Praha%2525252525208%252525252520liben, Czech Republic

Tuberculosis Cohort Avicenne Hospital

Globally, an estimated 10.0 million cases and 1.4 million deaths of tuberculosis diseases (TB) were reported in 2019. Despite a rate of latent tuberculosis estimated at 23% of the world population, there are very large disparities in incidence between continents and countries with an incidence of less than 10 cases per 100,000 inhabitants in Western Europe to more than 500/100,000 for countries like South Africa, the Philippines or Mozambique. Alt-hough the European Region accounted only for 2.5% of all cases, TB remains a common in-fection in immigration and poor areas. The overall objective of the WHO by 2035 (The End TB strategy) is to reduce the number of deaths from TB by 95% (compared to 2015) and to reduce the incidence rate of TB by 90% to less than 10/100,000 people. In France, there is a national notification rate of 7.6/100,000 but the North of Paris is the area of France with the highest incidence of tuberculosis (25.9/100,000 for 2016-2018). The decreasing notification rates observed in most countries are reassuring, but annual rates of decline are still insufficient to achieve the WHO target of TB elimination by 2050 in European low-incidence countries. TB control requires the early detection and treatment of patients, and investigation of potentially exposed contacts. These measures can prevent ongoing transmission of the infection and the development of drug resistance. Therefore, surveillance of TB treatment outcomes is also of great importance when evaluating TB programs. Since 2014, the target set by WHO is 90% of treatment success among new sputum smear-positive TB cases. In 2017, 30 of 31 EU/EEA countries notified TB 55,337 TB cases. Only two-thirds (67.6%) were treated successfully, and 7% died during TB treatment. Indeed, treatment outcome monitoring (TOM) is part of mandatory notification in France since 2007, with treatment outcome forms completed by clinician at 1 year. Unfortunately, in France, the available information on treatment outcome is limited by frequent missing data with only 64.8% of treatment outcomes files completed in 2018. Furthermore, thorough knowledge of a specific country's TB disease epidemiology is essential to map out a comprehensive national strategic plan for TB and could help identify determinants for unfavorable treatment outcome or loss to follow-up. The healthcare pathway of patients with tuberculosis presents glaring shortcomings with a large proportion of treatment outcomes unknown, including a large number of loss of follow-up resulting in secondary transmissions, recurrences of tuberculosis and emergence of resistance. Unknown treatment outcomes correspond to unspecified treatment outcomes 12 months from the start of treatment (lost to follow-up, transfer, absence of information). Health actors must mobilize to better understand the characteristics of patients with incomplete treatment outcomes and provide solutions to achieve better control of tuberculosis in our region. We also want to assess the relationship between plasma concentrations of major anti-TB drugs (rifampicin and isoniazid) and treatment outcomes. We propose to constitute for the first time in France a cohort of patients with tuberculosis disease in order to meet these objectives. The princeps study would recruit 75 patients per year for 4 years associated with 1 year of follow-up for a total duration of the study estimated at 5 years.By setting up a prospective cohort study of patients with tuberculosis disease in northern Paris, we aim to assess tuberculosis treatment outcomes and their determinants in the area with the metropolitan French highest TB incidence. At the same time, we want to evaluate the socio-demographic and clinical characteristics of our patients as well as the relationship between plasma concentrations of major anti-tuberculosis drugs (rifampicin and isoniazid) and treatment outcomes. Methods Study population and data collection An observational, prospective, monocentric cohort study of adult patients treated for TB disease will be carried out in 1 centre in the north of Paris: the department of infectious diseases and respiratory medicine of Avicenne hospital (Bobigny). Sociodemographic, physical, biological, and radiological data will be collected for patients meeting the inclusion criteria according to the study schedule: day 0 (D0), D15, month 1 (M1), M2, M6 and M12. The primary endpoint will be an unfavorable treatment outcome at 12 months. The categories of treatment outcomes were defined by adapting European and WHO recommendations to the French context. A patient who completed treatment within 12 months was considered to have favorable treatment outcome even if he did not attend the visit at M12. The secondary endpoints will include socioeconomic and clinical characteristics of TB cases, and rifampicin and isoniazid pharmacokinetic. The inclusion criteria are TB out- or in-patient newly treated in one of the inclusion center for pulmonary or extra-pulmonary TB confirmed bacteriologically (direct examination, Gen-eXpert MTB/RIF and/or positive culture), suggestive histology (epithelioid gigantocellular granuloma with or without caseous necrosis), or strong clinical suspicion of tuberculosis not yet biologically confirmed but with a decision to introduce treatment. The non-inclusion criteria are: opposition to participate in the study, anti-tuberculosis treatment for more than 7 days at the inclusion visit and participation in another research protocol. Data collected on inclusion will be: demographic, social and professional data (sex, age, country of birth, date of arrival in France, stay in a foreign country in the last 2 years, family situ-ation, profession, domiciliation, health insurance coverage, languages spoken, co-infections, clinical history, addictions (tobacco, alcohol, drugs), WHO performance status, clinical data (co-infections, WHO performance status, history of tuberculosis, tuberculosis location, presence of cough, fever, sweating nocturnal, diagnostic context), biological, microbiological and radiological data for monitoring the treatment and its tolerance. Pharmacokinetic data will be also collected on Day 15 from the start of treatment with peak dosing of rifampicin and isoniazid 3 hours after taking the treatment. The follow-up for each patient will last 12 months. Data will be entered into an electronic data capture system. Statistical analysis Qualitative variables will be described as frequency (%) and quantitative variables as median and interquartile range (IQR). Treatment outcome at 1 year and associated socioeconomic and clinical factors will be studied by multivariate analysis. Univariate and multivariate analyses will be performed using logistic regression. All statistical tests will be based on two-tailed p values, with p<0.05 considered to indicate statistical significance. Associations will be expressed using crude and adjusted Odds ratios with 95% Confidence Intervals. In our final model, we will include all statistically significant after a backward selection using a threshold of 0.20 for the p-value. All analyses will be performed using RStudio statistical software (Version 1.4.869 © 2009-2020 RStudio, Inc).

Optimisation Strategy for Emergency Tracheal Intubation

Several studies have reported positive impact of some interventions on the tracheal intubation-related complications incidence. Providing bag face-mask ventilation between medication administration and initiation of laryngoscopy significantly reduced the number of peri intubation hypoxemia episodes. The use of a non-depolarizing (rocuronium) paralytic agent instead of succinylcholine is associated with less post-intubation complications occurrence. Finally, use of a tracheal tube introducer (GEB) as an aid for intubation in emergency patients with at least one prognostic factor of difficult laryngoscopy has been shown to facilitate intubation. Assessment of a strategy combining these three interventions to reduce intubation related morbidity in emergency situations has never been assessed. It is expected that the combination of these interventions will drastically reduce the morbidity associated with emergency intubation. The strategy assessed will associate rocuronium use as paralyzing agent to facilitate intubation, bag mask ventilation before intubation and GEB use at first intubation attempt in all patients. The emergency physician in charge of the patients will record out-of hospital outcomes immediately after the out-of-hospital period. Intra-hospital data will be retrieved from the patient's medical record on the 28th day after inclusion.

Sulfasalazine in AML Treated by Intensive Chemotherapy: Elderly Patients-first Line Treatment

French Observational Study of Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in Real-World Settings

Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in the Western World. The disease is characterized by the accumulation and proliferation of mature, monoclonal, CD5+ B-cells with specific immunophenotype in the peripheral blood (above 5x109/L), bone marrow and secondary lymphoid organs. Small lymphocytic leukemia (SLL) is characterized by similar tumor cells but without increased lymphocyte count. In Europe, CLL has been identified as the second most frequent hematological malignancies after multiple myeloma (Eurocare 5 study) and its standardized incidence in the world has been estimated to be 4/100000 person-years for men and 2.1/100000 person-years for women. In France, 4674 new cases have been observed in 2018 (FRANCIM). A proportion of patients can initially be monitored only while others with symptomatic disease at diagnosis or during follow-up require therapies. The management of these patients have considerably changed over the last decade. Indeed, beyond chemo-immunotherapy, multiple targeted therapies have been approved on the basis of phase 2 and randomized phase 3 clinical trials and have subsequently been used in daily practice. The management of patients with SLL is similar to that of those with CLL. In addition to therapeutic advances, the advent of new sequencing technologies has also identified CLL genetic features that are now being incorporated in patient routine evaluation. Conventional chemo-immunotherapy (CIT) has been the long-standing option for CLL patient without TP53 disruption and different regimens have emerged depending on patient comorbidities (fludarabine-cyclophosphamide-rituximab, FCR; bendamustin-rituximab, BR; GA101-chloraminophene, G-CLB). These regimens fail to be effective in patients with TP53 disruption and alternative strategies are proposed for them. The CLL therapeutic panel is now enriched by oral kinase inhibitors targeting the B-cell receptor signaling. The Bruton's tyrosine kinase inhibitors (BTKi) have been shown to provide prolonged response, even in cases where CIT usually failed, such as patients harboring TP53 disruption. In relapsed/refractory patients, median PFS with the BTKi ibrutinib is 44 months. In the frontline setting, ibrutinib has recently been shown to result in superior PFS and less infectious complications than standard CIT regimens. The advent of the BCL2 (B-cell lymphoma 2) inhibitor venetoclax has recently added another option for the treatment of CLL patients. BCL2 is an antiapoptotic molecule governing mitochondrial apoptosis and is strongly expressed in CLL cells. Inhibiting BCL2 with venetoclax as monotherapy led to 79% response rate in the relapse/refractory setting. Combining venetoclax to rituximab demonstrated better PFS than bendamustine-rituximab in relapsed/refractory patients. However, these treatment approaches also come with new challenges that are difficult to-address in phase 3 clinical trials and that deserve larger scale studies and longer follow-up. The emergence of drug resistance, the changes of safety profiles to deal with in routine practice and the observance of these orally administered drugs are emerging as new concerns. How these compounds change the incidence of typical CLL complication such as Richter transformation, immune cytopenias and infections remains to be determined. A growing body of concerns is also raising regarding the unlimited administration of some of this the compounds (costs, resistance, tolerance). Finally, the optimal order of use of these drugs is unknown. The advent of the BCL2 (B-cell lymphoma 2) inhibitor venetoclax has recently added another option for the treatment of CLL patients 11,12. BCL2 is an antiapoptotic molecule governing mitochondrial apoptosis and is strongly expressed in CLL cells. Inhibiting BCL2 with venetoclax as monotherapy led to 79% response rate in the relapse/refractory setting. Combining venetoclax to rituximab demonstrated better PFS than bendamustine-rituximab in relapsed/refractory patients12. However, these treatment approaches also come with new challenges that are difficult to-address in phase 3 clinical trials and that deserve larger scale studies and longer follow-up. The emergence of drug resistance, the changes of safety profiles to deal with in routine practice and the observance of these orally administered drugs are emerging as new concerns. How these compounds change the incidence of typical CLL complication such as Richter transformation, immune cytopenias and infections remains to be determined. A growing body of concerns is also raising regarding the unlimited administration of some of this the compounds (costs, resistance, tolerance). Finally, the optimal order of use of these drugs is unknown. Primary objective : Setting a prospective cohort of real-world CLL/SLL patients with symptomatic disease in order to evaluate medical practices and their change and representativity over time. Secondary objectives : Overall survival and long-term toxicity, Response and PFS at each line of therapy, Impact of therapeutic trajectories on patient outcome, Representativity of the studied population

Testing Immunotherapy for Patients With Liver Cancer and Moderately Altered Liver Functions

The primary objective is to assess efficacy of anti-PD1 (in terms of Objective Response Rate [ORR] based on Best Overall Response across all time-points as defined by RECIST v1.1) in the Child-Pugh B / ALBI grade 1/2 population. Secondary objectives are : - To assess safety of anti-PD-1 - To assess efficacy in terms of: - Objective Response Rate based on best overall response across all time-point according to mRECIST and iRECIST tumor response evaluation - Overall survival (OS) - Progression-free survival (PFS) - Time to progression (TTP) - To assess Quality of Life according to EORTC QLQ-C30 and HCC-18. In order to confirm the eligibility of patients, a clinical examination, biological blood tests, ECG, CT scan and a urine or blood pregnancy test for women of childbearing age will be performed. A quality of life questionnaire will be administered to patients. Patients will also be asked to agree to a full eye examination by an ophthalmologist prior to the start of treatment to determine that there is no risk of worsening the patient's visual acuity with treatment with tislelizumab. After enrolment in the study, the patient will be required to visit the hospital every 3 weeks to receive intravenous treatment for up to 2 years. Once the treatment is completed, the patient will be seen at follow-up visits for 2 years, initially every 3 months for the first year and then every 6 months for the second year. Assessment of tumour response by CT or MRI will be done after the start of treatment at weeks 9, 18, 27, 54 and every 12 weeks until disease progression and throughout the treatment period. Tumour assessment by CT or MRI will be performed 2 years after the start of treatment or upon disease progression. Patients will be asked to consent to the use of a collected tumour sample, as well as to the collection of blood samples, for future scientific research which includes, but is not limited to, the detection of DNA, RNA and protein biomarkers. An independent Study Monitoring Board (DSMB), with expertise and experience in the pathology, and without direct involvement in the conduct of the study, will be set up specifically to ensure optimal safety monitoring during the early phase of the study and the feasibility of at least 2 treatment injections (6 weeks from inclusion), an early stopping rule has been defined for the first 20 patients included. This method was chosen for the evaluation of serious adverse events (SAEs), which may occur relatively early in this trial. A high frequency of occurrence may necessitate early termination of the trial.

Effect of Imipenem and Meropenem on the Digestive Microbiota and the Emergence and Carriage of Multidrug-resistant Bacteria

Assessment of HIV Remission Upon cART Interruption in Early Treated Individuals Carrying the MHC B35/53Bw4TTC2 Genotype

The ANRS 175 RHIVIERA 01 trial will focus on people who were initiated early and have a particular genotypic profile associated with HIV remission. The study proposes to test an intervention consisting in a ART-treatment interruption (of at least 6 months) in ANRS CO6 PRIMO cohort participants carrying the MHC B35/53Bw4TTC2 genotype and well controlled on cART. The study aims to enrol 20-30 participants in 30 French clinical sites. Participants will be enrolled after checking eligibility criteria and will interrupt ART immediatly after inclusion. Control of HIV-Infection, defined by a viral load less than 400 cp/mL, will be evaluated after 24 weeks of interruption. Study duration will vary by participant, depending on the time of ART interruption and the time to viral rebound. Participants will be followed maximum 48 weeks on ATI. If there is a viral rebound justifying the resumption of ART, participant will be followed 24 weeks maximum after resumption. The maximum duration of the study will be 48+24 = 72 weeks.

Study of Teclistamab in Combination in Elderly Patients With Multiple Myeloma

Validation of the Dual-isotope Method for Measuring Ileal Protein Digestibility

The test meal will consist of 60 g of lyophilized whole egg powder which contains 30 g of 2H-egg protein and 800 mg [U-13C]-spirulina or 400 mg of 13C free AA mixture, mixed with water and cooked as an omelet. The 2H-egg powder has been produced by our collaborators of the St John's Research Institute in Bangalore (India). Celite (acid insoluble ash, Advanced Minerals Corporation) will be added to the meal as an indigestible marker to check the recovery of the meal in effluents. The test-meal will be given as a bolus or in a plateau feeding (repeated mini-meals) depending of the groups of subjects. 600 g of 2H-labeled lyophilized eggs will be obtained from layer hens administered a uniformly 2H-labeled AA mix orally for 60 d with their daily feed. Microbiological analyses will be performed to ensure their safety for human consumption. 18 volunteers will be included at the end of the study and tested at the Human Nutrition Research Centre of Avicenne Hospital (France). The main inclusion criteria are men and women, 18 to 45 year-old, body mass index (BMI) 18 to 30 kg/m2. The main exclusion criteria are any digestive or hepatic pathology, allergy against eggs, allergy against latex, pregnant women. Due to the invasive procedure of intubation, the investigators plan to recruit 30 volunteers to accommodate for the usual 40% dropouts. The subjects will be divided in 3 groups of n = 6: - Bolus-spi, n = 6, the volunteers will consume the test-meal as a bolus in one time at t = 0, with 13C-spirulina as the reference protein - Plateau-spi, n = 6, the volunteers will consume the test-meal in a plateau feeding protocol, with 13C-spirulina as the reference protein - Plateau-AA, n = 6, the volunteers will consume the test-meal in a plateau feeding protocol, with 13C-free AA mixture as the reference "protein" One week before the experiment, the volunteers will follow a standard diet adapted to their body weight to control their protein intake (1.3 g protein/kg body weight). The volunteers will arrive at the Human Nutrition Research Centre of Avicenne Hospital on the morning before the day of the experiment. They will be equipped with a triple lumen intestinal tube that will be allowed to progress through the intestinal tract for 24 h. One of the lumen is radio opaque and serves to perfuse a non-absorbable maker in the intestine (slow marker method). The second lumen is dedicated to inflate a weighted balloon that facilitate the migration of the tube. The third lumen is dedicated to the continuous aspiration of the effluents, 15 cm below the perfusion site. The measurement of the non-absorbable marker in the effluents allows the determination of the effluent flow rate. On the day of the experiment, the position of the tube will be checked by radiography to verify its location at the terminal ileum. A catheter will be inserted in the forearm vein for blood sampling. The perfusion of the non-absorbable marker, polyethylene glycol (PEG) 4000 (20 g/l), will start at a flow rate of 1 ml/min. The intestinal flow and the basal ileal sample will be collected during 30 min. Basal plasma and urine sample will be collected. At t = 0, the volunteers of the group "Bolus-spi" will consume all the test-meal in less the 20 min. For the volunteers of the groups "Plateau-spi" and "Plateau-AA", the test-meal will be divided into 22 equal portions and they will consume the first meal as a priming dose of 6 mini-portions. Then, they will consume single mini-portions every 30 min for 7.5 h. One portion will be dedicated to meal analyses. Until t = 8, intestinal content will be continuously collected by aspiration and pooled every 30 min. Blood will be sampled hourly during 4 h and every 30 min from t = 5 to t = 8. Urine will be collected every 2 h until t=8 (total volume of urine output will be noted at each time point for proportional pooling). Breath samples will be collected every 30 min. Carbon dioxide output (VCO2) will be evaluated hourly during 10 min by indirect calorimetry (Canopy). Urine sample will be collected at the start of the experiment and during the study protocol. Fecal samples will be collected before the start of the experiment and within the next 24 h. The naso-ileal tube will be removed after the last collection of effluent at t = 8.The naso-ileal tube will be removed after the last collection of effluent at t=8. The following analyses will be performed: - Concentration of PEG-4000 by turbidimetric method in digesta samples - Total hydrogen content and 2H enrichment in meals and digesta samples by isotope-ratio mass spectrometry (IRMS) coupled to pyrolysis analyzer - Total carbon content and 13C enrichment in meals and digesta samples by Elemental analyzer (EA) coupled to IRMS - AA concentration in meals and digesta samples by Ultra High Performance Liquid Chromatography (UHPLC) - 13C-AA and 2H-AA enrichment plasma and meal samples by Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS) - 13C-AA and 2H-AA enrichment in digesta and meal samples by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) - Celite content in pooled (0-8 h) digesta samples - 13CO2 in breath sample by Multiflow-IRMS - Amino-acidome and peptidome of digesta, plasma, urine, and fecal samples Part of the analyses (13C-AA and 2H-AA enrichment plasma and meal by LC-MS/MS, -omic analyses) will be done by our collaborators of the St John's Research Institute in Bangalore (India).

Thirst in the Intensive Care Unit, Recognition, Sensitivity and Type

Thirst was reported in 70% of symptom assessments of intensive care patients. Thirst is a major source of physical discomfort. This should make it a concern for clinicians and ICU nurses whose mission is to alleviate symptoms in addition to treating pathology. Balancing extracellular and intracellular volume is a goal in the poorly communicating patient with no spontaneous access to water. Thirst may exist, persist, reappear, or increase again after the institution of water intake; it may reveal changes in the intra/extra sector or inappropriate intakes. Thirst could therefore be useful as a clinical management tool. However, it has not been studied to any great extent in mechanically ventilated patients. Neglecting thirst in these circumstances is bound to cause suffering. This neglect may also offset the physiological benefits in terms of clinical outcomes. It could also have a negative impact at a distance through negative memories. Nevertheless, thirst is not routinely assessed in ICU patients, except after extubation when the patient has access to spontaneous hydration. Mechanically ventilated patients have multiple causes of thirst and dry mouth and at the same time have difficulty communicating and limited access to water. It is essential to study thirst in this population. In particular, determining the prevalence of thirst in this population would raise awareness of its screening. Finally, understanding the main mechanisms involved in thirst in patients undergoing invasive mechanical ventilation would allow the development of therapeutic solutions to minimize it. In this context, the investigators wish to conduct a prospective observational study in mechanically ventilated patients able to communicate in order to better understand the prevalence, intensity, mechanisms and prognostic value of thirst as well as the sensation of dry mouth. They will also focus on the relationship of thirst with dyspnea, anxiety and pain. Description of the study population and rationale for its selection The management of thirst is usually ensured by free access to water and balancing the patient's extracellular volume. In the mechanically ventilated patient, this management is made more difficult by many factors: lack of free access to water, difficulty in communication, sensation of dry mouth induced by the mechanical ventilation device. The population studied corresponds to patients under invasive mechanical ventilation in three intensive care units of university hospitals: Pitié Salpêtrière intensive care medicine unit, Avicenne hospital intensive care medicine unit, and Saint-Louis hospital intensive care medicine unit. Justification of the duration of the research The objective would be to include 200 patients at a rate of approximately 66 patients per service. Eligibility criteria Recruitment will consist in considering any patient under mechanical ventilation and communicating as potentially eligible, provided that they meet the inclusion/non-inclusion criteria. Conduct of the research During the study period, patients from the 3 resuscitation sites are systematically screened for inclusion in the study on a daily basis, between 9:00 am and 12:00 pm. Subjects meeting the inclusion and non-inclusion criteria will be informed of the study by the principal investigator or any other investigator trained and declared in the research. The oral information will be supplemented by an information note. Patients who wish to participate in the study will be given up to 24 hours to consider their decision. If the patient agrees to participate in the study, his or her non-opposition is collected by the investigator on a dedicated form in duplicate. One copy will be given to the patient, and the other will be kept in the department with the research documents. In case of suspected confusion, a delirium screening test (CAM-ICU) will be performed to verify the patient's eligibility. If the test confirms the presence of confusion, the patient will be excluded from the study. The information and the collection of the non-opposition will be notified in the patient's medical file. Once recruited, patients are asked to rate the intensity of thirst by placing a cursor on a 100 mm visual analog scale (VAS) bounded on the left by "not thirsty" and on the right by "intolerably thirsty". If a patient understands the principle of the assessment but is unable to move the VAS cursor himself, the observer assists the patient by holding the scale and supporting the patient's forearm. If the subject is unable to move his or her arms (as in some cases of severe neuromuscular impairment), the observers are allowed to manipulate the VAS slider by following the patient's instructions. However, this is not recommended and should be avoided whenever possible. The slider should never be adjusted directly or solely by the investigator. Visual analog scales for dry mouth, anxiety, pain, and dyspnea will be performed as part of the protocol after the thirst assessment. The oral status, the search for edema or skin folds and the Revised Oral Assessment Guide (ROAG) score for intubated patients will also be performed at the same time. Follow-up of the population The included patients are evaluated only once during their stay in the ICU: the day of inclusion. The duration of their participation is estimated at 20 minutes. Conduct in the presence of thirst in the patient In the event that the patient is thirsty, the investigator will immediately inform the patient's physician.