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Category: Public health

High Temperatures Have Short-Term Impact on All Major Causes of Death, Including Suicide

Posted on by newround

The findings of this study are based on records of all deaths having occurred in France over a 49-year period, compiled by the Inserm CépiDc. © Adobe Stock

Temperature and mortality are linked. There is a short-term increase in mortality when temperatures are at their hottest or coldest – a phenomenon known as a “U-shaped relationship”. Inserm researchers at the Institute for Advanced Biosciences (Inserm/Université Grenoble Alpes/CNRS) and the Inserm Epidemiology Center on Medical Causes of Death (CépiDc) have sought to determine the extent to which this relationship between temperature and mortality varies according to the medical cause of death; for what causes of death is the effect of hot temperatures the highest; and whether there are signs of adaptation to extreme temperatures – an important question in the context of climate change. This new study, based on all of the deaths having occurred in France over a 49-year period, confirms the U-shaped relationship (see Graph 1 below) observed between temperature and the majority of the causes of death considered. However, an exception has been observed for death from suicide, which rose steadily in line with the temperature, without the increased risk at cold temperatures observed for the other causes of death. Furthermore, the effect of temperatures at either extreme on all-cause mortality seems to have reduced slightly during this period, which could mean that our society is adapting better. This research has been published in the American Journal of Epidemiology.

Previous scientific publications have studied the short-term link between mortality (irrespective of cause) and temperature – with excess mortality documented during both the hottest and coldest periods, which corresponds to a U-shaped relationship.

For the first time, Inserm researchers at the Institute for Advanced Biosciences in Grenoble were able to study this phenomenon over a period of almost 50 years and rank the causes of death according to their sensitivity to heat. They based their study on the Inserm medical causes of death (CépiDc) registry, whose records date back to 1968. A total of 24.4 million deaths were recorded over 49 years, including over 502,000 by suicide.

The scientists cross-referenced the number of deaths occurring each day in each region along with daily temperatures throughout the study period. The approach[1] concerned only the short-term links between temperature and mortality, and not long-term trends in mortality or geographic variations in mortality.

“Here we are seeing just one of the last stages of a long and complex multifactorial causal chain leading to death,” explains study leader and Inserm research director, Rémy Slama.

 

Graph 1: Association between temperature (x-axis) and relative risk of all-cause mortality (y-axis) for the 1968-2016 period (U-shaped relationship)

When all deaths were considered simultaneously, the mortality rate was minimal when the temperature was close to 20°C, and crossed when the temperature either increased above or decreased below 20°C. Among the 22 causes of death considered, almost all followed this U-shaped relationship described in previous studies (see graph above).

Suicide mortality was a notable exception, with a steady increase in line with temperature – from the lowest temperatures to the highest (see graph below). Among the 22 causes of death considered, suicide was ranked seventh place in terms of sensitivity to heat.

Graph 2: Association between temperature and suicide mortality over the 1968-2016 period

As far as the link between heat and suicide is concerned, the strongest association was found with the temperature on the day of death (rather than that of the preceding days), signifying that it is a very short-term association.

Finally, among the 10 causes of death most strongly related to heat, four involved the nervous system (mental and behavioral disorders, nervous system diseases, cerebrovascular diseases, and suicide). This suggests substantial nervous system sensitivity to high temperatures.

“In order to explore these findings in greater depth, it would be interesting to study the biological parameters that would enable us to understand the underlying mechanisms behind this link between temperature and suicide,” explains Slama.

“The existing hypotheses include at least two non-exclusive avenues: one being the changes in social relationships when temperatures are very high, which could influence suicide; the other being an alteration in endocrine and nervous system functioning in the event of extreme heat, which could increase the risk of suicide, he continues. Research shows that levels of the hormone serotonin tend to decrease when temperatures are high. However, lower levels of this neurotransmitter, which is involved in regulating mood and anxiety, could play a role in the decision to commit suicide,” concludes the research director.

Tendency of French society to adapt to extreme temperatures

The relative wealth of data offered by the registry of the causes of death also made it possible to study the question of adaptation to extreme temperatures. By dividing the study period into three, the scientists were able to study whether the effect of temperatures varied between these periods.

The effects of temperature on all-cause mortality and suicide mortality were attenuated between the 1968-1984 and 1985-2000 periods: for a given temperature, the risk of death was lower during the 1985-2000 period than during the 1968-1984 period. This was seen both for hot temperatures above 20°C and cold temperatures of around 0°C. However, no further attenuation was observed during the 2001-2016 period compared to the previous period (1985-2000).

These findings show the tendency of French society to adjust to extreme temperatures – hot and probably also cold – at the end of the 20th century.

“Although it was not the objective of the study to explain the drivers of this adaptation, we can hypothesize that it is essentially societal, involving improvements to housing and the health system rather than the result of biological evolution, which in principle is very slow,” explains Slama.

The short-term association between temperature and suicide risk could be taken into account in prevention campaigns related to the effects of heat and suicide. It also raises the question of the expected impact of climate change on mortality, which particularly depends on the relationship between temperature and mortality and the ability of societies to adapt to extreme temperatures.

[1] Known as a “time series” analysis

 

If you are having suicidal thoughts, call 3114. The national suicide prevention number is open 24/7. Free and confidential, professionals are there to listen to you.

Even at Low Doses, Exposure to the Endocrine Disruptor DEHP Impairs Tooth Development

Posted on by Graziella Cara

Sagittal section of the incisor of a mouse exposed to DEHP

Sagittal section of the incisor of a mouse exposed to DEHP showing delayed mineralization of the developing enamel, the brown layer between the protein matrix (pink) and the dentin (green). © Sylvie Babajko/Inserm

Some endocrine disruptors have already been associated with an impaired quality of tooth enamel. After demonstrating the harmful effects of bisphenol A on tooth development, a team of researchers from Inserm, Université Paris Cité and Sorbonne Université, at the Cordeliers Research Center in Paris, in collaboration with CNRS[1] went on to look at the effects of DEHP, an endocrine disruptor in the phthalate family, on dental development. While the use of DEHP is highly regulated, it still continues to be found in food containers and certain medical devices such as neonatal intensive care equipment. The scientists have shown that the teeth of mice exposed daily to low doses of this substance present defects whose intensity and prevalence depend on the exposure dose and sex of the animal, with males being more likely than females to develop dental impairments. This discovery confirms the relevance of considering dental enamel defects as an early marker of exposure to environmental toxins. This study has been published in Environmental Health Perspectives.

The significant environmental changes of recent decades have impacted the health and well-being of human populations and all living organisms. Finding markers of exposure to the toxic substances present in the environment therefore represents a major challenge for research.

The scientific literature suggests that dental enamel could be one such marker.

Its analysis enables, for example, retrospective evaluation of the environmental conditions, either by identifying the presence of pollutants trapped in the mineral or by distinguishing enamel defects linked to alterations in cell activity occurring during its formation.

Exposure to endocrine disruptors such as bisphenol A has already been associated with one type of enamel defect, molar incisor hypomineralization (MIH), which is found in around 15% of children between 6 and 8 years of age. Other substances are being monitored, such as the endocrine disruptor DEHP which, despite regulations and bans, can still be present in many medical devices, including neonatal intensive care unit equipment[2].

DEHP belongs to the family of phthalates, chemical compounds commonly used to make plastics flexible. Phthalates can be found in food containers, consumer goods, toys, cosmetics and medical devices. 

On November 23, 2021[3], the European Commission published Regulation no. 2021/2045 amending Annex XIV by adding endocrine disrupting properties to DEHP, BBP, DBP and DIBP. As a result of these changes, certain previously exempt uses are now subject to authorization, including “medical devices and food contact materials that contain DEHP“.

Given the widespread presence of DEHP, its potential contamination of children (whose teeth are still forming), and previous data on the effects of certain endocrine disruptors on enamel, researchers from Inserm, Université Paris Cité and Sorbonne Université, at the Cordeliers Research Center, in collaboration with CNRS, wished to explore the potential effects of DEHP.

In this mouse study, the scientists observed the effects of daily exposure to DEHP, at both low and higher doses. These doses were equivalent to those that can be found in the context of environmental exposure:

  • 5 micrograms/kilo/day: estimated daily exposure of a child to DEHP;
  • 50 micrograms/kilo/day: level of exposure in hospitalized patients on infusion or dialysis, for example.

After 12 weeks of exposure, defects were noted on the rodents’ incisors – teeth that have the particularity of continuous growth[4] and represent the ideal experimental model for studying developing dentition. Less mineralized and softer, the teeth of the exposed mice reflected impaired enamel quality, which worsened as the level of exposure to DEHP increased.

To supplement these data, the researchers then observed the effects of this exposure to DEHP at the cellular and molecular levels. They identified delayed enamel mineralization associated with altered expression of the key genes in enamel formation. Another particularity of the study was that the scientists compared the impact of exposure according to sex and observed greater susceptibility in males.

DEHP therefore disrupted the development of enamel in mice by acting directly on the dental cells, and with increased prevalence and severity in males.

Finally, the scientists point out that the effects observed on the growing teeth of rodents exposed to DEHP or bisphenol A are similar in terms of impaired enamel quality and greater susceptibility of males, and differ in terms of the cells targeted and the molecular mechanisms involved.

While these experimental data need to be consolidated, they do suggest that DEHP, like bisphenol A, could also contribute to enamel hypomineralization defects such as MIH.

“We know that the perinatal period and the first years of life are crucial to child development and health in adulthood. Dental enamel could be a very early reflection of the environmental conditions at this point in life,” explains Sylvie Babajko, Inserm Research Director and last author of the study.

For the research team, the next step is now to understand the effects of combinations of different classes of molecules – or “cocktail effects” – on dental health.

 

1 Contributors to these findings: Laboratory of Molecular Oral Pathophysiology (Cordeliers Research Center/INSERM/Université Paris Cité/Sorbonne Université), Laboratory for Biomedical Research in Odontology (BRIO, UPR2496/Université Paris Cité), Institute of Physical Chemistry (ICP, CNRS/Université Paris-Saclay), Paris-Saclay Laboratory of Mechanics (LMPS, CNRS/CentraleSupélec/ENS Paris-Saclay), and Paris Seine Neuroscience Laboratory at the Paris Seine Institute of Biology (IBPS, CNRS/Inserm/Sorbonne Université).

2 Malarvannan G, Onghena M, Verstraete S, et al. Phthalate and alternative plasticizers in indwelling medical devices in pediatric intensive care units. J Hazard Mater. 2019; doi:10.1016/j.jhazmat.2018.09.087

3 https://substitution-phtalates.ineris.fr/en/regulatory-information

4 The teeth of these animals continue to grow throughout their lives, unlike human teeth.

One in Four French Adults Thought to Have Some Form of Hearing Loss

Posted on by Léa Surugue

This hearing loss study is based on data from thousands of participants from the Constances cohort. © Adobe Stock

Hearing loss is a public health problem that affects billions of people worldwide. However, data on its prevalence – generally speaking, its frequency in the population – and on the use of hearing aids, remain imprecise. A new study by a research team from Inserm and Université Paris Cité at the Paris Cardiovascular Research Center (PARCC, Inserm unit 970)[1], in collaboration with the Paris Hospitals Group AP-HP and Foch Hospital in Suresnes, shows for the first time that 25% of adults in France are affected by some form of hearing loss. Disabling hearing loss, which is more severe, is thought to affect 4% of adults. This prevalence varies with age and other factors (standard of living, noise exposure at work, cardiovascular diseases, etc.), which are described in the study. In addition, the scientists have found that hearing aids remain largely underused, especially among seniors. These findings, based on data from thousands of participants from the Constances cohort, have been published in JAMA Open Network.

Hearing loss affects around 1.5 billion people worldwide, with World Health Organization (WHO) projections suggesting an increase to 2.5 billion by the year 2050. This is a major public health problem, especially since hearing loss is associated with decreased quality of life, social isolation, and other health problems such as depression, cognitive decline, and dementia.

However, it is still difficult to fully understand the extent of the problem and to improve prevention and screening measures, because the data available on the exact prevalence of hearing loss, the characteristics of those affected, and the use of hearing aids are still scarce.

They are most often derived from studies with small and nonrepresentative samples of participants from which it is complicated to draw generalizations, and from self-reported, unmeasured hearing loss data.

In order to have more robust data which can be used to inform public policy, a research team from Inserm, Paris Public Hospitals Group AP-HP, Université Paris Cité and Foch Hospital assessed the prevalence of hearing loss in France. For this they used data from 186,460 volunteers from the Constances cohort, who are representative of the general adult population and in whom hearing loss was measured using hearing tests.

The Constances cohort

Constances is a large-scale French epidemiological cohort, composed of a representative sample of 220,000 adults aged 18 to 75 years at the time of their inclusion. The participants are asked to have a health check every four years and to complete an annual questionnaire. Each year, their data are matched with the French national health insurance databases. This large-scale cohort is supported by the National health insurance fund and financed by the Investments for the future program.

The data collected, which concern health, socio-professional characteristics, use of health care services, and biological, physiological, physical, and cognitive parameters, enable us to learn more about the determinants of many diseases.

For more information: constances.fr

The volunteers, aged 18 to 75 years, completed questionnaires on their demographic and socioeconomic characteristics, their medical history and that of their relatives, as well as their lifestyles. They also underwent a health examination, between 2012 and 2019, which included a hearing test.

The study authors analyzed the entirety of this data and found that 25% of the individuals in the study sample had hearing loss, with 4% of the sample affected by disabling hearing loss (see box below). In addition, this research found that little use is made of hearing aids. For example, only 37% of patients with disabling hearing loss were wearing one.

Hearing loss

  • The term “hearing loss” is used to refer to a person who is unable to hear as well as someone with normal hearing, the threshold being 20 decibels (dB) of loss in the better ear.
  • “Disabling hearing loss” means a hearing loss greater than 35 decibels (dB) in the better ear.

Taking their interpretation further, the researchers then attempted to identify the factors associated with hearing loss. Their analyses suggest that older people, men, people with a high body mass index (BMI), people with diabetes, with cardiovascular risk factors, a history of depression, or exposed to noise at work had the highest likelihood of suffering from hearing loss.

Conversely, having a higher income or education level, living alone, or living in an urban area were associated with a lower likelihood of hearing loss.

Hearing aid use was particularly low among elderly people (who are proportionately more affected by disabling hearing loss), men, smokers, and those with a high BMI.

Improving our understanding of the prevalence of hearing loss and the profile of those it affects is very important if we are to better target patients who are at risk, in order to screen them, improve their care, and refine prevention measures.

“This is the first time in France that a study on the prevalence of hearing loss and the use of hearing aids has been conducted on such a large and representative sample of the country’s adult population. This allows us to establish a reliable picture and to provide keys to public decision-makers, even though effective solutions (such as hearing aids and cochlear implants) are available to manage this major health problem,” stress Quentin Lisan and Jean-Philippe Empana, who coordinated the study.

While France has recently passed a measure allowing the reimbursement of hearing aids by Social Security (which was not yet the case at the time the study was conducted), it would be interesting for future research to evaluate the efficacy of such an initiative in encouraging the use of hearing aids.

 

[1] Team 4: Integrative Epidemiology of Cardiovascular Disease

Phage Therapy: A Model to Predict Its Efficacy against Pathogenic Bacteria

Posted on by Graziella Cara

Photo (colorized) of scanning electron microscopy of a bacterium lyzed by the phages (© L. Debarbieux, Institut Pasteur; M. and C. Rohde, Helmholtz Centre for Infection Research).

Antibiotic resistance represents a major public health challenge, associated with a high mortality rate. While bacteriophages – viruses that kill bacteria – could be a solution for fighting antibiotic-resistant pathogens, various obstacles stand in the way of their clinical development. To overcome them, researchers from Inserm, Université Sorbonne Paris Nord and Université Paris-Cité at the IAME Laboratory, in close collaboration with their counterparts at Institut Pasteur and the Paris Public Hospitals Group (AP-HP), have developed a model to better predict the efficacy of phage therapy and possibly develop more robust clinical trials. Their findings have been published in Cell Reports.

The discovery of antibiotics had revolutionized the history of medicine in the 20th century, allowing us to effectively fight bacteria for the first time. However, antibiotic resistance – a phenomenon during which bacteria become resistant following mass, repeated use – has become a major public health issue in recent decades. Each year, these resistant bacteria are estimated to be responsible for 700,000 deaths worldwide. Yet the discovery of new antibacterial agents has been stagnating for several years.

In this context, phage therapy has recently generated renewed interest. This therapeutic approach involves the use of bacteriophages that target and destroy pathogenic bacteria whilst being unable to infect humans. While the concept has been in existence for a long time, its clinical development has been hampered by various limitations. Unlike “conventional” medicines, bacteriophages are complex biologics, whose action in the body, optimal dose, and most effective route of administration are difficult to study and anticipate.

In order to remove some of these obstacles, Jérémie Guedj’s research team at Inserm, in collaboration with Laurent Debarbieux’s team at Institut Pasteur, has developed a new mathematical model to better define the interactions between bacteriophages and pathogenic Escherichia coli bacteria in animals and to identify the key parameters that influence the efficacy of phage therapy.

Supporting clinical development

Various data from in vitro and in vivo experiments were used to construct this model. In particular, the researchers used the bacteriophages’ infection parameters determined in the laboratory (for example, the duration of the infectious cycle of the bacteria, the number of viruses released when a bacterium is destroyed…) and information collected during experiments using a mouse model of lung infection.

Some of the animals were infected with a bioluminescent strain of E. Coli (in order to best monitor it within the body). Among them, some were treated with bacteriophages at different doses and using different routes of administration. The quantities of bacteria and bacteriophages thus measured over time helped to feed the mathematical model and test which were the most important parameters for effective phage therapy. 

Using their model, the scientists show that the route of administration is an important parameter to consider when it comes to improving the animals’ survival: the more rapidly it brings the bacteriophages into contact with the bacteria, the more it is effective. In the animal model, the phage therapy administered intravenously was therefore less effective in comparison with the intratracheal route because fewer bacteriophages were reaching the lungs. On the other hand, when administered by intratracheal route, the model suggests that the dose of the medication given has little effect on the efficacy of the therapy.

Another important point is that this model incorporates data on the animals’ immune response in the context of phage therapy. The model confirms and extends the principle that bacteriophages act in synergy with the immune system of infected animals, enabling more effective elimination of pathogenic bacteria.

“In this study, we propose a new approach to streamline the clinical development of phage therapy, which otherwise continues to have its limitations. Our model could be reused to predict the efficacy of any bacteriophage against the bacteria it targets, once a limited number of in vitro and in vivo data are available on its action. Beyond phage therapy, the model could also be used to test anti-infective therapies based on the association between bacteriophages and antibiotics,” concludes Guedj.

Signature d’un accord cadre entre Santé publique France et l’Inserm

Posted on by Graziella Cara

Influenza: A New Avenue for Developing Innovative Treatments

Posted on by Graziella Cara

Cellules épithéliales respiratoires humaines

Human respiratory epithelial cells (in red) infected with an influenza virus (in green). © A. Cezard, D. Diakite, A. Guillon, M. Si-Tahar, PST ASB-Microscopy Department.

Seasonal influenza is a major public health issue because it continues to remain associated with considerable mortality, particularly among people who are elderly, immunocompromised, or both. It also has a significant socioeconomic cost. With vaccination and current treatments still being of limited efficacy, research teams are trying to develop new therapeutic approaches. At the Research Center for Respiratory Diseases in Tours, scientists from Inserm, Université de Tours and Tours Regional University Hospital have shown that in a context of influenza infection, a metabolite[1] called succinate, which is naturally present in the body, has an antiviral and anti-inflammatory action. These findings open up new therapeutic prospects based on the use of succinate derivatives. The study has been published in EMBO Journal.

Often considered a mild disease, influenza continues to cause the deaths of 10,000 to 15,000 people each year in France. The socioeconomic cost of the disease is also significant because it is associated with high levels of absenteeism and a major burden on hospitals.

Seasonal influenza vaccination is a central pillar of the preventive strategies deployed to reduce the number of cases and fight the disease. However, its efficacy can vary from year to year, depending on the influenza viruses in circulation and the suitability of the vaccine to them. Drugs that directly target the influenza virus are available for severe cases, but the window of time for effective action with these treatments is very short. What is more, influenza viruses have become resistant to their action.

In this context, the development of innovative therapies is a priority. While current treatments work by targeting certain components of the virus, Inserm Research Director Mustapha Si-Tahar and his colleagues at the Research Center for Respiratory Diseases are trying to better understand the host’s cellular and molecular responses to viral infection, with the long-term aim of developing novel therapeutic strategies aimed at strengthening these responses.

The role of metabolites in immune response

While metabolism1 has long been considered to be a purely energetic mechanism essential for cell function, recent research has shown that some metabolites can also regulate the immune response.

Based on these data, Si-Tahar’s team wondered whether an influenza infection could cause the reprogramming of the metabolism of the target cells of the virus and whether specific metabolites play an especially active role in the immune response.

In mice infected with influenza, the researchers observed that a metabolite called succinate accumulates in the lungs. A phenomenon which was then confirmed in humans by comparing respiratory fluids from intensive care patients with and without influenza pneumonia. The presence of succinate was found to be significantly higher in the influenza patients.

They then exposed cells from the pulmonary epithelium to succinate, thereby demonstrating that the molecule has antiviral activity by blocking multiplication of the virus. Succinate also helps to reduce the strong inflammatory response that is triggered in the lungs following infection with influenza.

The researchers also found that mice exposed to the virus receiving intranasal succinate are better protected against infection and have a higher survival rate than those that do not receive it.

In search of molecular mechanisms

In order to better understand these different phenomena, the scientists sought to decipher the molecular mechanisms behind the antiviral action of succinate.

This involved analyzing the impact of succinate on the various stages of the viral replication cycle and demonstrating that, while there is no influence on the early stages of the cycle (entry, transcription, and translation), there is an influence on a later stage. The findings show that this metabolite prevents a major structural protein of the virus, the “nucleoprotein”, from exiting the nucleus of infected cells, thereby preventing the assembly of the final viral particle and interrupting the multiplication cycle of the virus.

These data all point to the key role of succinate in controlling influenza infection, as well as its therapeutic value.

“Our research has an interesting outlook in that it potentially paves the way for the development of new antiviral treatments derived from succinate,” underlines Si Tahar[2].

Additional studies are needed in order to test the therapeutic potential of succinate and identify other metabolites of interest.

 

[1] Metabolism refers to all of the chemical reactions that take place inside the body’s cells. A metabolite is an organic substance derived from metabolism.

[2] In keeping with this research, Si-Tahar has since early 2021 coordinated a French National Research Agency (ANR) program entitled “Development of succinate-based formulations and analogues against SARS-CoV-2-induced respiratory infections and influenza viruses.” His team is also the beneficiary of an “ERS-RESPIRE4 Marie Skłodowska-Curie fellowship” to develop a project entitled “Succinate-Producing Probiotics as an Innovative Therapy for Viral Respiratory Infections: a proof-of-concept study”.

Infertility: New Avenues to Understand the Harmful Effects of Chemotherapy

Posted on by Léa Surugue

Immunostaining of a mouse testicle section

Immunostaining of a mouse testicle section, with (in red) the undifferentiated germ cells and (in green) the GFP protein reflecting TGR5 receptor expression in this study model. ©David Volle/Inserm

Infertility is a public health problem affecting millions of couples in France. Among the possible causes, chemotherapy has been singled out as having particularly harmful effects on the fertility of both women and men. In order to better prevent and restore fertility in cancer survivors, understanding the mechanisms behind these negative effects is a priority. In a new study, researchers from Inserm, CNRS and Université Clermont Auvergne investigated a receptor found on male germ cells that produce gametes, their aim being to find out more about its role in chemotherapy-related infertility. Their findings, published in Advanced Science, pave the way for a better understanding of male infertility and the development of treatments to reduce the risk of sterility from chemotherapy.

Around 3.3 million people in France are directly affected by infertility. Concerning both men and women, it has continued to increase in recent years, making it a major public health problem [1].

While there are many causes of infertility, it is currently well established that cancer treatments, including chemotherapy, can have particularly harmful effects on male and female fertility. Although cancer therapies have improved in recent years, tackling this issue is becoming a matter of urgency, as an increasing number of cancer survivors will be affected by infertility problems.

For almost 15 years, Inserm researcher David Volle and his team at the Genetics, Reproduction and Development Laboratory (Inserm/CNRS/Université Clermont Auvergne) have sought to improve their understanding of the biological mechanisms underlying infertility. Part of their research focuses on the impact of chemotherapy on male fertility, with the longer-term objective of identifying avenues to counter the adverse effects of this treatment.

In their new study, the researchers looked at TGR5 receptors, which are present on cell membranes, in order to understand their role in the harmful effects of chemotherapy.

TGR5 receptors are widely studied in the context of metabolic diseases, such as diabetes and obesity. They are activated by bile acids – molecules produced in the liver that regulate certain physiological functions, including blood glucose and energy expenditure.

 However, previous research by the team had shown that these receptors are also present in germ cells, the cells that produce gametes. In mouse models mimicking liver disease, with elevated bile acid levels, the scientists had found that the TGR5 receptors on germ cells were activated – which was associated with increased sterility in animals.

Germ cell death

To further understand the impact of TGR5 on fertility in the context of chemotherapy, the scientists in their latest study exposed mice to a chemotherapy agent called busulfan. They then showed that the chemotherapy induces the death of some of the germ cells in healthy mice, thereby affecting their fertility. “The fact that it is the germ cells, at that point undifferentiated, which are affected is particularly problematic because we are talking about the reserve of cells that produce gametes. This can reduce their renewal and contribute to post-chemotherapy infertility,” says Volle.

However, in mice that have been genetically modified to have an absence of TGR5 receptors, the effects of chemotherapy on germ cells are attenuated. This results in an accelerated return of fertility in these busulfan-treated mice compared with the control mice.

“Our study has therefore improved our understanding of the molecular mechanisms involved in the harmful effects of chemotherapies on germ cells and fertility. These findings show that TGR5 receptors play an important role in the harmful effects of chemotherapy on infertility,” adds Volle.

In the longer term, the objective is to develop methods to modulate TGR5 receptor activation in a targeted manner within germ cells, in order to protect them and restore fertility after chemotherapy.

The idea is also to assess whether these data can be extrapolated to other disease contexts in which TGR5 receptor activity could be modulated, such as obesity and diabetes, conditions known to impair fertility.

In addition, in parallel to this research, the team observed that even when fertility was maintained in mice exposed to chemotherapy, the quality of the gametes was affected. The scientists will therefore now endeavor to understand both the quantitative and qualitative impacts on germ cells in order to limit not just fertility disorders but also the longer-term consequences on the offspring of animals.

 

[1] A report requested by the French Minister of Health and the Secretary of State for Childhood and Family in February 2022 outlines a national strategy to combat infertility: https://solidarites- sante.gouv.fr/IMG/pdf/rapport_sur_les_causes_d_infertilite.pdf

Long COVID: When Symptoms Persist Months after the First Wave

Posted on by Léa Surugue

During the first wave of COVID-19, participants from the Constances cohort completed two questionnaires to determine the presence of symptoms during the previous 15 days. Credits: Adobe Stock

Several months after infection with SARS-CoV-2, some patients are still having symptoms – a phenomenon known as “long COVID” or “post-COVID-19 condition”. Still poorly understood, scientists are now attentively studying long COVID in order to improve knowledge and offer patients the best possible treatment. Researchers from Inserm, Université Paris-Saclay and Sorbonne Université at the Pierre-Louis Institute of Epidemiology and Public Health, in collaboration with ANRS | Emerging Infectious Diseases, have used data from around 26,000 Constances cohort volunteers to identify the persistent symptoms most commonly reported by SARS-CoV-2 patients compared with the rest of the population. These are mainly loss of taste or smell, difficulty breathing and fatigue and are particularly seen in patients who experienced typical COVID symptoms at the time of infection. Their findings have been published in The Lancet Regional Health – Europe.

Many people report symptoms that persist for several months after infection with SARS-CoV-2. Still poorly understood, “long COVID” is currently the subject of rigorous research in order to better define its prevalence in the general population and decipher its underlying pathophysiological mechanisms.

The persistent symptoms most commonly described in the scientific literature include dyspnea (difficulty breathing), asthenia (fatigue), joint and muscle pain, cognitive complaints, digestive complaints, and anosmia/dysgeusia (loss of smell and taste).

Apart from anosmia/dysgeusia, these clinical manifestations are not specific to COVID-19 and may, for example, be related to other infections occurring during the same period or to more restricted access to health care during the pandemic.

In order to better understand and treat long COVID, it is therefore essential for scientists to determine which persistent symptoms are more specifically associated with SARS-CoV-2 infection than with other conditions.

A general population study

A new study published in The Lancet Regional Health has examined this issue. One of the aspects that makes this research original is that it was carried out in a general population cohort.

General population cohorts differ from cohorts constructed from samples of COVID patients (who, by definition, are all “symptomatic”, often with severe clinical forms or hospitalized), which are not representative of everyone with the infection.

General population cohorts therefore make it possible to understand public health problems through the creation of comparison groups, for example focusing on the severity of symptoms at the time of infection.

Another novel aspect is that the participants all underwent a serological test to screen for a history of SARS-CoV-2 infection. This differentiates this study from the majority of its counterparts, which focus on those having performed a PCR test and who have presented symptoms.

For example, this study compared the persistence of symptoms seven to eight months after the first wave of the pandemic in four groups of participants[1] distributed according to the symptoms they had during that first wave and their serological status (whether or not they had been infected with SARS-CoV-2). 

Long-term symptoms according to serological status

A total of 25,910 participants from the Constances cohort (see box) completed two questionnaires during the first wave of COVID-19 to determine the presence of symptoms during the fifteen days prior. They then underwent a serological test, between May and November 2020, to identify those who had been exposed to the virus.

Finally, between December 2020 and February 2021, they completed a third questionnaire, which looked at symptoms having persisted or persisting for at least two months. This questionnaire included the list of symptoms focused on during the first waves of questionnaires, as well as new symptoms presented by people with long COVID (problems with concentration and attention, chest pains, etc.).

The researchers compared the individuals having presented symptoms suggestive of acute respiratory infection based on the results of their serological test. They observed that symptomatic individuals seropositive for SARS-CoV-2 had more persistent anosmia/dysgeusia, dyspnea and fatigue than those who were seronegative. The frequency of the other symptoms was equivalent.

Links between symptoms at the time of infection and persistent symptoms

The researchers then explored the link between infection, acute symptoms, and persistent symptoms. The results of their statistical analyses show that SARS-CoV-2 mainly affects the persistence of symptoms if it induces certain symptoms during the acute phase of the infection.

“Our findings confirm the importance of the clinical expression of the initial infectious episode in the risk of developing persistent symptoms. They can help guide public policies by providing more accurate data on the type of persistent COVID-19 symptoms and encourage the development of strategies for more effective treatment. Promoting preventive therapies and approaches, such as vaccination, that reduce symptoms in the acute phase of the disease could also have a beneficial effect on long COVID,” the study authors noted.

These findings reflect the complexity of the mechanisms that can explain the persistent symptoms, emphasizing that these symptoms may be related to the virus, to the initial clinical presentation of the infection, and to other non-specific causes.

They also suggest the importance of conducting studies on post-infectious conditions, regardless of the micro-organism in question.

Further research is under way to understand the mechanisms behind long COVID and to quantify the extent to which these persistent symptoms can be attributed to SARS-CoV-2 infection

The Constances cohort

Constances is a large-scale French epidemiological cohort, composed of a representative sample of 220,000 adults aged 18 to 69 years at the time of their inclusion. Participants are asked to have a health check every four years and to complete an annual questionnaire. Each year, their data are matched with the French national health insurance databases. This large-scale cohort is supported by the National Health Insurance Fund and financed by the Investments for the Future Program.

The data collected, which concern health, socio-professional characteristics, use of health care services, and biological, physiological, physical and cognitive parameters, enable us to learn more about the determinants of many diseases.

Constances is one of three cohorts on which is based the SAPRIS-SERO project led by Inserm and ANRS | Emerging Infectious Diseases – a project which aims to quantify the incidence of SARS-CoV-2 in the French population on the basis of serological tests.

For more information: constances.fr

[1] The members of the first group of participants all had a positive COVID-19 serological test and had reported symptoms during the first wave. Those of the second group had a positive test but no symptoms. Those of the third group had a negative test and symptoms, while those of the fourth group were asymptomatic during the first wave and with a negative test.

HIV: The Antibodies of “Post-treatment Controllers”

Posted on by Léa Surugue

VIH

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A very small percentage of people with HIV-1, known as “post-treatment controllers” (PTCs), are able to control their infection after interrupting all antiretroviral therapy. Understanding the fundamental mechanisms that govern their immune response is essential in order to develop HIV-1 vaccines, novel therapeutic strategies to achieve remission, or both. A recent study investigated the humoral immune response – also known as antibody-mediated immunity – in some PTCs in whom transient episodes of viral activity were observed. The researchers have shown their humoral immune response to be both effective and robust, which could help to control the infection in the absence of treatment. The findings of this study, carried out in collaboration with teams from Institut Pasteur, Inserm and Paris Public Hospitals Group (AP-HP) and supported by ANRS | Emerging Infectious Diseases and the National Institutes of Health (NIH), were published in Nature Communications on April 11, 2022.

A very small percentage of people with HIV-1 and who received early treatment maintained over several years have the capacity to control the virus over the long-term when their treatment is interrupted. However, the mechanisms of this control have not been fully elucidated.  

The team of researchers, led by Dr. Hugo Mouquet, director of the Laboratory of Humoral Immunology at Institut Pasteur (partner research organization of Université Paris Cité), conducted an exhaustive study in PTCs in order to characterize their humoral response (i.e. their production of B cells and specific antibodies), compared with non-controllers.

The scientists have shown that the humoral immune response profiles vary according to the activity of the virus observed in the subjects.

In PTCs who experience short episodes in which the virus resumes low-level activity after interruption of treatment, transient exposure to the viral antigens induces:

  • a strong anti-HIV-1 humoral response, involving more frequent intervention of HIV-1 envelope-specific memory B cells;
  • the production of antibodies with a cross-neutralizing action and which possess “effector” antiviral activities in which the innate immune cells recognize the infected cells bound to the antibodies, thereby inducing their elimination;
  • the increase in the blood of atypical memory B cells and subpopulations of activated helper T cells.

This specific, multifunctional, and robust humoral response could help to control their infection in the absence of treatment.

However, other PTCs in whom the virus continuously remains undetectable after treatment interruption do not develop a strong humoral response. The control mechanisms in these patients continue to be investigated in the VISCONTI study.

The discovery of these two types of humoral immune response, which depend on the profile of the PTCs, sheds new light on the phenomenon of HIV control. For Dr. Mouquet, researcher at Institut Pasteur and principal investigator of the study, “these findings show that early antiretroviral treatment can facilitate the optimal development of humoral immune responses, in some cases countering viral rebound after treatment interruption.” The example of the immune response of the PTCs having short episodes of “awakening” of the virus could even inspire novel therapeutic or vaccine strategies.

ANRS VISCONTI: to improve understanding of the HIV control mechanisms in “post-treatment controllers”

The “post-treatment controllers” whose samples were used for this research are part of the VISCONTI (Viro-Immunological Sustained COntrol after Treatment Interruption) study, coordinated by Dr. Asier Sáez-Cirión (Institut Pasteur) and Dr. Laurent Hocqueloux (Orleans Regional Hospital) and supported by ANRS for several years. This is the largest cohort of long-term “post-treatment controllers”.

It includes 30 patients who had received early treatment that was maintained for several years. Upon interruption of their antiretroviral therapy, they are able to control their viremia for a period exceeding 20 years in some cases. VISCONTI therefore provides the proof of concept of a possible and sustained state of remission for HIV-1-infected patients. It has paved the way for the development of novel therapies that target remission from the infection – if not its eradication. The objective is to enable people living with HIV-1 to stop their antiretroviral treatment on a lasting basis, while maintaining viremia at the lowest level and avoiding the risk of transmission of the virus.

Older Adults: Understanding and Preventing Barriers to an Active Lifestyle

Posted on by Graziella Cara

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To prevent older adults from settling into an unhealthy sedentary lifestyle, public health policies have been implemented to promote physical activity, which is essential for maintaining good health. Researchers from Inserm and Université Paris Cité within the Center for Research in Epidemiology and Statistics have studied the impact of individual sociodemographic, behavioral and health factors on the practice of daily physical activity in later life, using data from 3,896 participants of the Whitehall II cohort. This research, published in JAMA Network Open, highlights the complexity of individual barriers to an active lifestyle among older adults and suggests that this complexity should be better taken into account when redefining public health policies.

By maintaining many essential functions that prevent chronic disease and mortality, physical activity is one of the keys to healthy aging. Although it is currently recommended to do 21 minutes of moderate to intense physical activity per day and reduce the amount of time spent sitting (being sedentary), few people actually follow this advice – especially older adults. In addition, public health messages aimed at older adults take little account of individual factors, whether environmental or personal, that may limit the adoption of an active lifestyle.

A team led by Séverine Sabia, Inserm researcher at the Center for Research in Epidemiology and Statistics (Inserm/Université Paris Cité), studied the factors that influence physical activity and sedentary behavior in later life.

The scientists looked at data from Whitehall II1, a British cohort of which 3,896 of its participants, between 60 and 83 years of age, had worn a measuring device for a nine-day period in 2012-2013. This device, called an accelerometer, continuously recorded data on the intensity and duration of their daily physical activity. In addition, data relating to their sociodemographic characteristics (age, sex, ethnicity, occupation, marital status), behaviors (consumption of tobacco, alcohol, fruits and vegetables), health (body mass index, quality of life, chronic diseases) and physical activity were collected between 1991-1993 and 2012-2013, representing a 20-year period prior to the accelerometer measurements.

In terms of physical activity, the researchers considered three levels of intensity: sedentary (low-energy activity while sitting or lying down), light (e.g. slow walking), and moderate to vigorous (e.g. swimming, cycling).

Their first finding was that men spend more time being sedentary or engaging in moderate to vigorous activity than women, who spend more time than men doing light physical activity.

Depending on the factors studied, a longer duration of time spent being sedentary by older adults had differing effects on the duration of the other levels of intensity. For example, in comparison with those living with partners, people living alone spend on average an additional 11 minutes being sedentary, mostly at the expense of time devoted to light physical activity. In contrast, although a five-year age difference results in a similar increase in time spent being sedentary, this comes at the expense of time devoted to moderate to vigorous activity – which is more than half the recommended daily time (21 minutes).

The behavioral factors all appear to impact the time devoted to the different levels of intensity. The largest difference is seen with male smokers, who spend 37.4 more minutes per day being sedentary, at the expense of 23.3 minutes of light activity and 14.1 minutes of moderate to vigorous activity (i.e. two-thirds of the time recommended for the latter). However, in women who smoke, the increase in sedentary time comes at the expense of moderate to vigorous activity.

Among the factors relating to health status, poor general health, the presence of chronic diseases, and obesity are associated with a significant increase in the time spent being sedentary.

The largest discrepancies are seen with obesity: at the same age, people with obesity spend 50.7 minutes longer per day being sedentary than those with a normal body mass index, at the expense of 28.6 minutes of light activity and 22.1 minutes of moderate to vigorous activity – i.e. all of the time recommended for the latter.

In general, for women, nearly all of the factors impact the time spent on the different intensities of physical activity – an impact that is similar but globally attenuated in comparison with men.

“We wanted to know if barriers to physical activity among older adults were already present earlier in life and we found that they were. Living alone, being overweight or obese, the presence of chronic diseases, poor physical functioning or poor lifestyle at the average ages of 50 and 60 were associated with low activity levels in later life,” explains Mathilde Chen, lead author of the study. We were also able to see a clustering of behavioral risk factors: people who are more sedentary tend to smoke and eat fewer fruits and vegetables. This research reflects the complexity of the determinants of an active lifestyle among older adults. “

Séverine Sabia, study investigator, concludes: “In the fight against the health impacts of high levels of inactivity among older adults, this research provides arguments in favor of targeted prevention strategies, integrating all components of physical activity and healthy lifestyle behaviors, and addressing as early as possible those who are most likely to be sedentary in later life. “

1 The Whitehall II cohort was set up between 1985 and 1988; a total of 10,308 British participants (67% male) aged 35-55 years were recruited and have been followed up ever since.

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