotid-subclavian bypasses required additional left subclavian artery embolization due to type II endoleak. One of these patients died before embolotherapy on the 5th postoperative day from presumed aneurysm rupture (14% 30-day mortality rate). Over a follow-up period ranging from 15 to 72 months (mean 37), all the false aneurysms have remained thrombosed and the mean diameter has decreased from 44 to 23 mm. No endograft-related complications have occurred, and no further interventions have so far been necessary. CONCLUSION: TEVAR is a feasible alternative treatment for patients who have already undergone surgical repair of aortic coarctation. Technical issues regarding the endovascular strategy should be discussed with a multidisciplinary team to define the correct interventional plan.

Comparison of blood activation in the wound, active vent, and cardiopulmonary bypass circuit.

BACKGROUND: During cardiopulmonary bypass, aspirated blood exhibits strong activation features, but the triggering event remains unclear. Contact of blood with the pericardial cavity and surgical wound has been advocated as the main trigger, but suction forces are also considered as a possible contributor. We thus designed a study to identify the possible causes involved in this activation. METHODS: In 10 patients, we analyzed hemostasis activation markers and inflammatory mediators in blood collected in the pericardial cavity and in blood actively aspirated from the left ventricle without any contact with the pericardial cavity. In addition, the same variables were determined in blood sampled in the cardiopulmonary bypass circuit. RESULTS: Markers of tissue factor pathway activation and of thrombin generation, microparticles, free hemoglobin, interleukin 6, and tumor necrosis factor-alpha were significantly increased in pericardial samples as compared with the left ventricle and cardiopulmonary bypass circuit samples. All measured variables were similar between left ventricle and cardiopulmonary bypass samples, except free hemoglobin, interleukin 6, and microparticle levels, which were significantly higher in the left ventricle. CONCLUSIONS: Blood contact with the pericardial cavity induces strong hemolysis, inflammatory mediator release, and coagulation activation, driven by tissue factor pathway activation. By contrast, suction forces applied to left ventricular blood poorly contribute to blood trauma and activation. Comparison of pericardial and left ventricular blood shows that contact with the pericardial cavity, and not suction forces, is the leading cause of blood activation. The specific trigger for blood trauma and activation present in the pericardial cavity remains to be identified.

Results of endoluminal occlusion of the inferior vena cava during radical nephrectomy and thrombectomy.

BACKGROUND: The surgical management of renal tumours with thrombi in the inferior vena cava (IVC) has become the gold standard treatment. OBJECTIVE: To evaluate endoluminal occlusion of the IVC during radical nephrectomy with either retrohepatic (level II) or suprahepatic (level III) caval tumour thrombus. DESIGN, SETTING, AND PARTICIPANTS: From January 2000 to October 2007, 28 consecutive patients with renal cell carcinoma presenting a thrombus level II or III were treated with endoluminal occlusion of the free IVC cranial. SURGICAL PROCEDURE: The occlusion balloon was positioned under transesophageal echography (TEE) control through a cavotomy performed at the level of the renal vein ostium. Thrombectomy and radical nephrectomy were then performed. MEASUREMENTS: Operative time, perioperative bleeding, and pre- and postoperative complications were assessed. Overall patient survival time, disease-free survival, and development of metastasis were assessed. RESULTS AND LIMITATIONS: Caval thrombectomy was performed successfully in all patients. IVC replacement with an expanded polytetrafluoroethylene graft or patch closure after lateral cavectomy was performed in 10 and 4 patients, respectively. Average operative time was 160 min (range: 120-210). There was no perioperative mortality. The complications were one splenectomy and one early thrombosis of the IVC. Mean length of follow-up was 22.1 mo (range: 3-90). There was no local or IVC tumour recurrence. Cause-specific death and metastasis occurred in six (21.4%) and nine patients (32.1%), respectively. Thirteen patients (46.4%) are disease-free. CONCLUSIONS: Endoluminal occlusion of the IVC with TEE monitoring for level II and III thrombus avoided a suprahepatic or subdiaphragmatic approach of the IVC. Segmental resection and reconstruction of the IVC could also be performed in case of adherent thrombi.

Conservative surgical treatment for active infective tricuspid valve endocarditis according to the "clover technique".

AIMS: This prospective study was undertaken to analyze the outcomes of conservative surgery with the "clover technique" for active infective tricuspid valve endocarditis. METHODS: Five consecutive patients underwent surgery for active infective tricuspid valve endocarditis. The mean age was 36.6 years. Four of the patients were men. In all patients, the tricuspid valve had become mutilated and infected. One patient had associated mitral endocarditis, and one had aortic endocarditis. Staphylococcus aureus was the most common bacterial species. Conservative surgery was indicated in all patients with infection limited to the leaflets and/or subvalvular apparatus of the tricuspid valve. Total resection of infected tissues was achieved in all cases. The tricuspid valve was then reconstructed according to the clover technique. A tricuspid annular ring was used in 2 patients. RESULTS: All 5 patients survived surgery. Intraoperative transesophageal and predischarge transthoracic echocardiographic evaluations showed good results in all patients. The mean follow-up time was 26.4 +/- 12.5 months. No recurrent bacterial tricuspid endocarditis occurred during follow-up. All patients were in New York Heart Association functional class I. A transthoracic echocardiography evaluation at the latest control examination showed trivial leakage (3 patients) or no residual regurgitation (2 patients); no transvalvular gradient was found in any of the patients. No tricuspid valve calcification has been detected to date. Cardiac magnetic resonance imaging analyses showed no postoperative void flow and confirmed the preservation of right ventricular function and thus the reliability of this technique. CONCLUSIONS: This novel technique is indicated for tricuspid valve endocarditis and should be considered as an adequate approach in cases of uncontrollable infection involving the tricuspid valve that is responsible for extended valve destruction.

Chordal cutting VIA aortotomy in ischemic mitral regurgitation: surgical and echocardiographic study.

BACKGROUND: Chordal cutting through atriotomy has been proposed to treat significant resting ischemic mitral regurgitation (MR) due to anterior leaflet tenting. In addition, MR may exacerbate during exercise not only trough exercise-induced ischemia but also through an increase in tenting area. Accordingly, we aimed to perform chordal cutting through aortotomy in patients with exercise-induced ischemic worsening of MR. METHODS: Five patients with ischemic MR, due to anterior leaflet tenting, which worsened during exercise echocardiography were enrolled. All patients underwent cutting of the 2 basal chordae attached to the anterior mitral leaflet associated with myocardial revascularization. Three patients had additional mitral valve annuloplasty. Postoperative MR was evaluated using exercise echocardiography. RESULTS: Age ranged from 63 to 78 years and 4 patients were male. Preoperative LV ejection fraction averaged 39 +/- 3%. Chordal cutting was performed through aortotomy allowing comfortable access to the anterior mitral valve. Mitral effective regurgitant orifice at rest and at peak exercise was reduced by surgery (10 +/- 3 to 0.6 +/- 0.5 mm(2) at rest and from 20 +/- 3 to 6 +/- 2 mm(2) at peak exercise; p = 0.03). Mitral tenting area at rest and at peak exercise was concomitantly reduced by surgery (1.83 +/- 0.21 cm(2) to 0.50 +/- 0.4 cm(2) at rest and from 3.11 +/- 0.58 to 1.7 +/- 0.5 cm(2) at peak exercise; p = 0.03). Left ventricular size and function remained unchanged after surgery. CONCLUSIONS: Chordal cutting through aortotomy may be an effective option to treat ischemic MR due to anterior leaflet tenting. Associated with myocardial revascularization, it resulted in a decrease of MR at rest and during exercise through a decrease in tenting area without impairment of LV function.

Chordal cutting technique through aortotomy to treat chronic ischemic mitral regurgitation: surgical technique.

OBJECTIVE: To describe original surgical treatment in patients with ischemic mitral valve regurgitation due to tenting phenomenon. BACKGROUND: The optimal surgical treatment of ischemic mitral regurgitation (MR) in patients with coronary artery disease is controversial. The standard treatment is revascularization and reduction annuloplasty. We describe the first clinical application of an original technique to treat MR, through aortotomy. The chordal cutting technique was described first in experimental studies by Messas et al. METHODS: The procedure consisted in cutting the 2 strut chordae of the anterior mitral valve through a small aortotomy, using a brief conventional cardiopulmonary bypass. All the cases were controlled at the end of the procedure by transesophageal echocardiography (TEE). RESULTS: Five patients were treated using this technique; the procedure was brief, effective and safe in all the patients. TEE showed no mitral regurgitation. No preoperative morbidity or mortality occurred and post-operative course was uneventful. CONCLUSION: Chordal cutting technique through aortotomy is a safe and effective technique that should be considered to treat severe ischemic mitral regurgitation due to tenting phenomenon.

Extracorporeal membrane oxygenation in severe acute respiratory failure in postpartum woman with rheumatic mitral valve disease: benefit, factors furthering the success of this procedure, and review of the literature.

Pregnancy is a common decompensation factor for women with post-rheumatic mitral disease. However, valvular heart diseases causing severe acute respiratory distress are rare. Use of extracorporeal membrane oxygenation (ECMO) early in the event of cardiorespiratory failure after cardiac surgery may be of benefit. Indeed, ECMO cardiopulmonary bypass (CPB) support could help pulmonary recovery if the mitral pathology is involved. A 31-year-old female patient at 30 weeks of amenorrhea was admitted to the obstetrics department with 40 degrees C hyperthermia and New York Heart Association (NYHA) class 4 dyspnea. The patient's medical history included a post-rheumatic mitral stenosis. Blood gases showed severe hypoxemia associated with hypocapnia. The patient needed to be rapidly intubated and was placed on ventilatory support because of acute respiratory failure. Transesophageal echocardiography showed a severe mitral stenosis, mild mitral insufficiency, and diminished left ventricular function, hypokinetic, dilated right ventricle, and a severe tricuspid regurgitation. An urgent cesarean section was performed. Because of the persistent hemodynamic instability, a mitral valvular replacement and tricuspid valve annuloplasty were performed. In view of the preoperative acute respiratory distress, we decided, at the beginning of the operation, to carry on circulatory support with oxygenation through an ECMO-type CPB at the end of the operation. This decision was totally justified by the unfeasible CPB weaning off. ECMO use led to an efficient hemodynamic state without inotropic drug support. The surgical post-operative course was uneventful. Early use of cardiorespiratory support with veno-arterial ECMO allows pulmonary and right heart recovery after cardiac surgery, thus avoiding the use of inotropic drugs and complex ventilatory support.

In vivo autologous recellularization of a tissue-engineered heart valve: are bone marrow mesenchymal stem cells the best candidates?

OBJECTIVE: Bone marrow stem cells, especially the mesenchymal stem cell subpopulation, have been used to create in vitro tissue-engineered heart valves. We hypothesized that autologous bone marrow cells, injected in a decellularized porcine scaffold before surgical implantation, could promote in vivo recolonization and limit valve deterioration. We thus analyzed the effects of in situ injection of autologous bone marrow mononuclear cells and of mesenchymal stem cells on the outcome of xenogenic decellularized scaffolds in a lamb model. METHODS: Decellularized porcine pulmonary valves were implanted in the pulmonary artery under cardiopulmonary bypass in 14 lambs after injection in the scaffold of autologous bone marrow mononuclear cells (BMMC) group (n = 7) or of mesenchymal stem cells (MSC) group (n = 7). At 4 months, valve function was evaluated by echocardiography, and valves were explanted for macroscopic and histologic analysis. RESULTS: Mean transvalvular and distal gradients (millimeters of mercury) were lower in the MSC than those in the BMMC group (1.3 +/- 0.39 vs 4.24 +/- 0.91 and 4.05 +/- 1.89 vs 12.02 +/- 6.95, respectively; P < .02). Histologic examination showed significant recolonization and re-endothelialization in both groups. However, significant valve thickening and inflammatory cell infiltration were observed in the BMMC group. By contrast, valves from the MSC group displayed extracellular matrix and cell disposition close to those of native pulmonary valves. CONCLUSIONS: Tissue-engineered heart valves created from mesenchymal stem cells, injected directly in a decellularized xenograft scaffold, exhibited satisfactory hemodynamic and histologic aspects after 4 months. Further long-term studies are needed to demonstrate the potential of mesenchymal stem cells for clinical application in heart valve surgery.

A case of mitral endocarditis due to Campylobacter fetus subsp. fetus.

This report describes a patient presenting mitral native endocarditis due to Campylobacter fetus subsp. fetus, which was revealed by syncope and identified using 16S ribosomal RNA gene sequencing. This gene sequencing method has become the preferred approach to identifying the new emerging pathogens when discrepancies exist between phenotypical tests.