Pérenchies, France

A Study to Learn About How Safe BAY 3389934 is, Its Suitable Dose, and How it Affects the Participants With Sepsis Induced Coagulopathy

Impact of an Early and Extended Rehabilitation Program Combining Individually Tailored Nutrition and Physical Activities on Patient Outcomes After Invasive Mechanical Ventilation and Vasopressor Therapy in the ICU

Antimicrobial Therapy for Difficult-to-treat Pseudomonas Aeruginosa

Infections due to Pseudomonas aeruginosa isolates with acquired resistances to all first-line antipseudomonal beta-lactams and fluoroquinolones (difficult-to-treat isolates - DTR), pose serious therapeutical challenges, especially in critically ill and/or immunocompromised patients. Certain new beta-lactam/beta-lactamase inhibitor combinations (BL/BLI (beta lactamine/ beta lactamase inhibitor) - i.e., ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, others) and cefiderocol have shown promising results for the treatment of infections due to DTR P. aeruginosa. However, multicenter data on their real-life utilization in this indication are still scarce. The ADDICT study is a prospective, multicenter cohort study including unselected patients with DTR P. aeruginosa infection requiring definite intravenous antimicrobial therapy. The primary objective of the study is to investigate the clinical efficacy of available options (new BL/BLI, cefiderocol or older agents such as aminoglycosides and colistin) in this population. Secondary objectives are to compare the clinical and microbiological efficacy of available options in infections due to DTR P. aeruginosa with in vitro susceptibility to more than one last-resort drug, to compare the incidence of non-ecological adverse events observed with these drugs, to assess the incidence of resistance emergence under therapy and to elucidate the molecular mechanisms of resistance emergence, to assess the benefits and risks of combination therapy in this indication, to compare the acquisition rates of multidrug-resistant bacteria other than DTR P. aeruginosa, and Clostridioides difficile infection, to compare Day-28 and in-hospital all-cause mortality rates. Patients will be recruited in 60 hospital centers contributing to four French networks of research in infectious diseases and critical care (CRICS-TRIGGERSEP, ReaRezo, OutcomeRéa, RENARCI - PROMISE metanetwork). Clinical variables will be collected through an electronic case-report form. DTR P. aeruginosa isolates will be sent to the National Reference Center of Antimicrobial Resistance in P. aeruginosa for centralized analyses (extended antimicrobial susceptibility testing, MLST, whole-genome sequencing of successive isolates if resistance emergence under therapy).

Sudden Cardiac Arrest Related to Sport in Young and Value of the Genetic Assessment: a French Prospective Register

Background: The beneficial effects of moderate physical activity on health are well-established. However, it is also well-proven that intense sports participation increases the risk of cardiovascular events by 2.4 to 4.5 times before the age of 35 in individuals with known or unknown heart conditions. Sudden cardiac arrest (SCA), sometimes leading to sudden cardiac death (SCD), is the most dramatic event linked to sports. Before the age of 35, sports-related SCA/SCD is rare, occurring in 0.7 to 2.7 per 100,000 athletes, which amounts to approximately 80 cases per year according to two French prospective studies. Despite its rarity, these events are often traumatic and highly publicized, presenting a significant public health and safety concern. Non-traumatic sports-related SCA/SCD is primarily of cardiovascular origin, irrespective of the level of sports participation. In most cases, SCA results from ventricular arrhythmia caused by known or undiagnosed arrhythmogenic cardiovascular disease, which varies by the victim's age. After the age of 35, atheromatous coronary artery disease accounts for 80-85% of cases. However, before the age of 35, a wider range of etiologies are observed. Arrhythmogenic genetic heart diseases-structural (e.g., arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy) or non-structural (e.g., channelopathies)-are the most frequent causes. Congenital abnormalities, particularly anomalous connection of coronary artery, represent the second most common cause. Acquired heart diseases, such as fibrous scars (mainly post-myocarditis) and atheromatous coronary lesions, are less frequently involved. In this younger population, classical autopsy often fails to determine the cause in more than 40% of cases, leading to the term "sudden arrhythmic syndrome". Few prospective studies have combined classical autopsy with systematic genetic analysis to identify the cause of SCA/SCD in the general young population, with no specific link to sports. One Australian study demonstrated the value of genetic testing, identifying a "clinically relevant" cardiac genetic variant for sudden death in 27% of cases. Moreover, the same pathology was identified in 13% of relatives of the victims who underwent clinical and genetic screening. Another small Swedish study (n=15), focusing specifically on channelopathies in cases of negative autopsies, revealed the disease in 40% of victims' families through genetic analysis. Additionally, the role of acute or chronic toxic substance intake has been suggested, albeit without formal proof, as a factor promoting sports-related SCA/SCD. Toxicological screening is thus recommended as part of the etiological assessment. Including toxicological analysis alongside other etiological evaluations could help clarify the impact of illicit substances on sports-related SCA/SCD. Justifications for the Study: No prospective study has systematically combined the recommended hospital assessment in cases of successful resuscitation or the recommended medical autopsy in the event of death with global genetic and toxicological analyses in victims of sports-related SCA/SCD. This combined approach is justified for several reasons. First, it would enhance our understanding of the etiologies of these events. Notably, so-called idiopathic left ventricular hypertrophy is found in more than 10% of sports-related SCD cases following classical autopsies. Further genetic exploration could help determine whether these anatomical forms are pathological. Additionally, many arrhythmic cardiac diseases are associated with an elevated risk of sports-related SCA/SCD. While arrhythmogenic right ventricular cardiomyopathy is well-documented, other forms of disease are characterized by areas of fibrosis or fatty infiltration in the myocardium, often due to genetic mutations affecting intercellular desmosomes. Comprehensive genetic testing, including whole exome sequencing, could clarify the contribution of various arrhythmogenic heart diseases to unexplained sports-related SCA/SCD. Improving this knowledge will benefit ongoing discussions about enhancing the content and effectiveness of pre-participation screening for athletes. Moreover, identifying the cause of SCA/SCD is critical for the victims and their families. Understanding the cause may help families come to terms with the event and assist in preventing recurrence for successfully resuscitated individuals. Furthermore, since most hereditary heart diseases follow an autosomal dominant inheritance pattern, each first-degree relative has a 50% chance of carrying the same genetic mutation. Predictive testing, clinical assessment, and, if necessary, preventive treatment can be offered to these family members to reduce the risk of arrhythmic events. Statistical Analysis: Data analyses will be performed using specialized software, with a significance threshold set at 5%. Hypotheses will be formulated bilaterally. A descriptive analysis of the collected population data will be conducted. Qualitative variables will be presented as numbers and percentages, while quantitative variables will be described using the mean, standard deviation, median, interquartile range, minimum, and maximum values. For the primary analysis of the main outcome, the cause of sports-related SCA/SCD will be described in terms of numbers and percentages, along with the corresponding 95% confidence intervals. For the secondary analyses, the judgment criteria, both overall and by vital status (survived or deceased), will be described in numbers and percentages, with 95% confidence intervals.

MOLECULAR BASIS OF LANGUAGE DEVELOPMENT AND ASSOCIATED DISORDERS

Clearance of Vasoactive Metabolites With Blood Purification

This is a pilot study, non-interventional research involving the human subjects, category 3, aimed at measuring the clinical and biological the clinical and biological effects of using the oXiris hemofiltration hemofiltration membrane. As part of the treatment: oXiris membrane hemofiltration with Prismaflex system, Phoxylium or Hémosol B0 dialysis solution, upper or lower dialysis catheter. Anticoagulation with heparin, citrate or none in case of severe haemostasis disorders. Treatment volume of 35 ml/kg/h maximum. For research purposes: collection of additional blood tubes (2 x 5mL heparinized tube) added to the usual samples, at the following times: Baseline (before starting treatment), under hemofiltration at 24h +/- 6h of treatment and at 72 hours +/- 12 hours. These samples will be analyzed by liquid chromatography - mass spectrometry / mass spectrometry (LC-MS/MS) by Attoquant diagnostics®, a laboratory specialized in analyses of the Renin-Angiotensin system. The angiotensins assayed are Angiotensin I, II, III and IV, as well as the intermediate peptides (1-5, 1-7, 1-9, 2-10, 2-7 and 3-7) and regulatory enzymes (renin, angiotensin converting enzyme, angiotensin 2-converting enzyme and neprilysin). Angiotensin metabolites have a very short half-life. Their depends on enzyme activity and degradation by circulating proteases. Two techniques are used to determine circulating concentration rapid treatment with protease inhibitors or the equilibrium technique. For the equilibrium technique, samples are incubated again to restore metabolite concentration prior to analysis. The samples at 3 time points (Baseline, H24 and H72) are analyzed using the equilibrium. The H24 sample will also be analyzed with a protease inhibitor pre-treatment. Patients will be monitored for 3 months (90-day mortality) using data collected collected in the course of care. Data from medical records and biological analyses will be entered into an eCRF. Data management will be carried out throughout the study, to enable baseline freezing and statistical analysis as early as possible after the end of the last patient's follow-up.

Association of Dysbiosis and Immune Response in Bronchiolitis in Under 12 Months -Old Infants

neonAtal motoR paTtErn autoMatIc analySis

Neonatal Care and Newborn Examination: Every newborn undergoes a comprehensive clinical examination in the delivery room before being transferred to the postpartum ward with their mother (decree of October 18, 1994). At least one additional full examination is conducted during the maternity stay. Mandatory before the 8th day of life, this examination is recorded in the health booklet and allows for the issuance of the first health certificate (8th day certificate). It is performed in the presence of the mother or both parents, in a well-lit, adequately heated room, preferably before a meal or during a care routine, when the child is alert, and following hygiene rules (handwashing, use of a dedicated gown for the newborn, and disinfection of equipment). Significant clinical variations are possible among newborns, and a number of minor anomalies may be detected. The neurological assessment of the newborn begins with gathering maximum information about prenatal history and birth context. Family and social backgrounds are also crucial. For instance, previous neonatal deaths in the family may indicate autosomal recessive metabolic disorders, while details of any previous maternal miscarriage are particularly relevant in suspected X-linked dominant disorders, where male lethality is common. Medical records are extremely useful sources for Apgar scores, blood gas results, antepartum monitoring data, and any obstetric complications. Clinical information regarding the immediate postpartum period, known as the "golden hour" in high-risk groups, can also be very valuable. Additionally, nurse observations, when available, are generally invaluable. When evaluating newborns with paroxysmal disorders, video sequences of the events in question can provide valuable diagnostic clues. Clinical examination remains a central element and perhaps the most cost-effective and safest tool for evaluating newborns suspected of having a neurological problem ("Wusthoff CJ. How to use: the neonatal neurological examination. Arch Dis Child Educ Pract Ed. 2013;98:148-53." Extract from: Mustafa A. M. Salih. "Clinical Child Neurology." iBooks.). Thus, the main objectives of the examination are to determine whether the newborn is "neurologically normal" or not and to initiate further investigations if necessary. It also serves to assess the worsening (or improvement) of the newborn's condition over time. It should be noted that the newborn's neurological status often cannot be fully determined by a single neurological examination, especially if it is performed quite early. In fact, the predictive value of the neurological examination tends to improve with the newborn's chronological age, as illustrated by the case of a newborn who suffered significant hypoxic-ischemic injury at birth, for example. Indeed, this child's clinical presentation will vary over time, and a complete and accurate assessment of lesions is often possible remotely. Furthermore, it is well known that the newborn's neurological status can be affected by a range of "non-neurological" factors such as medications administered to the mother during pregnancy, infections, respiratory disorders, and unpleasant stimuli such as pain (from the cold hand of an examiner, for example) and hunger. Description of the Research Focus There are several standardized and validated scales and approaches widely used in various neonatal units. Each has its strengths and weaknesses, but they are all comprehensive enough to provide an idea of the neurodevelopmental profile of both full-term and premature newborns. Many of them, such as the Dubowitz examination, are freely accessible on the internet and in most neonatology manuals. Given the unique characteristics of the developing neonatal nervous system, it is necessary to adapt the formal neurological examination applicable to older children and adults. Observation is the first step of the examination, and it is crucial to spend as much time as possible observing the baby and their interaction with the environment ("Dubowitz L, Mercuri E, Dubowitz V. An optimality score for the neurologic examination of the term newborn. J Pediatr. 1998;133:406-16." Extract from: Mustafa A. M. Salih. "Clinical Child Neurology." iBooks.). This observation step is paramount in assessing the child and superior to the so-called manual examination, which involves palpation and directed manipulation of the child. This visual examination includes several registers related to the position and spontaneous movement of the child, both in terms of limbs, head movements, eye movements, and vocalizations. Interactivity is also crucial, as it indicates whether the child responds to voices and if automatic tracking mechanisms are in place. This newborn observation step is crucial. It allows for the evaluation of cardinal functions such as motor skills, reactivity, and interaction, and provides insight into the functioning of the patient's central and peripheral neurological structures. It is important to understand that these elements allow for a much more comprehensive evaluation of the newborn, and that these same functions will be impaired during systemic pathophysiological phenomena for which neurological involvement is only secondary or indirect, such as sepsis, metabolic diseases, anoxic-ischemic encephalopathies, etc. This is why this clinical examination, even if very generic and not highly directed, is of crucial importance in the newborn's progression before discharge. Best practices often appear to be dependent on the caregiver. Although the use of standardization in observation and data collection is unavoidable, clinical examination remains a phenomenon, an experience that includes a subjective element linked to the practitioner's experience and competence. Its expression thus exhibits a certain variability among patients. In addition to interindividual variability and variability in the evaluator's assessment, there is the difficulty of evaluation related to the child's age. Therefore, the observational component of the clinical examination in neonatology relies on the combination of three elements: facial expression, cry, peripheral mobility, and/or postural tone. Additionally, despite various assessment scales, pain remains challenging to evaluate and consequently to manage in the hospital setting in general and particularly in newborns. The AI MOTHER Neo solution is based on the technical foundation of 1. automated facial expression recognition. 2. Cry Recognition: 3. Movement and Posture Recognition: The justification for the duration of the research is based on several factors: 1. Number of births per year: The number of births recorded at Poissy-Saint-Germain Hospital is 4,500 per year. 2. Frequency of acquisitions: Acquisitions will be made during visits on days 0, 1, 2, 3, and 4 after birth, providing a potential of 22,500 acquisitions per year. 3. Recruitment objective: The goal is to obtain 10,000 acquisitions during the research. 4. Desired recruitment/acquisition rate: A recruitment/acquisition rate of less than 15% is targeted. Based on these data, a duration of 3 years is proposed to achieve the goal of 10,000 acquisitions. This allows for maintaining a reasonable and achievable recruitment/acquisition rate within the scope of the research. Primary Objective Our project aims to develop a computerized clinical assessment system for newborns that takes into account the three major criteria of various clinical scales: facial expression, cry, posture, and movement. Secondary Objectives The secondary objective is to characterize motor patterns that are specific to a given situation, particularly a pathological situation. The primary goal is to differentiate between a "normal" pattern and an "abnormal" pattern. Once a sufficient number of acquisitions have been obtained, we will attempt to identify specific patterns, meaning to make diagnoses based on computerized analysis. Patterns corresponding to early neonatal infection, anoxic-ischemic encephalopathy, brachial plexus paralysis, among others, will be identified and defined with the aim of maximizing the specificity and sensitivity of the tests. Primary Evaluation Criterion The chosen evaluation criterion is the comparison of the computer score with the clinical examination. These scores will be described for each patient by the mean and standard deviation on normally distributed numerical parameters (median, 25th and 50th percentiles). Comparisons between the two groups will be made using paired tests. Secondary Evaluation Criteria List the secondary evaluation criteria that address the secondary objectives. The acquisitions consist of 2D videos at 60Hz lasting 1 to 2 minutes, taken during bathing or clinical examination of an awake, undressed child, either in a diaper or onesie. These acquisitions can be made at multiple times during the maternity stay (Days 0/1/2/3/4) for the same child and for different children. The collected data will include skeleton data where variables such as amplitude, symmetry, acceleration, limb angles, etc., will be analyzed. These various data will be combined to provide a specific movement profile and define specific patterns for a group of patients with a common characteristic. Number of Participating Centers This is a multicenter research involving two centers located in the Paris region: - The maternity and neonatal medicine and intensive care units at Poissy-Saint-Germain Hospital - The Pediatric Intensive Care Unit at Raymond Poincaré Hospital, Garches. (Possible extension to a surgical intensive care unit and/or neonatology service). Subject Identification In this research, subjects will be identified as follows: Center number (3 numeric positions) - Person's selection order number within the center (4 numeric positions) - Initial of last name - Initial of first name This reference is unique and will be retained throughout the duration of the research. Eligibility Criteria After informing the parents or legal guardians about the objectives and procedures of the study (oral information), the protocol will be proposed to them. Inclusion Criteria The inclusion criteria are as follows: - Children hospitalized in the maternity ward and in the Neonatal Medicine and Intensive Care Unit at Poissy-Saint-Germain Hospital. - Agreement of legal guardians / non-opposition. Exclusion Criteria - Refusal of legal guardians. - Minor parents. Conduct of the Research The project aims to develop an automated analysis system for sound and image using computer vision in newborns in maternity units. The first phase of this project involves recording, with consent, sound and video sequences of newborns hospitalized in the maternity ward or in the Neonatal Medicine and Intensive Care Unit at Poissy-Saint-Germain Hospital. These video sequences will be analyzed by facial recognition programs developed at the R2P2 Laboratory of the Pediatric Intensive Care Unit at Raymond Poincaré Hospital in Garches and by the company OSO Ai. Method: The acquisition is performed on a naked or diapered, awake child lying on their back for 1 minute before bathing or clinical examination. Clinical data of patients such as sex, gestational age, birth weight, Apgar score, cord blood gases (pH and lactates), and mode of delivery will be associated with each video. The first phase of the project involves retrieving video/audio sequences of newborns at Days 0/1/2/3/4 or beyond if hospitalization is prolonged. These sequences will focus on the child and provide a complete view including the limbs. The videos are stored on an encrypted hard drive under the responsibility of Professor Bergounioux, who will regularly extract them. These sequences will then be analyzed at the R2P2 Laboratory affiliated with the Pediatric Neurology, Rehabilitation, and Intensive Care Unit at Raymond Poincaré Hospital using modified open-source programs for facial and posture recognition as well as sound analysis. A correlation will be established with clinical evaluations conducted in parallel with the video recordings. Population Follow-up Video/audio sequence acquisition will be conducted for newborns at Days 0/1/2/3/4 and beyond in case of continued hospitalization, either in the maternity ward or in the Neonatal Medicine and Intensive Care Unit at Poissy-Saint-Germain Hospital. Duration of Patient Participation Patient participation is limited to the capture of images during their hospitalization. Non-interventional research involving human subjects poses no risk to patients. Any adverse effects observed in patients participating in the research are reported by the investigators according to the local surveillance plans established within the framework of healthcare activities. The objective is to develop a system that allows for automated analysis of the newborn on both visual and auditory levels. The primary goal is to define the "normality" of this clinical presentation, which involves acquiring a total of 10,000 video acquisitions (1 to 2 minutes each) at Days 0/1/2/3 and Day 4 for newborns hospitalized in the maternity ward or in the Neonatal Medicine and Intensive Care Unit. These films will be obtained with parental consent and solely intended for research and development of the automated system AI MOTHER Neo under the responsibility of Professor Bergounioux. The analysis aims to establish classification algorithms using neural networks that differentiate between a "normal examination" and an "abnormal examination."

Natural History Study of Children With LAMA2-related Dystrophies

The international workshop on LAMA2-RD, held in 2019 in Maastricht, stressed the importance of the identification of LAMA2-RD patients and the natural history studies worldwide. Together with the recent progress in preclinical applications, the road to therapy is paved. However, no effective treatment has currently received market approval. Given the phenotype variability in LAMA2-RD patients, even in very young ones, determining which outcome measure(s) could be the most appropriate to assess the efficacy of potential therapies, and which variables are prognostic of the disease course, is required. In consequence, it is clearly necessary to explore all the aspects of the pathology: physiological, clinical/motor, biological, aligning with current or future international studies though collaboration. Unlike results obtained through a retrospective study, data from a prospective natural history will be less subject to bias and error. Control of the studied population will also lead to reduce the variability of the results. The different variables explored during this study aim to cover all aspects of the disease and appear to be relevant candidates as outcomes. The aim of the study is to focus on the clinical phenotyping and to establish a well-described cohort of patients in France with LAMA2-RD for prospective follow-up and recruitment for future clinical trials. One other objective is to validate the use of a large subset of outcome measures in LAMA2-RD. Adding an electrophysiological data will give more insight to the neuropathology of the disease and enlarge the scope of futures therapies. An exploratory part will test if denaturation profiling of plasma from patients can be used to follow disease progression. Finally, serum and plasma samples from patients will also be stored for future studies focused on searching and validating novel biomarkers in LAMA2-RD.

The Role of Peripheral Afferents in Modulating Post-stroke Central Pain

The primary endpoint will be the change in neuropathic pain intensity (assessed on an 11-point pain intensity scale), expressed as a difference in pain intensity between the value obtained before each block and that obtained 45 minutes after, corresponding to the maximum expected effect. Secondary endpoints will include exertional pain, pain quality, % relief, clinical global impression, pain assessment on a patient diary for a fortnight after each block and adverse events. Patients will be randomised to receive one of 3 study treatments (lidocaine 2%, levobupivacaine 1.25 mg/ml or placebo). The treatment protocol will involve 2 perineural blocks performed 14 days apart. Assessment will continue for up to 2 weeks after each block, i.e. up to one month after the start of treatment. An evaluation of pain will be carried out before the block and after each block, at 45 minutes and at 5 hours, and then daily by the patient on a self-evaluation booklet for the 14 days following each block. Randomisation will be centralised on a server from a list drawn up in advance by computer rogramme, balanced by blocks of variable size. Allocation between the 3 arms will be done according to a balanced 1:1:1 distribution. Treatments will be numbered from 1 to n, and allocated to patients in the chronological order of their inclusion in the trial. Patients will be randomised on the day of treatment using a centralised computerised randomisation procedure to receive one of the 3 study treatments (lidocaine 20 mg/ml levobupivacaine 1.25 mg/ml or saline). No matching by age or duration of pain is planned, as randomisation usually results in groups matched at baseline on these criteria. The treatment will be administered over two visits performed 14 days apart by a qualified anaesthetist using the peri-nervous route according to current ecommendations (see above). Only one randomisation will be performed at baseline, so that a patient on active treatment cannot receive placebo at a later date and vice versa (see figure 1). The investigators plan to randomise 10 patients per group and a total of 30 patients to achieve 90% power with a two sided α risk=0.05,. Given the estimated premature discontinuation rate, the investigators consider it necessary to include 12 patients per group for a total of 36 patients. This study opens the way to new therapeutic avenues for these patients who often fail all treatments