A new review of existing evidence proposes eight hallmarks of environmental exposures that chart the biological pathways through which pollutants contribute to disease: oxidative stress and inflammation, genomic alterations and mutations, epigenetic alterations, mitochondrial dysfunction, endocrine disruption, altered intercellular communication, altered microbiome communities, and impaired nervous system function.
The study by researchers at Columbia University Mailman School of Public Health, Ludwig Maximilian University, and Hasselt University is published in the journal Cell.
“Every day we learn more about how exposure to pollutants in air, water, soil, and food is harmful to human health,” says senior author Andrea Baccarelli, MD, PhD, chair of Environmental Health Sciences at Columbia Mailman School. “Less understood, however, are the specific biological pathways through which these chemicals inflict damage on our bodies. In this paper, we provide a framework to understand why complex mixtures of environmental exposures bring about serious illness even at relatively modest concentrations.”
We are continually exposed to a mixture of pollutants, which lead to changes in our bodies in multiple domains, from conception to old age. They govern gene expression, train and shape our immune systems, trigger physiological responses, and determine wellbeing and disease.
The paper summarizes evidence for eight hallmarks of environmental insults:
1. Oxidative stress and inflammation: When antioxidant defenses are depleted, inflammation, cell death, and organ damage occur.

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2. Genomic alterations and mutations: An accumulation of DNA errors can trigger cancer and other chronic diseases.
3. Epigenetic alterations: Epigenetic changes alter the synthesis of proteins responsible for childhood development and regular function of the body.
4. Mitochondrial dysfunction: A breakdown in the cellular powerplant may interfere with human development and contribute to chronic disease.
5. Endocrine disruption: Chemicals found in our environment, food, and consumer products disrupt the regulation of hormones and contribute to disease.
6. Altered intercellular communication: Signaling receptors and other means by which cells communicate with each other, including neurotransmission, are affected.

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7. Altered microbiome communities: An imbalance in the population of bacteria and other microorganisms in our body can make us susceptible to allergies and infections.
8. Impaired nervous system function. Microscopic particles in air pollution reach the brain through the olfactory nerve, and can interfere with cognition.
Not all environmental exposures are harmful. The researchers note that exposure to nature has been reported to have beneficial impacts on mental health.
These eight hallmarks are by no means comprehensive and do not capture the full complexity of the chemical and physical properties of environmental exposures, including mixtures of exposures over the short and long-term. Further research is needed to understand the complex mechanisms by which exposures affect human biology, and how altered processes interact and contribute to disease or confer health benefits, across the life course.
“We need research to expand our knowledge of disease mechanisms going beyond genetics.
Advances in biomedical technologies and data science will allow us to delineate the complex interplay of environmental insults down to the single-cell level,” says Baccarelli. “This knowledge will help us develop ways to prevent and treat illness. With the serious environmental challenges like air pollution and climate change, most of all, we need strong local, national, and inter-governmental policies to ensure healthy environments.”

Intellectual disability puts individuals at higher risk of dying earlier in life than the general population, for a variety of medical and institutional reasons. A new study from Jefferson Health examined how the COVID-19 pandemic has affected this group, which makes up 1-3% of the US population. The study, published today in the New England Journal of Medicine (NEJM) Catalyst, found that intellectual disability was second only to older age as a risk factor for dying from COVID-19.
“The chances of dying from COVID-19 are higher for those with intellectual disability than they are for people with congestive heart failure, kidney disease or lung disease,” says lead author Jonathan Gleason, MD, the James D. and Mary Jo Danella Chief Quality Officer for Jefferson Health. “That is a profound realization that we have not, as a healthcare community, fully appreciated until now.”
The authors examined 64 million patient records from 547 healthcare organizations between January 2019 to November 2020 to understand the impact of the COVID-19 pandemic on patients with intellectual disabilities. They identified variables such as COVID-19, intellectual disability or other health conditions, as well as demographic factors such as age.
The results showed that those with intellectual disabilities were 2.5 times more likely to contract COVID-19, were about 2.7 times more likely to be admitted to the hospital and 5.9 times more likely to die from the infection than the general population.
“Our failure to protect these deeply vulnerable individuals is heart-breaking,” says co-author Wendy Ross, MD, a developmental and behavioral pediatrician and director for the Center for Autism and Neurodiversity at Jefferson Health. “I believe that if we can design a system that is safe and accessible for people with intellectual disabilities, it will benefit all of us.”
The authors write that patients with intellectual disabilities may have less ability to comply with strategies that reduce the risk of infection, such as masking and social distancing. In addition, the researchers showed that these patients are more likely to have additional health conditions that contribute to a more severe course of COVID-19 disease. The results of the study highlight how these issues become compounded in this population.
“We need to understand more about what is happening with these patients,” says Dr. Gleason. “I do believe these patients and their caregivers should be prioritized for vaccination and healthcare services. We should reflect on why we have failed this vulnerable population, and how we can better serve them during this health crisis, and into the future,” Dr. Gleason says. “Even prior to the pandemic, individuals with intellectual disabilities have had poor health outcomes. We need to do much better.”
The authors suggest key action steps that require a rapid response. “First, those with intellectual disabilities and their caregivers should be prioritized for vaccines by organizations that set federal guidelines, including the CDC,” says Dr. Gleason. “Second, federal and state healthcare regulatory offices should measure access, quality and safety in this population in order to track our ability to improve health outcomes for these patients. Finally, the United States should redesign the care model for individuals with intellectual disabilities.”
“As an organization deeply committed to advocating for the health of one of the most marginalized populations — those with intellectual disabilities (ID) — we have seen the need for people with ID to be prioritized as a high-risk group during this pandemic. It’s devastating to hear that people with ID are almost six times more likely to die from COVID-19,” said Alicia Bazzano, MD, PhD, MPH, Chief Health Officer of the Special Olympics. “Most health authorities do not recognize that people with ID who get COVID-19 have a much higher risk of dying. Special Olympics is grateful to the Jefferson team for shining a spotlight on these devastating numbers.”

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Studies of the microbiome in the human gut focus mainly on bacteria. Other microbes that are also present in the gut — viruses, protists, archaea and fungi — have been largely overlooked.
New research in mice now points to a significant role for fungi in the intestine — the communities of molds and yeasts known as the mycobiome — that are the active interface between the host and their diet.
“We showed that the gut mycobiome of healthy mice was shaped by the environment, including diet, and that it significantly correlated with metabolic outcomes,” said Kent Willis, M.D., an assistant professor at the University of Alabama at Birmingham and co-corresponding author of the study, published in the journal Communications Biology. “Our results support a role for the gut mycobiome in host metabolic adaptation, and these results have important implications regarding the design of microbiome studies and the reproducibility of experimental studies of host metabolism.”
Willis and colleagues looked at fungi in the jejunum of the mouse small intestine, site of the most diverse fungal population in the mouse gut. They found that exposure to a processed diet, which is representative of a typical Western diet rich in purified carbohydrates, led to persistent differences in fungal communities that significantly associated with differential deposition of body mass in male mice, as compared to mice fed a standardized diet.
The researchers found that fat deposition in the liver, transcriptional adaptation of metabolically active tissues and serum metabolic biomarker levels were all linked with alterations in fungal community diversity and composition. Variations of fungi from two genera — Thermomyces and Saccharomyces — were the most strongly associated with metabolic disturbance and weight gain.
The study had an ingenious starting point. The researchers obtained genetically identical mice from four different research animal vendors. It is known that gut bacterial communities vary markedly by vendor. Similarly, the researchers found dramatically different variability by vendor for the jejunum mycobiomes, as measured by sequencing internal transcribed spacer rRNA. At baseline, mice from one of the vendors had five unique fungal genera, and mice from the other three vendors had three, two and one unique genera, respectively.

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They also looked at interkingdom community composition — meaning bacteria as well as fungi — and found large baseline bacterial community differences. From this initial fungal and bacterial diversity, they then measured the effects of time and differences in diet — standardized chow versus the highly processed diet — on fungal and bacterial community composition.
The researchers also addressed a fundamental question: Are the fungal organisms detected by next-generation sequencing coming from the diet, or are they true commensal organisms that colonize and replicate in the gut? They compared sequencing of the food pellets, which contained some fungi, and the contents of the mouse jejunum to show the jejunum fungi were true commensal colonizers.
Thus, this study, led by Willis — and co-corresponding author Joseph Pierre, Ph.D., and co-first authors Tahliyah S. Mims and Qusai Al Abdallah, Ph.D., from the University of Tennessee Health Science Center, Memphis, Tennessee — showed that variations in the relative abundance and composition of the gut mycobiome correlate with key features of host metabolism. This lays a foundation towards understanding the complex interkingdom interactions between bacteria and fungi and how they both collectively shape, and potentially contribute to, host homeostasis.
“Our results highlight the potential importance of the gut mycobiome in health, and they have implications for human and experimental metabolic studies,” Pierre said. “The implication for human microbiome studies, which often examine only bacteria and sample only fecal communities, is that the mycobiome may have unappreciated effects on microbiome-associated outcomes.”
The research was mostly done at the University of Tennessee Health Science Center, where Willis was an assistant professor before joining the Division of Neonatology in the UAB Department of Pediatrics last summer.
The translational research in the Willis Lung Lab at UAB seeks to understand how such commensal fungi influence newborn physiology and disease, principally via exploring the gut-lung axis in bronchopulmonary dysplasia, a lung disease of premature newborns. The study in Communications Biology using adult animals, Willis says, helped develop models for on-going research in newborn animals.
Co-authors with Willis, Pierre, Mims and Al Abdallah in the study, “The gut mycobiome of healthy mice is shaped by the environment and correlates with metabolic outcomes in response to diet,” are Justin D. Stewart, Villanova University, Radnor, Pennsylvania; and Sydney P. Watts, Catrina T. White, Thomas V. Rousselle, Ankush Gosain, Amandeep Bajwa and Joan C. Han, the University of Tennessee Health Science Center.
Support came from National Institutes of Health grants CA253329, HL151907, DK117183 and DK125047.

In 1993, scientists discovered that a single mutated gene, HTT, caused Huntington’s disease, raising high hopes for a quick cure. Yet today, there’s still no approved treatment.
One difficulty has been a limited understanding of how the mutant huntingtin protein sets off brain cell death, says neuroscientist Srinivasa Subramaniam, PhD, of Scripps Research, Florida. In a new study published in Nature Communications on Friday, Subramaniam’s group has shown that the mutated huntingtin protein slows brain cells’ protein-building machines, called ribosomes.
“The ribosome has to keep moving along to build the proteins, but in Huntington’s disease, the ribosome is slowed,” Subramaniam says. “The difference may be two, three, four-fold slower. That makes all the difference.”
Cells contain millions of ribosomes each, all whirring along and using genetic information to assemble amino acids and make proteins. Impairment of their activity is ultimately devastating for the cell, Subramaniam says.
“It’s not possible for the cell to stay alive without protein production,” he says.
The team’s discoveries were made possible by recent advancements in gene translation tracking technologies, Subramaniam says. The results suggest a new route for development of therapeutics, and have implications for multiple neurodegenerative diseases in which ribosome stalling appears to play a role.
Huntington’s disease affects about 10 people per 100,000 in the United States. It is caused by an excessive number of genetic repeats of three DNA building blocks. Known by the letters CAG, short for cytosine, adenine and guanine, 40 or more of these repeats in the HTT gene causes the brain degenerative disease, which is ultimately fatal. The more repeats present, the earlier the onset of symptoms, which include behavioral disturbances, movement and balance difficulty, weakness and difficulty speaking and eating. The symptoms are caused by degeneration of brain tissue that begins in a region called the striatum, and then spreads. The striatum is the region deep in the center of the brain that controls voluntary movement and responds to social reward.
For their experiments, the scientists used striatal cells engineered to have three different degrees of CAG repeats in the HTT gene. They assessed the impact of the CAG repeats using a technology called Ribo-Seq, short for high-resolution global ribosome footprint profiling, plus mRNA-seq, a method that allows a snapshot of which genes are active, and which are not in a given cell at a given moment.
The scientists found that in the Huntington’s cells, translation of many, not all, proteins were slowed. To verify the finding, they blocked the cells’ ability to make mutant huntingtin protein, and found the speed of ribosome movement and protein synthesis increased. They also assessed how mutant huntingtin protein impacted translation of other genes, and ruled out the possibility that another ribosome-binding protein, Fmrp, might be causing the slowing effect.
Further experiments offered some clues as to how the mutant huntingtin protein interfered with the ribosomes’ work. They found it bound directly to ribosomal proteins and the ribosomal assembly, and not only affected speed of protein synthesis, but also of ribosomal density within the cell.
Many questions remain, Subramaniam says, but the advance offers a new direction for helping people with Huntington’s disease.
“The idea that the ribosome can stall before a CAG repeat is something people have predicted. We can show that it’s there,” Subramaniam says. “There’s a lot of additional work that needs to be done to figure out how the CAG repeat stalls the ribosome, and then perhaps we can make medications to counteract it.”

Scars inside the abdomen, known as adhesions, form after inflammation or surgery. They can cause chronic pain and digestive problems, lead to infertility in women, or even have potentially life-threatening consequences such as intestinal obstruction. If adhesions develop, they must be operated on again. They also make subsequent surgical interventions more difficult. This leads to substantial suffering for those affected and is also a significant financial burden for the healthcare system. In the USA alone, adhesions in the abdomen result in healthcare costs of 2.3 billion dollars per year.
Knowledge about the cause of adhesions is still incomplete, and there no therapy for them. “Because the disease has been largely overlooked in research, we have started this program in Bern to find out more about the development of adhesions,” says Daniel Candinas, Co-author of this study. It had already been suspected that special immune cells, called macrophages, play a decisive role in the development. This was confirmed by Joel Zindel and Daniel Candinas from the Department of Visceral Surgery and Medicine at Inselspital and Department for BioMedical Research (DBMR) at the University of Bern.
Then, Zindel continued his research at the University of Calgary in Canada in the group led by Paul Kubes, as they are considered world-leading in the field of macrophages in the abdominal cavity. Thanks to Zindel’s clinical expertise and the Canadian researchers’ know-how, it was possible to develop a new imaging system using cutting-edge microscopy that allows to see inside the living body. This allowed them to catch the macrophages in flagrante and on film, as they form shapes that then lead to the adhesions.
The researchers were also able to describe the molecular mechanisms behind this. The results of the study have now been published as the cover story of the journal Science.
New technology developed
Macrophages are found in what is called peritoneal fluid, a lubricant between the peritoneum, which is inner lining of the abdominal wall, and a similar lining around the organs in the abdominal cavity. Macrophages passively swim around in this fluid, much like plankton in the sea. Their tasks include eliminating pathogens, but also sealing injuries in the abdominal cavity as quickly as possible.

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How they accomplish the latter, i.e., recognizing an injury and moving there, was unclear until now. Since these cells behave in the test tube very differently from the way they do in the body, Zindel and Kubes developed a new microscopy technique that allowed them to use the thinnest part of the abdominal wall as a window to look into the peritoneal caity, the “native habitat” of these macrophages and film them as they move arround.
When macrophages lose control
When there is an injury within the abdominal cavity, macrophages aggregate within minutes to form clot-like structures. In this way, they seal the injury. As the researchers led by Zindel and Kubes have discovered, the molecular mechanism behind this is based on special, non-specific receptors that recognize a variety of structures. Simply by being moved through the fluid via respiratory or digestive movement, these receptors act to initiate clotting around a wound. What works fine for smaller injuries becomes a problem for large ones, however, such as surgically opening the abdominal wall, or inserting an implant. “In larger injuries, the macrophages get out of control — the clots don’t stop growing and form long strands,” Zindel explains. “We were able to show that these strands are what lead to the adhesions.”
This could have evolutionary reasons: Macrophages are optimized by evolution to cope well with small injuries. “Let’s take the example of a hunter who is injured by a deer antler,” Zindel says. “The macrophages seal all the internal holes as quickly as possible — which is the only way to survive.” However, when air enters the abdominal cavity during abdominal surgery or foreign bodies are implanted, the macrophages are overwhelmed because evolution has not prepared them for this challenge. “In this case, the macrophages become harmful and cause adhesions,” Zindel explains.
Patent pending
The researchers found that when the corresponding receptors are blocked in mice, it leads to fewer adhesions. Thus, a patent application has been filed for the use of the active ingredient against adhesions. The findings are relevant to many areas of research, as there are no other immune cells which are being recruited as quickly as macrophages in the abdominal cavity. Similar mechanisms could be present in other cavities such as the heart or lungs, or could play a role not only in injuries but also diseases such as abdominal tumors.
“This is an example of how laboratory research has high translational value,” says Daniel Candinas. Together with Calgary, the Bernese researchers will now look for partners in the industry and are hopeful that they will be able to confirm the efficacy of the compound in human tissue as well. In the future, patients could, for example, be given a drug before surgery that suppresses the macrophage reaction and inhibits the formation of adhesions.

In recent years, therapeutic antibodies have transformed the treatment of cancer and autoimmune diseases. Now, researchers at Lund University in Sweden have developed a new, efficient method based on the genetic scissors CRISPR-Cas9, that facilitates antibody development. The discovery is published in Nature Communications.
Antibody drugs are the fastest growing class of drug, and several therapeutic antibodies are used to treat cancer. They are effective, often have few side effects and benefit from the body’s own immune system by identifying foreign substances in the body. By binding to a specific target molecule on a cell, the antibody can either activate the immune system, or cause the cell to self-destruct.
However, most antibody drugs used today have been developed against an antibody target chosen beforehand. This approach is limited by the knowledge of cancer we have today and restricts the discovery of new medicines to currently known targets.
“Many antibody drugs currently target the same molecule, which is a bit limiting. Antibodies targeting new molecules could give more patients access to effective treatment,” says Jenny Mattsson, doctoral student at the Department of Hematology and Transfusion Medicine at Lund University.
Another route — that pharmaceutical companies would like to go down — would be to search for antibodies against cancer cells without being limited to a pre-specified target molecule. In this way, new, unexpected target molecules could be identified. The problem is that this method (so-called “phenotypic antibody development”) requires that the target molecule be identified at a later stage, which has so far been technically difficult and time-consuming.
“Using the CRISPR-Cas9 gene scissors, we were able to quickly identify the target molecules for 38 of 39 test antibodies. Although we were certain that the method would be effective, we were surprised that the results would be this precise. With previous methods, it has been difficult to find the target molecule even for a single antibody,” says Jenny Mattsson.
The research project is a collaboration between Lund University, BioInvent International and the Foundation for Strategic Research. The researchers’ method has already been put into practical use in BioInvent’s ongoing research projects.
“We believe the method can help antibody developers and hopefully contribute to the development of new antibody-based drugs in the future,” concludes Professor Björn Nilsson, who led the project.

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DNA sequencing of bacteria found in pigs and humans in rural eastern North Carolina, an area with concentrated industrial-scale pig-farming, suggests that multidrug-resistant Staphylococcus aureus strains are spreading between pigs, farmworkers, their families and community residents, and represents an emerging public health threat, according to a study led by researchers at the Johns Hopkins Bloomberg School of Public Health.
S. aureus is commonly found in soil and water, as well as on the skin and in the upper respiratory tract in pigs, other animals, and people. It can cause medical problems from minor skin infections to serious surgical wound infections, pneumonia, and the often-lethal blood-infection condition known as sepsis. The findings provide evidence that multidrug-resistant S. aureus strains are capable of spreading and possibly causing illness in and around factory farm communities in the U.S. — a scenario the authors say researchers should continue to investigate.
The study was published online February 22 in Emerging Infectious Diseases, a journal published by the U.S. Centers for Disease Control and Prevention.
The researchers in recent years have been collecting samples of S. aureus from pigs, farmworkers, farmworkers’ family members, and community residents — including children — in the top pig-producing counties in North Carolina. For the study, they sequenced the DNA from some of these samples to determine the relation of the strains found in pigs and people. They found that the strains were very closely related, providing evidence for transmission between pigs and people. Most of the strains carried genes conferring resistance to multiple antibiotics.
“We found that these livestock-associated S. aureus strains had many genes that confer resistance to antimicrobial drugs commonly used in the U.S. industrialized pig production system,” says study first author Pranay Randad, PhD, a postdoctoral researcher in the Bloomberg School’s Department of Environmental Health and Engineering.
“These findings warrant future investigations into the transmission dynamics in nearby communities and disease burden associated with these strains in the United States,” says study senior author Christopher Heaney, PhD, associate professor in the same department. Epidemiologists have long suspected that S. aureus and other bacteria are transmitted from humans to pigs on factory farms, and thereafter evolve antibiotic resistance within the pigs. The animals are routinely given antibiotics to prevent outbreaks in their dense concentrations on factory farms. The drug-resistant bacterial strains may then be transmitted back to humans, becoming a potentially serious source of disease.

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In recent years, Heaney and colleagues have been gathering S. aureus isolates from pigs and farmworkers at factory-scale pig farms in North Carolina, one of the leading pig-farming states. Their research has shown that livestock-associated strains of S. aureus, many of them antibiotic-resistant strains, can be found not only in pigs but also in farmworkers, their family members, and residents living nearby.
For the new study they performed whole-genome sequencing on 49 of these S. aureus isolates to characterize these strains at the DNA level and get a more precise picture of their interrelatedness.
One finding was that all these isolates, whether taken from humans or pigs, belonged to a grouping of S. aureus strains known as clonal complex 9 (CC9).
“This CC9 is a novel and emerging subpopulation of S. aureus that not many people have been studying, apart from a few reports in Asia,” Randad says.
The researchers also determined from their analysis that the CC9 isolates from North Carolina were closely related, in many cases implying recent transmission between pigs and people. Moreover, virtually all of the isolates that appeared to be involved in transmission between pigs and humans were multidrug resistant, suggesting that diseases these isolates cause could be hard to treat.
The scope of the study didn’t include evaluating S. aureus-related disease among people in the affected communities, but one of the pig farmworkers who carried a CC9 isolate in their nose reported a recent skin infection.
“In other countries, such as in Europe, we see a high level of coordinated research on this topic from a public health perspective, with open access to collect bacterial isolates from pigs raised on factory farms, but so far in the U.S. not as much is being done,” Randad says.
Support for the study was provided by the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Discovery Program at the Johns Hopkins University School of Medicine; the GRACE Communications Foundation; the National Institute for Occupational Safety and Health, the National Science Foundation, the National Institute of Allergy and Infectious Diseases, and the National Institute of Environmental Health Sciences, among other funding sources.

Two thirds of children use more than one screen at the same time after school, in the evenings and at weekends as part of increasingly sedentary lifestyles, according to new research at the University of Leicester.
An NIHR study of more than 800 adolescent girls between the ages of 11 and 14 identified worrying trends between screen use and lower physical activity — including higher BMI — as well as less sleep.
The use of concurrent screens (termed ‘screen stacking’) grew over the course of the week — with 59% of adolescents using two or more screens after school, 65% in the evenings, and 68% at weekends.
Some teens reporting using as many as four screens at one time.
But further analysis showed the use of any screen was still detrimental to the indicators of health and wellbeing. More than 90% owned or had access to a smart phone and using this after school had a knock on effect on their sleep.
Researchers from the Leicester Diabetes Centre at the University measured physical activity and sleep using accelerometers worn on participants’ wrists, while those involved in the study self-reported the number of screens they were using at the same time — such as scrolling on a mobile phone while also watching TV — as well as perceptions of self-esteem and physical self-worth.

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Dr Deirdre Harrington, Lecturer in Physical Activity for Health led the study during her time at Leicester and now works in the School of Psychological Sciences and Health at the University of Strathclyde. She said:
“Intuitively, we believe there must be negative effects on teenagers of using too many screens at the same time. Our data show it isn’t as simple as that.
“This research was done before the COVID-19 lockdown, where much more of our day is spent in front of a screen. More than ever the effects of this on adolescents need to be known — there are positives too, no doubt.
“These adolescents wore an accelerometer 24 hours a day for a week allowing us to capture their daily routines and even estimate their sleep. Uniquely, they also reported how many screens they used at the same time which is not well known.”
Melanie Davies, Professor of Diabetes Medicine at the University of Leicester and Co-Director of the Leicester Diabetes Centre based at Leicester General Hospital, said:
“Sadly, this study reminds us that we are in danger of creating a new generation of sedentary children. Increased sedentary time is closely linked to type 2 diabetes, which is increasing in younger age groups.
“The number of young people with type 2 diabetes has gone up by 50% in just five years.”
The study was supported by the National Institute for Public Health Research programme as well as the NIHR Leicester Biomedical Research Centre, and the NIHR Applied Research and Care (ARC) East Midlands.

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