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Tuberculosis: children hospitalized with severe pneumonia in high-incidence countries should be screened for TB

© Copyright TB-Speed

Tuberculosis affects 1 million children each year; less than half of them are diagnosed and treated for the disease, which leads to more than 200,000 deaths. In a new study, researchers and clinicians from the TB-Speed consortium funded by global health agency Unitaid and led by the University of Bordeaux, in collaboration with the French Research Institute for Sustainable Development (IRD) and MU-JHU (a research collaboration between Makerere University and John Hopkins University in Uganda), showed that screening for tuberculosis at the time of hospital admission was feasible in children with severe pneumonia.

In addition, screening with a molecular test called Xpert Ultra improved the diagnosis of tuberculosis in children in countries with high incidence of the disease. The results of the study argue for a more systematic use of the Xpert Ultra in these children, especially in those suffering from severe acute malnutrition. They also confirm the importance of tuberculosis as a cause of severe pneumonia. These findings were published on November 15th, 2022 in The Lancet Infectious Diseases.

In countries with a high incidence of tuberculosis, the disease can be a cause of severe pneumonia and can contribute to mortality in young children. Usually the diagnosis of tuberculosis is considered only in children presenting with prolonged symptoms, those failing antibiotic courses prescribed for community-acquired pneumonia, or those with a history of contact with an adult with tuberculosis disease. Thus, many tuberculosis cases are missed or diagnosed with delays, which can result in poor outcomes and death.

However, young children presenting with tuberculosis-related severe pneumonia can have acute symptoms and would not be considered as presumptive tuberculosis cases. In this context, the TB-Speed consortium made the hypothesis that a tuberculosis screening in young children admitted with severe pneumonia with immediate treatment initiation for those who tested positive could reduce mortality of severe pneumonia related to tuberculosis.

TB-Speed Pneumonia is the first large-scale international cluster-randomized trial to assess the effect of doing systematic molecular tuberculosis detection in addition to the World Health Organization WHO standard of care in children admitted with severe pneumonia. The study, funded by Unitaid and the Initiative, and sponsored by INSERM, was conducted in 16 tertiary hospitals across six countries with high tuberculosis incidence (Cote d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia).

It aimed to assess the impact on mortality of adding systematic molecular tuberculosis detection using the Xpert MTB/RIF Ultra (Ultra) assay performed on one nasopharyngeal aspirate and one stool sample to the standard of care recommended by the World Health Organization for children with severe pneumonia (that includes antibiotics course, oxygen when indicated and treatment of HIV infection and severe malnutrition). Hospitals were randomly selected to start molecular testing and the flow was organized in order to reduce time to results to 3 hours. All children with Ultra positive results were immediately started on tuberculosis treatment. Children were followed for 12 weeks after enrolment.

2570 children were enrolled in the study (1401 in the control arm and 1169 in the intervention arm) between March 2019 and March 2021. 95% of children had nasopharyngeal aspirates and 80% had stools collected and tested with Ultra.

Although this tuberculosis screening intervention did not lead to a reduction in 12-week all-cause mortality as compared to the standard of care, it increased the rates of tuberculosis detection and microbiological confirmation and reduced the time to treatment initiation.

In addition, mortality and tuberculosis diagnosis rates were four to five times higher in children with severe acute malnutrition as compared to those without severe acute malnutrition. The study also showed that collecting and testing nasopharyngeal aspirates and stool samples with Xpert MTB/RIF Ultra in highly vulnerable children was highly feasible and well tolerated.

A New Gene Therapy Strategy for Sickle Cell Disease and Beta-Thalassemia

Sickle-shaped red blood cells (sickle cell disease) © Inserm/Anne-Marie Chevance de Boisfleury

 

Both sickle cell disease and beta-thalassemia are genetic disorders that affect hemoglobin, and as such are categorized as beta-hemoglobinopathies. A team of scientists from Inserm, Université Paris Cité and the Paris Public Hospitals Group AP-HP at the Imagine Institute has shown the efficacy of a gene therapy approach to treat these two disorders. The principle is to reactivate in patients the production of fetal hemoglobin, a protein whose expression usually ceases after birth. In a study published in Nature Communications, the research team describes a promising approach for future therapeutic applications.

Sickle cell disease and beta-thalassemia are genetic disorders known as beta-hemoglobinopathies. They are caused by mutations on chromosome 11 of the gene responsible for the production of beta globin, a constituent protein of hemoglobin which is the main component of red blood cells.

In sickle cell disease, the structure of beta globin is altered, affecting the integrity of red blood cells and leading to anemia, very painful local obstructions of the blood circulation (vaso-occlusive crisis), and gradual organ damage. In beta-thalassemia, beta globin production is drastically reduced, causing hemoglobin deficiency and leading to severe anemia.

In the 1970s, researchers observed that rare individuals with mutations specific to each of these conditions did not develop the disease. What was it they had in common? They were all carriers of compensatory mutations on another chromosome 11 gene, which stimulated the production of fetal hemoglobin (gamma globin). This protein that usually ceases to be produced at the end of fetal life is able to advantageously replace the defective adult beta globin to form healthy hemoglobin, thereby ensuring the production of perfectly functional red blood cells in sufficient quantities.

A research team led by Annarita Miccio, Inserm researcher at the Imagine Institute (Inserm/Université Paris Cité/Paris Public Hospitals Group AP-HP) conducted a series of in vitro experiments to determine the most effective strategy for stimulating fetal hemoglobin production, using gene therapy to reproduce these beneficial mutations for treatment purposes. The most effective approach was to insert a genetic mutation that generates, in red blood cells, a molecular mechanism with the dual advantage of stimulating fetal hemoglobin production and blocking the mechanism that naturally inhibits that production.

Furthermore, the researchers have shown in animals that this strategy is effective over the long term, which is a very important finding in the context of therapeutic application.

There is still a long way to go before this new gene therapy approach can be used in a clinical setting,” explains Panagiotis Antoniou, first author of the study, for example, we need to optimize the protocol in order to genetically modify more red blood cells, as only 60% are done so with the current protocol. Nevertheless, our research is paving the way for the clinical development of a safe and innovative treatment for patients with beta-hemoglobinopathies, with the objective of improving their quality of life,” concludes the researcher.

 

Sickle cell disease, which affects 5 million people worldwide, is the leading genetic disorder worldwide and the most common in France. Every year, about 100,000 children worldwide are born with a severe form of beta-thalassemia. In order to continue to support the advances of research in fighting rare diseases, the 2022 edition of the Telethon (only available in French) will be broadcast over a 30-hour period on December 2-3, on France Télévisions.

Alzheimer’s disease: newly identified rare gene variants significantly increase the risk of developing this pathology.

Fluorescent marking of the Tau protein in a human cell hNT; the Tau protein, has a role in Alzheimer’s disease, particularly in its familial forms ©Inserm/U837

An international consortium has identified rare variants in two new genes that markedly increase the risk of developing Alzheimer’s disease (AD). The work was led by two research groups in France (headed respectively by Gaël Nicolas, Rouen and Jean-Charles Lambert, Lille) and a group in the Netherlands (headed by Henne Holstege, Amsterdam). The new results provide a better understanding of the genetics of AD and open up new research themes on more relevant in vitro and in vivo models. The consortium’s findings are also likely to catalyze the development of new strategies for treating AD. The results were published in the journal Nature Genetics in November 2022.

As the most prevalent neurodegenerative disease, AD affects about 55 million people across the world – 4% of whom are under the age of 65. It is a complex, multifactorial disease caused by interactions between many genetic and non-genetic predisposing factors. Given that AD has a large genetic component, the characterization of these factors is a major challenge for basic research and therapeutic development.

Our knowledge of the involvement of common gene variants (those present in more than 1% of the general population) in AD has improved enormously over recent last years, through the discovery of 75 chromosomal/gene regions associated with the risk of developing the disease. However, the role of rare or even very rare variants has not been extensively studied. In fact, these variants might contribute significantly to genetic predisposition to AD as a result of their direct biological effects and their great diversity.

 

Two new genes identified

It is in this context that a large international consortium has identified a number of rare mutations in two genes that markedly increase the risk of developing AD. Along with their European and American colleagues, researchers from the INSERM, the Pasteur Institute in Lille, Lille University Medical Centre, the University of the Lille, the University of Rouen Normandy, and the French National Reference Centre for Patients with Early-Onset Alzheimer’s Disease (Centre national de référence pour les malades Alzheimer jeunes (CNRMAJ)) at Rouen University Medical Centre and from the Amsterdam University Medical Center performed a high-throughput sequencing study of 16,032 AD patients and 16,522 controls. This sequencing approach provides the most precise possible picture of an individual’s genetic variants.

By specifically studying the DNA regions that code for the proteins in our body (the exons), the researchers were able to map deleterious, rare variants that might change the corresponding proteins’ biological functions. The researchers confirmed the pathological role of rare variants in the SORL1, TREM2 and ABCA7 genes and, for the first time, highlighted potentially pathological variants in two other genes (ATP8B4 and ABCA1). The potentially pathological role of variants in one other gene (ADAM10) remains to be confirmed.

Some of the rare variants in these genes are associated with a significantly greater risk of developing AD in general and early-onset forms of the disease in particular.

 

Better understanding the mechanisms of AD

The identification of the effects of these rare variants should provide a better understanding of the mechanisms that underlie AD.

In fact, two disease pathways have already been well documented in the AD brain: the accumulation of beta-amyloid peptides, and changes in and the accumulation of Tau protein. Importantly, some of the genes studied by the researchers are involved in the production or aggregation of beta-amyloid peptides – confirming the latter’s central role in the development of AD. Furthermore, the present research confirmed previous reports of the importance of microglial cells (cells that help to remove waste from the brain) in AD.

These results from the largest yet sequencing study in this field constitute a major step forward in our understanding of the genetics of AD and the underlying biological mechanisms. Furthermore, these results will open up new research themes on more relevant in vitro and in vivo models in which the newly identified genes are knocked out. By continuing this work, the consortium’s scientists’ also hope to foster the development of new strategies for treating AD.

Research shows fatty liver disease endangers brain health

Liver cells invaded by lipid droplets (in white) from an animal on a diet rich in sugars and fats. © University Institute of Pathology of the University of Lausanne.


People with liver disease caused by eating too much sugar and fat could be at increased risk of developing serious neurological conditions like depression or dementia. In a study examining the link between non-alcoholic fatty liver disease (NAFLD) and brain dysfunction, scientists at the Roger Williams Institute of Hepatology, affiliated to King’s College London and the University of Lausanne, found an accumulation of fat in the liver causes a decrease in oxygen to the brain and inflammation to brain tissue – both of which have been proven to lead to the onset of severe brain diseases.

NAFLD affects approximately 25% of the population and more than 80% of morbidly obese people. Several studies have reported the negative effects of an unhealthy diet and obesity can have on brain function however this is believed to be the first study that clearly links NAFLD with brain deterioration and identifies a potential therapeutic target.

The research, conducted in collaboration with Inserm (the French National Institute of Health and Medical Research) and the University of Poitiers in France , involved feeding two different diets to mice. Half of the mice consumed a diet with no more than 10% fat in their calorie intake, while the other half’s calorie intake contained 55% fat; intended to resemble a diet of processed foods and sugary drinks.

After 16 weeks researchers conducted a series of tests to compare the effects of these diets on the body and more specifically, on the liver and the brain.

They found that all mice consuming the higher levels of fat were considered obese, and developed NAFLD, insulin resistance and brain dysfunction.

The study which was funded by the University of Lausanne and Foundation for Liver Research, published today in The Journal of Hepatology, also showed that the brain of mice with NAFLD suffered from lower oxygen levels. This is because the disease affects the number and thickness of the brain blood vessels, which deliver less oxygen to the tissue, but also due to specific cells consuming more oxygen while the brain is becoming inflamed. These mice were also more anxious and showed signs of depression.

By comparison, the mice consuming the healthy diet did not develop NAFLD or insulin resistance, they behaved normally, and their brain was completely healthy.

It is very concerning to see the effect that fat accumulation in the liver can have on the brain, especially because it often starts off mild and can exist silently for many years without people knowing they have it,” said lead author Dr Anna Hadjihambi, sub-team lead in the Liver-Brain Axis group at the Roger Williams Institute of Hepatology and honorary lecturer at King’s College London.

To try and combat the dangerous effect that NAFLD has on the brain, the scientists bred mice with lower levels of a whole-body protein known as Monocarboxylate Transporter 1 (MCT1) – a protein specialised in the transport of energy substrates used by various cells for their normal function.

When these mice were fed the same unhealthy fat- and sugar-rich diet as those in the initial experiment, they had no fat accumulation in the liver and exhibited no sign of brain dysfunction – they were protected from both ailments.

Identifying MCT1 as a key element in the development of both NAFLD and its associated brain dysfunction opens interesting perspectives,” said Professor Luc Pellerin, director of the Inserm U1313 research unit at the University of Poitiers in France and senior researcher in the study. “It highlights potential mechanisms at play within the liver-brain axis and points to a possible therapeutic target.

Dr Hadjihambi added: “This research emphasises that cutting down the amount of sugar and fat in our diets is not only important for tackling obesity, but also for protecting the liver to maintain brain health and minimise the risk of developing conditions like depression and dementia during ageing, when our brain becomes even more fragile.

The full paper is available to view online in The Journal of Hepatology.

A potential therapy to reduce the side effects of a chemotherapy

Convergent effect of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells. Blue corresponds to cell nuclei and red to a protein that marks DNA damage © Dewaeles et al

Cisplatin is a chemotherapy indicated to fight tumors in many types of cancer. However, it does have major side effects – especially kidney toxicity, that can lead to acute kidney failure. In addition, patients treated with cisplatin also often report high levels of neuropathic pain. Scientists from Inserm, Université de Lille, University Hospital Lille, CNRS and Institut Pasteur de Lille within the CANTHER and Lille Neuroscience & Cognition laboratories, in collaboration with researchers from Michigan State University (USA), have identified a drug that could be a game changer for patients. Istradefylline, which is already approved for Parkinson’s disease, could not only reduce the harmful effects of cisplatin but also improve its anti-tumor properties. These findings will now need to be confirmed in a clinical trial. The study is published in The Journal of Clinical Investigation.

Cisplatin is a chemotherapy used to treat several types of cancer, in particular lung, ovarian and testicular cancers. While its anti-tumor efficacy has been proven, cisplatin promotes side effects. These include intense pain (peripheral neuropathy) and kidney damage, leading to acute kidney failure in one third of cases. Currently, there is no effective solutions to limit side effects for patients exposed to cisplatin.

An international work conducted by Christelle Cauffiez, David Blum and Geoffroy Laumet[1] have now identified a molecule that reduces cisplatin-induced side effects, while preserving or even potentiating its anti-tumor properties.

 

A Parkinson’s disease drug

The scientists focused on a drug called istradefylline, which is already approved in the USA and Japan for the treatment of Parkinson’s disease. Biologically, this compound blocks the adenosine receptors receptors at the surface of cells.

Blum’s team, which is working on neurodegenerative diseases, had previously observed an increased density of these receptors in the brains of patients with dementia, a phenomenon involved in the development of these diseases. Interestingly, a comparable increase of adenosine receptors was also observed by Cauffiez’s team in the kidneys, under exposure to cisplatin.

With this in mind, the scientists decided to join forces with Laumet’s lab, a specialist of  cisplatin-induced neuropathic pain, to test the impact of istradefylline to mitigate the harmful effects of cisplatin.

 

Findings to confirm in a clinical trial

Their experiments, conducted on animal and cellular models, indeed pointed towards a beneficial role of istradefylline. In mice exposed to cisplatin, the molecule not only reduced kidney damages but also prevented neuropathic pain.

In addition, cisplatin’s ability to reduce tumor growth was increased in the animals receiving istradefylline – an effect subsequently confirmed in cell models.

Before considering the widespread application of this therapeutic approach to patients with cancer, these findings must however first be consolidated by organizing a rigorous clinical trial. The fact that istradefylline is already used in humans to treat another disease already constitutes an interesting perspective.

“In fact, we already have a lot of clinical data showing that this molecule is safe. While it is necessary to conduct a clinical study to test its efficacy in reducing the side effects of the chemotherapy, the possibility of therapeutic repositioning is a promising perspective for improving patient care in the short term,” the researchers point out.

 

[1] from the CANTHER laboratory (Inserm/Institut Pasteur de Lille/CNRS/Université de Lille/University Hospital Lille), the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille/University Hospital Lille) and the Department of Physiology of Michigan State University

Long COVID: A Dysregulated Immune Response Could Explain Symptoms Persistence

Covid-19: Intracellular observation of reconstituted human respiratory epithelium MucilAir™ infected with SARS-CoV-2. © Manuel Rosa-Calatrava, Inserm; Olivier Terrier, CNRS; Andrés Pizzorno, Signia Therapeutics; Elisabeth Errazuriz-Cerda UCBL1 CIQLE. VirPath (International Research Center in Infectiology U1111 Inserm – UMR 5308 CNRS – ENS Lyon – UCBL1). Colorized by Noa Rosa C.

 

Several months after SARS-CoV-2 infection, some patients continue to have symptoms. This phenomenon, known as “post-COVID condition” or, more commonly, “long COVID”, remains poorly documented. In order to address this and improve patient care, research teams are trying to improve their understanding of the underlying biological and immunological mechanisms. In a new study, scientists from Inserm and Université de Montpellier at the Montpellier Cancer Research Institute, in collaboration with Montpellier University Hospital[1], have highlighted the possible role of the dysregulation of a part of the innate immune defense. They suggest that the production of “extracellular neutrophil traps”, a first-line defense mechanism against pathogens, could play a role in the persistence of symptoms six months later in patients having developed a severe form of COVID-19. Their findings have been published in the Journal of Medical Virology.

Neutrophils are the most abundant class of white blood cells and the first line of defense against viruses and bacteria. When activated, they are capable of producing a specific defense mechanism known as “neutrophil extracellular traps” (NETs). Made up of DNA fibers, bactericidal enzymes and pro-inflammatory molecules, NETs contribute to fighting pathogens, but in some cases can also trigger excessive inflammation that is harmful to the body.

In previous studies, Inserm researcher Alain Thierry’s team at the Montpellier Cancer Research Institute had shown that part of the innate immune response is dysregulated in patients with severe forms of COVID-19. In these patients, the formation of NETs is amplified, resulting in multi-organ damage.

In their new study, the scientists wanted to go further in studying the biomarkers characteristic of COVID-19. To do this they analyzed the biological samples of over 155 patients. These were individuals with COVID-19 in the acute non-severe (hospitalized) or severe (intensive care) phases, or who had a post-acute infection assessment more than six months after their discharge from critical care. These samples were compared with those of 122 healthy individuals.

NETS and auto-antibodies persisting in the body

The analyses performed in this study confirm that NET production is higher in SARS-CoV-2 patients than in healthy individuals. In addition, the patients have higher levels of auto‑antibodies known as “anticardiolipin auto-antibodies”. Produced by the immune system, these auto‑antibodies are often associated with the abnormal formation of clots in the veins (phlebitis) and in the arteries (arterial thrombosis).

Furthermore, the data collected by the research team also suggest that this dysregulated immune response is maintained in people who present symptoms of long COVID, six months after being hospitalized for a serious form of the disease. The amplified and uncontrolled production of NETs six months after infection as well as the persistent presence of auto‑antibodies could partly explain the symptoms of long COVID, notably via the formation of microthromboses.

“Our findings could indicate the persistence of a sustained imbalance of the innate immune response, and potential prolonged pro-thrombotic activity that could explain the sequelae of post-acute infection or ‘long COVID’. It is necessary to continue the research in order to both confirm this and better understand the nature of this phenomenon, which could be serious and long-lasting, to improve patient care,” concludes Thierry.

Research is already underway in some laboratories around the world to consolidate this data and explore other avenues of interest, with the aim of gaining a better understanding of the long COVID phenomenon in all its complexity. Thierry’s team had also filed an international patent application in August 2022.

 

[1] The research was partially funded by SIRIC Montpellier Cancer.

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