Inserm Newsroom - Press room of the French national institute of health and medical research

Menu
close
Search

Month: July 2021

Suspension provisoire des travaux sur les prions dans les laboratoires de recherche publics français

Posted on by Graziella Cara

In France, Drug Prescriptions for Children Remain at High Levels

Posted on by Graziella Cara

médicaments

The under 6 year-olds are the category of children most exposed to drug prescriptions. © Myriam Zilles – Unsplash

France is one of the countries with the highest levels of drug consumption in Europe. In the absence of updated data from the last ten years on pediatric drug prescriptions, researchers from Inserm and teacher-researchers from Université de Paris at the Center for Research in Epidemiology and Statistics  (CRESS), along with researchers from Université de Versailles Saint-Quentin-en-Yvelines / Université Paris-Saclay, the Paris hospitals group AP-HP, and the Epi-Phare scientific interest group, quantified pediatric outpatient prescriptions in France and studied their evolution between 2010 and 2019. Their findings have been published in The Lancet Regional Health Europe.

The pediatric population, especially very young children, is particularly vulnerable to the short and long-term side effects of drugs because of its immaturity. In addition, the safety profile of many drugs used in pediatrics is only partially known. These elements should encourage rational prescribing in this population.

The first French national study of drug prescriptions in pediatric outpatient populations, based on data from the Generalist Sample of Health Insurance Beneficiaries (EGB) from 2011, showed worrying results with the highest frequency of prescriptions in the world. However, since 2011, new recommendations on the proper use of certain drugs have been issued and reimbursement delisting policies have been implemented, which were expected to lead to changes in these prescriptions.

The objective of the new study, conducted by researchers and teacher-researchers from Inserm, Université de Paris, Université de Versailles Saint-Quentin-en-Yvelines / Université Paris-Saclay, the Paris hospitals group AP-HP, and the Epi-Phare scientific interest group (GIS), was to determine the frequencies of drug prescriptions in pediatric outpatients in 2018-2019 in France and to compare them with those of 2010-2011, at the national level, using French National Health Data System (SNDS)2 data.

The analysis covered all reimbursed dispensations of drugs prescribed in an outpatient setting (so excluding those prescribed during stays in hospital), by a doctor, midwife or dentist, and intended for all children under 18 years of age living in France. In order to take into account the influence of infectious epidemics on outpatient prescriptions, annual drug prescription frequencies were averaged over two years for the two study periods. For the 2018-2019 period, over 230 million dispensed prescriptions were analyzed.

 

Children under 6 years of age are the category most exposed to drug prescriptions

The study found that over the recent period (2018-2019), on average, 86 out of every 100 children under 18 years of age had been exposed to at least one drug prescription over the course of one year, representing a 4% increase in relation to 2010-2011. Children under six years of age were the category most exposed to drugs, with over 97 out of every 100 children affected in a year.

The most prescribed therapeutic classes for the 2018-2019 period were analgesics (64%3), antibiotics (40%), nasal corticosteroids (33%), vitamin D (30%), nonsteroidal anti-inflammatory drugs (24%), antihistamines (25%), and oral corticosteroids (21%).

“Following the publication of the 2011 data, we expected to see a significant change for certain therapeutic classes given the regulations put in place or recommendations issued since 2011. A 12% decrease in the frequency of antibiotic prescriptions over the past ten years was noted in our study, but this remains insufficient because more than one in two children under 6 years of age were prescribed antibiotics during the year,” explains Dr. Marion Taine, co-author of the study.

In addition, the study found that one in three children under 6 years of age had received a prescription for oral corticosteroids during the year 2018-2019. A level that has remained stable since 2010-2011, despite the known side effects of this therapeutic class.

Finally, 2% of infants under 6 weeks of age were prescribed proton pump inhibitors4 during the year 2018-2019, “even though the frequency of conditions for which this treatment is recommended is much lower at this age,” explains Dr. Taine.

 

France, one of the highest prescribing countries for outpatient pediatric drugs

France is one of the countries that prescribes the most drugs in outpatient pediatrics, but international comparisons need to be treated with caution given that health care systems and drug reimbursement policies (particularly for those available over the counter) differ from country to country.

For example, comparisons between a few advanced-economy countries show that the frequencies of oral corticosteroid prescriptions for French children were 5 and 20 times higher than those observed for American and Norwegian children in other recent studies. For antibiotics, the frequency of prescriptions to French children was 5 times higher than that observed in the Netherlands. The inappropriate prescription of antibiotics increases bacterial resistance. As for systemic corticosteroids, their side effects are well-documented.

For the researchers, these high levels of prescriptions could be explained by the positive image associated with drugs in France, both in the population and among prescribers. In other countries with advanced economies, more heed is given to the drugs’ risk-benefit balance.

“These worrying results require in-depth analysis in order to better target future educational campaigns to optimize pediatric medication use. Better information for the population and prescribers regarding the use of medicines in children is essential”, concludes Dr. Taine.

 

1 Benard-Laribiere A, Jove J, Lassalle R, Robinson P, Droz-Perroteau C, Noize P. Drug use in French children: a population-based study. Arch Dis Child 2015;100 (10):960–5.

2 The SNDS covers 98.8% of the French population and compiles reimbursement data for outpatient care for all children covered by the Universal Public Health Insurance in France

3 643 out of every 100 children received at least one prescription for pain medication over one year on average during the 2018-2019 period.

4 Medications recommended only for complications of gastroesophageal reflux disease.

Confirmation of promising results from the CORIMUNO-TOCI-1 trial showing improved survival in patients with moderate to severe COVID-19 pneumonia

Posted on by Graziella Cara

SARS-CoV-2

Electronic microscopy of a cell infected with SARS-CoV-2 © Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault, unité Inserm U1259 MAVIVH & Université de Tours, France

 

An article published in JAMA Internal Medicine and WHO meta-analysis of 27 controlled trials confirm the promising initial results of the test-CORIMUNO TOCI-1, indicating an improved prognosis of patients with moderate to severe COVID-19 pneumonia. This trial was conducted by the COVID-19 academic research collaboration Assistance Publique-Hôpitaux de Paris / Université Paris-Saclay / Université de Paris / INSERM-REACTing. They reveal the clinical efficacy of tocilizumab, a monoclonal antibody which blocks the receptor for the cytokine interleukin-6 (IL-6) and which is used in particular in the treatment of rheumatoid arthritis.

The 90-day results of the CORIMUNO-TOCI-1 trial published on May 24, 2021 in the journal JAMA Internal Medicine show an improvement in the survival of patients with moderate to severe COVID-19 pneumonia with tocilizumab in highly inflammatory patients .

In some patients with COVID-19 pneumonia, an immune-mediated hyperinflammatory condition contributes to acute respiratory failure and death. The CORIMUNO-19 platform was quickly set up in March 2020 to test the efficacy and safety of various immunomodulatory drugs in adult patients with moderate, severe or critical COVID-19 pneumonia, thanks to a series of ‘multicenter randomized controlled trials, which began on March 27, 2020 and are currently continuing.

Tocilizumab is a monoclonal antibody that blocks the cytokine interleukin-6 (IL-6) receptor.

The CORIMUNO-TOCI-1 randomized trial that compared tocilizumab with the usual treatment, published on October 20, 2020 in the journal JAMA Internal Medicine with a 28-day follow-up , demonstrated that tocilizumab had a 95% chance of reducing the need for ventilation (mechanical or non-invasive) or death at D + 14 (Hazard ratio (HR) = 0.58 (0.33-1.00), but did not decrease mortality at D + 28 (11% and 12%, respectively).

The new update results of this study published on May 24, 2021 in the same journal JAMA Internal Medicine concern longer-term survival (D + 90) and according to the inflammatory state of the patient, in particular according to a threshold of C reactive protein (CRP) (150 mg / L) at the start of treatment.

Mortality at D + 90, a secondary endpoint of the trial, is numerically but not significantly lower in the treated group (11% vs. 18%; HR = 0.64 [0.25-1.65]. A post-hoc analysis shows an interaction between survival and CRP level with, in the group of patients whose CRP is> 150 mg / L, a reduction in mortality with tocilizumab (9% versus 35%; HR = 0.18 [0.04 to 0.89]. the CRP is <or = at 150, the mortality is very low in the 2 treatment groups.

These results obtained on secondary endpoints and in post-hoc analysis had to be confirmed by additional studies and a meta-analysis of all the controlled trials. This is what was done by a group of WHO researchers.

U do the WHO meta-analysis of 27 controlled trials evaluating inhibitors of IL-6 in patients hospitalized for pneumonia Covid-19 confirms a profit of these drugs on survival . It was published in JAMA on July 6, 2021 .

A meta-analysis was carried out by the WHO on all the randomized trials that evaluated inhibitors of IL-6 or its receptor in patients hospitalized with COVID-19 pneumonia requiring oxygen or ventilation. non-invasive or mechanical.

In this prospective meta-analysis of 27 randomized trials (including 4 trials from the CORIMUNO platform) that included 11,112 patients, 2,565 of whom died, 28-day mortality and progression to invasive mechanical ventilation or death were lower in patients who received interleukin-6 antagonists compared to those who received usual care or a placebo (OR = 0.86 [95% CI, 0.79-0.95]; P = 0.03 and OR = 0.77 (95% CI, 0.70-0.85, P <0.001) respectively).

For the 19 trials that evaluated the effect of tocilizumab, the effect on 28-day mortality and progression to invasive mechanical ventilation or death was 0.83 (95% CI, 0.74-0.92; P <0.001 and 0.74, respectively) (95% CI, 0.66-0.82).

In this meta-analysis, tocilizumab did not cause more secondary infections than usual treatment.

In total, these two articles confirm the promising initial results of the CORIMUNO-TOCI-1 and RECOVERY trials.

One of the important questions that remains unanswered is: “Should IL-6 receptor inhibitors replace the standard treatment of these patients which has now become corticosteroid therapy or be added to it?” “.

The CORIMUNO-TOCIDEX protocol which compares dexamethasone alone to the combination of dexamethasone with tocilizumab and which included more than 450 patients is currently attempting to answer this important question.

WHO is due to make recommendations soon on the use of tocilizumab in the different subgroups of patients hospitalized for COVID-19 pneumonia. The FDA announced on June 24, 2021 an emergency authorization for the use of tocilizumab in severe coronavirus lung disease.

 

Coordinating investigator: Prof. O. Hermine, Hôpital Necker, AP-HP, Imagine Institute, INSERM U1163, University of Paris

Co-coordinating investigator: Prof. X. Mariette, Bicêtre Hospital, AP-HP, INSERM U1184, Université Paris-Saclay

  • Scientific Director: Dr PL Tharaux, Paris Cardiovascular Research Center (PARCC), INSERM U970, European Hospital Georges Pompidou, AP-HP, University of Paris.

Design and coordination of the CORIMUNO trial platform: Pr P. Ravaud, Center for Clinical Epidemiology, Hôpital Hôtel Dieu, AP-HP, CRESS, INSERM U1153, University of Paris

Statistician: Dr R. Porcher, Center for Clinical Epidemiology, Hôpital Hôtel Dieu, AP-HP, CRESS, INSERM U1153, University of Paris

  • Monitoring and data management: Pr M. Resche-Rigon (Clinical Trial Unit, Hôpital Saint Louis, AP-HP), CRESS, INSERM U1153, University of Paris.

Organization of the data collection: Pr M Dougados, Hôpital Cochin, AP-HP, CRESS, INSERM U1153, University of Paris

The CORIMUNO-19 clinical trials platform is promoted and funded by Assistance Publique – Hôpitaux de Paris, and supported by Inserm via its REACTing consortium (integrated into the ANRS Emerging Infectious Diseases since January 2021).

The trial received funding from the Clinical Research Hospital Program of the Ministry of Health, seed funding from Inserm through the REACTing / INSERM consortium via the Fondation pour la Recherche Médicale, Paris, France, and a funding from the AP-HP Foundation for Research, Paris, France. Tocilizumab as well as 4,000 Elecsys interleukin 6 assay kits were unconditionally provided by the Roche laboratory, which was not involved in the assay design, data collection, analysis, interpretation, writing of the manuscript nor in the governance of the essay.

A Genetic Cause of Tree Man Syndrome (Skin Papillomavirus) Identified for the First Time

Posted on by Graziella Cara

Papillomavirus

Papillomavirus. © Inserm/U190

 

Most of us carry human papillomaviruses (HPVs) – particularly skin papillomaviruses that generally cause warts or benign local lesions. However, on very rare occasions worldwide patients develop severe forms of these viral diseases, including “tree man” syndrome. This highly debilitating disease manifests as the uncontrolled growth of horn-like skin lesions for which surgery is ineffective. As part of an international collaboration, researchers from Inserm, teacher-researchers from Université de Paris, and doctors from AP-HP, all grouped at the Imagine Institute (Inserm/Université de Paris, Paris hospitals group AP-HP) located at Necker Hospital for Sick Children AP-HP, have been the first to reveal a genetic cause of tree man syndrome. This research was conducted by Vivien Béziat, under the supervision of Profs. Jean-Laurent Casanova and Laurent Abel, who run a laboratory with branches in Paris and New York’s Rockefeller University1. It was published on July 1, 2021, in the journal Cell.

There are over 200 human papillomaviruses (HPVs), with some causing benign skin lesions such as common or plantar warts, and others with the potential to cause cervical cancer. The Human Genetics of Infectious Diseases laboratory has focused on skin HPVs, working for several years to understand why these usually harmless infections take a severe turn in a few very rare cases.

A genetic mutation increases susceptibility to skin papillomaviruses

In a publication in the journal Cell, the team of Vivien Béziat, Inserm researcher in the Human Genetics of Infectious Diseases laboratory and first author of the publication, studied the genetic characteristics of an Iranian patient with tree man syndrome, and two members of his family presenting with a severe skin HPV infection involving large numbers of warts on their hands and feet, but who had not developed the syndrome. What the three patients were found to have in common was a mutation of the CD28 gene, which usually plays a major role in activating T cells – the immune cells that destroy the cells infected by a virus.

In these patients, the CD28 gene mutation prevents the immune system from recognizing the virus and from mounting an appropriate response. The virus then proliferates in the keratinocytes, the cells that make up the skin’s epidermis, causing the uncontrolled multiplication of skin warts and/or horn-like lesions. This is the first time that a genetic cause of tree man syndrome has been identified.

The CD28 gene, central for resisting certain skin papillomaviruses, but not for the immune system

However, it was when analyzing the CD28 mutation that the researchers made a different discovery. The CD28 gene, until now considered a mainstay in immune system function and T cell response, does not appear to play such a major role. The medical histories of the three patients showed exposure to several HPV types and to a very large number of other pathogens. Yet only the patient with tree man syndrome developed a severe reaction to HPV2, and only the two members of his family did so to HPV4.

“These patients only showed abnormally high susceptibility to certain papillomaviruses of the gamma-HPV and alpha-HPV genus. Based on the work done over the past 30 years, we thought that a CD28 gene dysfunction would actually make patients susceptible to many infectious agents. But even if their immune response is weakened, the patients defend themselves well against other pathogens,” explains Béziat.

A discovery which therefore provides new insights into genetic susceptibility to HPVs and challenges the dogmas of T cell-mediated immune response.

“No treatment has so far been shown to be effective against tree man syndrome”. A hematopoietic stem cell transplant to replace the patient’s immune system is being considered. However, this major, costly treatment is not easily accessible to populations living in less developed countries, who will progress towards very severe forms of the disease, notably due to lack of access to care. By advancing research, the team hopes to accelerate access to treatment for these patients.

 

1 The Human Genetics of Infectious Diseases laboratory is directed by Jean-Laurent Casanova and Laurent Abel and is located at the Imagine Institute in Paris and Rockefeller University in New York. At both branches, Casanova heads up genetics and experimental immunology, whereas Abel heads up genetics and mathematical epidemiology.

The Key Role of Astrocytes in Cognitive Development

Posted on by Graziella Cara

Primary culture of astrocytes © Inserm/Ruiz, Anne-Laure

Astrocytes are cells in the brain which have long been considered only as mere support cells for neurons. In recent years, the study of astrocytes has grown, gradually revealing their importance in brain function. Researchers from Inserm, CNRS and Collège de France at the Center for Interdisciplinary Research in Biology have now uncovered their crucial role in closing the period of brain plasticity that follows birth, finding them to be key to the development of sensory and cognitive faculties. Over the longer term, these findings will make it possible to envisage new strategies for reintroducing brain plasticity in adults, thereby promoting rehabilitation following brain lesions or neurodevelopmental disorders. This research has been published in Science.

 

Brain plasticity is a transient key period after birth in which the brain remodels the “wiring” of the neurons according to the external stimulations it receives (environment, interactions, etc.). The end – or “closure” – of this period marks the stabilization of the neural circuits, associated with efficient information processing and normal cognitive development. Plasticity is still possible in the future, although at a much lower level than at the beginning of life.

 

Problems occurring during the brain plasticity period could have major long-term consequences. For example, in the event of an eye condition preventing an individual from seeing correctly, such as strabismus (crossed eyes), the corresponding brain wiring will be permanently altered if it is not treated in time.

 

To remedy this, the researchers aim to remodel this wiring by identifying a therapy that would reintroduce brain plasticity, even once closure has occurred. To achieve this, they also seek to better characterize the biological mechanisms that underlie this closure.

Pioneering studies from the 1980s showed that transplanting immature astrocytes into the brains of adult animals reintroduced a period of major plasticity. The team of Inserm researcher and study coordinator Nathalie Rouach at the Center for Interdisciplinary Research in Biology (Inserm/CNRS/Collège de France)[1] took inspiration from this procedure to reveal the hitherto unknown cellular process responsible for the closure of plasticity.

Transplanting immature astrocytes to reintroduce brain plasticity

Through experiments on the mouse visual cortex, the researchers show that the presence of immature astrocytes is the key to brain plasticity. The astrocytes are then later involved in developing interneuron maturation[1] during the plasticity period, ultimately leading to its closure. This maturation process occurs via a novel mechanism involving the protein Connexin 30, of which the researchers found high levels in mature astrocytes during closure.

 

 

Could transplanting astrocytes into adult mice reintroduce brain plasticity?

 

To find out, the researchers cultured immature astrocytes from the visual cortex of young mice (1 to 3 days’ old). These immature astrocytes were transplanted into the primary visual cortex of adult mice, following which the activity of the visual cortex was evaluated after four days of monocular occlusion – a standard technique used to assess brain plasticity. They found that the mice transplanted with the immature astrocytes presented a high level of plasticity, unlike the control mice which did not receive the transplant.

 “This study is a reminder that in the neurosciences we must not only focus on neurons. The glial cells, of which the astrocytes are a subtype, regulate most of the brain’s functions. We realized that these cells have active roles. Glial cells are less fragile than neurons and so represent a more accessible means of acting on the brain, ” emphasizes Rouach.

[1]  The interneurons establish connections between an afferent neural network (which sends information to the central nervous system) and an efferent neural network (which sends this information to the organs responding to the stimulation)

Search
fermer