Publisher Health

A pioneering new study led by UCL and National Institutes of Health (NIH) scientists has revealed, for the first time, why a common genetic variant worsens disease outcomes for people with the devastating adult-onset neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Published in Nature, the study shows how TDP-43 protein depletion, associated with almost all cases (97%) of ALS and half of FTD cases, corrupts the genetic instructions for the critical neuronal protein UNC13A.
Strikingly, it found that a mysterious genetic variant previously associated with disease risk increases the chance of UNC13A’s genetic instructions being corrupted among people with the diseases, thereby worsening risk and severity of ALS and FTD.
UNC13A enables neurons (nerve cells) to communicate with each other via neurotransmitter release, and data from animal models suggests its loss from neurons can be fatal. The researchers believe that the corruption of UNC13A’s genetic instructions in patients may have similarly harmful consequences.
ALS is the most common motor neuron disease and there is no known cure; it affects the brain and spinal cord by attacking the neurons and nerves which control movement, causing them to die. There is currently only one approved drug for ALS in the UK, which extends lifespan by a few months, and is only effective for a tiny minority of patients. One third of patients die within one year of diagnosis.
FTD is a related disease with similar underlying causes; symptoms include language impairment, changes in personality and cognitive difficulties.

On extremely hot summer days, US adults were at an increased risk of visiting emergency rooms for mental health crises related to substance use, anxiety, stress, and more.
During periods of extreme heat, clinicians should expect to see an increase in patients requiring mental health services, according to a new study led by Boston University School of Public Health researchers.
Published in the journal JAMA Psychiatry, the study found that days with higher-than-normal temperatures during the summer season in the United States were associated with increased rates of emergency department (ED) visits for any mental health-related condition, particularly substance use, anxiety and stress disorders, and mood disorders.
The impact of heat on physical health is well documented, but few studies have examined the effects of extreme heat on mental health. This nationwide study is the largest and most comprehensive analysis of daily ambient temperature and mental health-related ED visits among US adults of all ages. As days of extreme heat are expected to increase due to worsening climate change, the findings fill a critical gap in research and provide evidence-based support for proactive interventions and policy solutions that can reduce heat-related crises.
“Emergency department visits represent some of the costliest interactions within the healthcare system,” says study lead author Dr. Amruta Nori-Sarma, assistant professor of environmental health at BUSPH. “Addressing the needs of the most vulnerable to preempt some of these visits can have a positive impact on individual health and costs, as well as preserve healthcare resources for other emergencies.”
The new findings should prompt healthcare providers to prepare for an increased need in mental health services during times when extreme heat is predicted, Nori-Sarma says. “When heat waves are forecasted, clinicians and public health experts may use our findings to prepare especially for outreach to patients with existing mental health conditions.”
The general public can also benefit from this insight, says study senior author Dr. Gregory Wellenius, professor of environmental health and director of the Climate and Health Program at BUSPH.

During the pandemic, news reports surfaced of a surge of young adults showing up at doctors’ offices with unexplainable movement disorders that looked, perhaps to a nonspecialist, a little bit like Tourette syndrome.
But when those patients were sent to see a specialist, “They’d say, ‘that doesn’t look at all like any of my first thousand patients,'” said Kevin Black, MD, a professor of psychiatry at Washington University School of Medicine in St. Louis. People with experience knew that there were telltale properties of the tics associated with Tourette’s, even though there is no one tool that allows a doctor to give a diagnosis on the spot.
However, research published Feb. 23 in the Journal of the Royal Society Interface by Black and Rajan Chakrabarty, the Harold D. Jolley Career Development Associate Professor of Energy, Environmental & Chemical Engineering at the university’s McKelvey School of Engineering, may signal that a diagnostic tool is near.
They have replicated and expanded on previous work to show that tics associated with Tourette syndrome have a fractal pattern. They also discovered that a key characteristic of that pattern in any individual can predict how severe the disease will become.
Specialists had long suspected there was some kind of pattern to tics associated with Tourette’s, and in the late 1990s, a seminal paper by Bradley Peterson and James Leckman was able to uncover that pattern — but only over a period of seconds to minutes.
Black, a neuropsychiatrist who specializes in movement disorders, has been heading a research study on tics for years. As part of the New Tics Study, he had collected an impressive amount of data about tics in children as they were going through the yearlong diagnosis process.

Scientists at Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) have identified a promising drug candidate for the treatment of multi-inflammatory syndrome in children (MIS-C), they report in Clinical Care Explorations. MIS-C is a rare but severe and potentially life-threatening condition that usually develops in children weeks to months after they have experienced a mild or even asymptomatic case of COVID-19.
MIS-C occurs mainly in children and leads to high fevers and a hyperinflammatory response that can affect multiple organs, including the heart, brain and gastrointestinal organs. Symptoms include stomach pain, diarrhea, vomiting, dizziness and rash. Fifty-five of the 6,431 children diagnosed with MIS-C have died since May 2020, according to the Centers for Disease Control and Prevention.
A previous study by researchers from MGH and BWH showed that in cases of MIS-C, the SARS-CoV-2 virus, which causes COVID-19, can remain in the gut for weeks to months after the infection. When SARS-CoV-2 is present in the gut, an impaired mucosal barrier can allow small viral particles, such as the spike protein, to enter the bloodstream, leading to infections such as COVID-19 and in rare cases, the hyperinflammatory response that triggers MIS-C.
“Working collaboratively, we’ve been able to demonstrate that viral particles that remain in the gut long after COVID-19 infection can instigate MIS-C,” says co-senior author David Walt, PhD, principal investigator of the Walt Laboratory in the Brigham’s Department of Pathology. “Building on this important discovery, we wanted to see if treatment with a drug developed for another condition — celiac disease — could help resolve symptoms in children experiencing MIS-C.”
Based on these findings, the team administered the drug larazotide acetate to four extremely ill children ages 3 to 17 being treated for MIS-C at MGH. Larazotide decreases the release of zonulin, a molecule that can lead to increased gut permeability and an impaired mucosal barrier. The researchers compared the clinical outcomes of the four children who received larazotide plus steroids and intravenous immune globulin (IVIG) to 22 children who received only steroids and IVIG.
The children who received four daily oral doses of larazotide acetate had a significantly faster resolution of gastrointestinal symptoms and a slightly shorter hospital stay. Serum levels of the highly inflammatory spike protein associated with the SARS-CoV-2 virus dropped much more quickly in children treated with larazotide, clearing from the blood within one day, versus 10 days for children not treated with larazotide.
“These findings suggest that larazotide may provide a safe and beneficial adjuvant therapy for the treatment of MIS-C,” state the authors in the new paper. Adds lead author Lael Yonker, MD, pediatric pulmonologist and director of the Cystic Fibrosis Center at MassGeneral Hospital for Children (MGHfC): “Our results demonstrate the urgent need for the development of diagnostic and prognostic tools to advance our understanding and treatment of this devastating disease.”
Yonker, with the support of Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and chief of the Division of Pediatric Gastroenterology and Nutrition at MGHfC, first applied to the FDA for emergency compassionate use of larazotide in the treatment of MIS-C in February 2021. With the approval of parents, the clinicians successfully administered larazotide to several severely ill children who were not responding to the prescribed therapies. Yonker and Fasano, along with colleagues from MGH, the Walt Laboratory at BWH and other institutions, published their results in July 2021 about earlier clinical successes with larazotide.
An expert in celiac disease and autoimmune disorders, Fasano developed larazotide acetate in the early 2000s as an adjunctive treatment for celiac disease. Larazotide is currently in Phase 3 human clinical trials for this purpose. Given its outstanding safety profile and early success in treating gastrointestinal complications of MIS-C, Yonker and Fasano initiated a clinical “proof of concept” randomized, double-blind, placebo-controlled study in August 2021 to evaluate the efficacy of larazotide acetate for children hospitalized with MIS-C at MGH.
The latest research is the cumulative result of “a strong team effort,” notes Fasano. “We connected the dots to capitalize on the ongoing research related to the activation of the zonulin pathway in a variety of inflammatory conditions.” Recent research includes findings that demonstrate how closely MIS-C resembles Kawasaki disease, another inflammatory condition in children.
“Kawasaki disease is caused by a zonulin-dependent mechanism that has a similar effect upon important organs, including the heart and gastrointestinal system,” says Fasano. “This led us to the conclusion that a similar mechanism can also be at play in MIS-C. It was only logical to propose the compassionate use of larazotide in kids affected by MIS-C,” he says, adding that clinical results with a small number of children have been “so promising that the FDA gave us the green light last August to start a clinical trial in children admitted to MGH who are affected by MIS-C.”
“What makes our approach unique is that we have been able to identify the zonulin-dependent leak of the spike protein from the gut lumen into the circulatory system. This provides us not only with a diagnostic tool by searching for the spike protein in blood but also with a therapeutic target of blocking zonulin-dependent increased gut permeability to treat this serious complication of COVID-19 infection,” says Fasano.

Some gut bacteria have a spooky superpower: they can reanimate dormant viruses lurking within other microbes.
This viral awakening unleashes full-blown infections that destroy the virus-carrying cells, Howard Hughes Medical Institute Investigator Emily Balskus’s lab first published as a preprint on bioRxiv and later in the journal Nature on February 23, 2022. A cryptic molecule called colibactin can summon the killer viruses from their slumber, they found.
Microbes often generate noxious compounds to attack one another within the cramped quarters of the gut. But among these chemical weapons, colibactin appears unusual, says Balskus, a chemical biologist at Harvard University. “It doesn’t directly kill the target organisms, which is what we normally think of bacterial toxins doing within microbial communities.” Instead, colibactin tweaks microbial cells just so, activating latent — and lethal — viruses tucked away in some bacteria’s genomes.
Humans have long sought out the potent compounds that microbes produce. “We know a lot about their chemical properties, we purify them in the lab, and we use them as medicine, including antibiotics,” says Breck Duerkop, who studies bacterial viruses at the University of Colorado School of Medicine.
But why bacteria make these compounds and what effects they have on neighboring organisms are open-ended questions, says Duerkop, who was not involved in this research. He calls Balskus’s teams new work “one step in the right direction.”
Chemical dark matter
Scientists have known for years that colibactin can wreak havoc on human cells. Research by Balskus and many others has shown that the compound damages DNA, which can lead to colorectal cancer. But establishing a connection between this compound and disease proved particularly formidable.

Patients treated for Merkel cell carcinoma (MCC) face a five-year recurrence rate of 40% — markedly higher than the recurrence rates for melanoma and other skin cancers, according to research published today in JAMA Dermatology.
Additionally, in the study cohort of more than 600 patients, 95% of MCC recurrences happened in the first three years, suggesting that surveillance efforts should be focused on that span the authors wrote.
“Merkel cell cancer is a life-changing diagnosis. It can be time-consuming, costly and exhausting to undergo clinic visits, imaging studies and blood draws. Now we have data on the time intervals and cancer stages that merit higher or lower surveillance intensity,” said Dr. Aubriana McEvoy, who led the research while she was at the University of Washington School of Medicine. She is currently a dermatology resident at Washington University in St. Louis.
Merkel cell cancer is a rare, aggressive skin cancer, more often fatal than invasive melanoma and basal-cell and squamous-cell carcinomas. Merkel cell carcinoma is composed of cells that look very similar to ‘Merkel’ cells that are a key part of the epidermis, the skin’s outer layer. Normal Merkel cells communicate touch-related information such as pressure and texture to the brain.
This study comprised 618 patients (37% female) whose ages ranged from 11 to 98 and whose median age was 69. In this cohort, initial treatment (surgery, radiation and systemic therapy) had a median duration of 90 days.
The authors sought to characterize post-treatment recurrence risk of MCC diagnosed at pathologic (listed below) and clinical stages.

People who worked out in even moderately polluted air did not show the kinds of brain improvements tied to a lower risk of dementia.Work out in polluted air and you may miss out on some of the brain benefits of exercise, according to two, large-scale new studies of exercise, air quality and brain health. The studies, which involved tens of thousands of British men and women, found that, most of the time, people who ran and rode vigorously had larger brain volumes and lower risks for dementia than their less active peers. But if people exercised in areas with even moderate levels of air pollution, the expected brain improvements from exercise almost disappeared.The new studies raise questions about how to balance the undeniable health gains of working out with the downsides of breathing in bad air and underscore that our environment can change what exercise does — and does not do — for our bodies.A large body of evidence demonstrates that, on the whole, exercise bulks up our brains. In studies, active people generally sport more gray matter in many parts of their brains than sedentary people. Gray matter is made up of the brain’s essential, working neurons. Fit people also tend to have healthier white matter, meaning the cells that support and connect neurons. White matter often frays with age, shrinking and developing Swiss-cheese-like lesions even in healthy adults. But fit people’s white matter shows fewer and smaller lesions.Partially as a consequence of these brain changes, exercise is strongly linked with lower risks for dementia and other memory problems with age.But air pollution has the opposite effects on brains. In a 2013 study, for example, older Americans living in areas with high levels of air pollution showed bedraggled white matter on brain scans and tended to develop higher rates of mental decline than older people living elsewhere. And in a 2021 study of rats housed in cages placed near a heavily trafficked, exhaust-clogged road tunnel in Northern California, most of those bred with a predisposition to a rodent analogue of Alzheimer’s disease soon developed dementia. But so did another set of rats with no genetic inclination to the disease.Few studies, though, had explored how exercise and air pollution might interact inside our skulls and whether working out in smoggy air would protect our brains from noxious fumes or undermine the good we otherwise gain from working out.So, for the first of the new studies, published in January in Neurology, researchers at the University of Arizona and University of Southern California pulled records for 8,600 middle-aged adults enrolled in the UK Biobank. A huge trove of health and lifestyle records, the Biobank holds information on about more than 500,000 British adults, such as their ages, home locations, socioeconomic status, genomes and extensive health data. Some of the participants also completed brain scans and wore activity monitors for a week to track their exercise habits.The researchers focused on those who had worn a monitor, had a brain scan and, according to their trackers, often exercised vigorously, such as by running, which meant they breathed heavily during workouts. The heavier you breathe, the more air pollutants you draw in. The researchers also included some people who never worked out vigorously, for comparison.Using established air quality models, they then estimated air pollution levels where the people lived and, finally, compared everyone’s brain scans.Disappearing benefitsAs expected, vigorous exercise was linked, in general, to sturdy brain health. Men and women who lived and presumably worked out in areas with little air pollution showed relatively large amounts of gray matter and low incidence of white matter lesions, compared to people who never exercised hard. And the more they exercised, the better their brains tended to look.But any beneficial associations almost disappeared when exercisers lived in areas with even moderate air pollution. (Levels in this study were mostly within the bounds considered acceptable for health by European and American air quality standards.) Their gray matter volume was smaller and white matter lesions more numerous than among people living and exercising away from pollution, even if their workouts were similar.Extending these findings in a second, follow-up study published this month in Medicine & Science in Sports & Exercise, the same scientists repeated aspects of this experiment with another 35,562 older UK Biobank participants, comparing people’s exercise habits, local pollution levels and diagnoses of dementia, if any. The data showed the more people exercised, the less likely they were to develop dementia over time — provided their local air was clear. When it was moderately polluted, though, they had an increased long-term risk of dementia, whether they exercised or not.Keith E. Morrison for The New York Times‘Alarming’ finding“These data are of significant importance in terms of our understanding of modifiable risk factors for brain aging,” said Pamela Lein, a professor of neurotoxicity at the University of California, Davis, who led the earlier study of rats and pollution. She was not involved with the new studies. “The observation that air pollution negates the well-established beneficial effects of exercise on brain health is alarming and increases the urgency for developing more-effective regulatory policies” related to air quality.The studies have limitations. They are observational and show links between exercise, pollution and brain health, but cannot prove that bad air directly counteracts the brain benefits of exercise, or how this might occur. They also did not look into where people worked out, only that some lived in places with iffy air.But the results do intimate that the quality of the air influences the results of the workout and that for the sake of our brains, we should try not to exercise in bad air, said David Raichlen, a professor of biological sciences at U.S.C. and co-author of the new studies.Boosting brain healthIn practice, a number of measures may help to bolster the brain benefits of exercise, experts say.“Stay away from busy highways, if at all possible,” Dr. Raichlen said. Automobile exhausts are among the worst pollutants for human health.Check local conditions at airnow.gov, which uses the color-coded Air Quality Index to rate air quality by ZIP code. Most weather apps also include the local A.Q.I. Aim to workout in air quality rated as Green, which is Good. Air quality changes throughout the day, so check back in a few hours if conditions seem unfavorable at first.Working out indoors may be no better. “The available evidence suggests pollution levels indoors are about the same as those outside,” Dr. Raichlen said, unless a building, such as a gym, has installed extensive air filtration systems. Pollutants can readily enter buildings through open doors or windows or cracks in the structure, and the government doesn’t routinely monitor indoor air quality. You can learn more at the Environmental Protection Agency website.Masking might help. Both surgical and N95 masks filter some unhealthy particulates, such as soot and other matter, said Melissa Furlong, an environmental epidemiologist at the University of Arizona and co-author of the two studies. “If you don’t mind wearing a mask while exercising,” she said, “this would likely result in a reduction of exposure to particulates.”Most important, keep exercising. Exercise has multiple benefits for cardiovascular health, and “we do not want to discourage people from being physically active,” Dr. Raichlan said, even if air conditions are not ideal. In the new studies, the brains of people who exercised in polluted air looked no better, he pointed out — but their brains were also no worse than those of people who did not exercise at all.So, if your only opportunity to exercise is with some pollution hanging in the air, don a mask and go. Then check your local A.Q.I. forecast to look for clearer conditions in the future. The better the air quality is around you as you exercise, Dr. Raichlen said, the better the workout will be for your brain.

Some genetic mutations linked to leukemia are less than useful guides to making treatment decisions for patients. A new study from the University of Wisconsin-Madison suggests a group of clinical signs that can be paired with genetic testing to better inform the timing of more aggressive treatment.
Studies of leukemia, which is cancer of the blood and blood-forming cells, have revealed alterations in genes that can be associated with the disease, and these genetic changes can be passed from one generation to the next. In certain cases, these alterations give doctors a way to gauge disease risk. For others, the consequences remain obscure. Even when the link between a particular genetic red flag and disease is strong, it may be difficult to pinpoint when serious stages of the disease may begin.
“That can be extremely variable. In a family that shares a common mutation, a grandfather might not present with symptoms until leukemia abruptly emerges,” says UW-Madison cancer researcher Alexandra Soukup. “By contrast, one of their grandchildren with the same genetic alteration may have serious symptoms starting at age seven — like lymphedema, which is severe swelling in the arms and legs, or low blood cell levels called cytopenia, which can cause life-threatening infections. We want to know what environmental and genetic factors trigger the disease presentation.”
Clinicians treating patients with genetic mutations likely to cause leukemia would like to know as well, because their options range from light-handed monitoring or drugs to invasive procedures including radiation, chemotherapy and stem cell transplants.
“Right now, the gold standard for treatment is a bone marrow transplant,” Soukup says. “But those occur when there’s already relatively severe disease presence, elderly patients are often not eligible for a transplant, and there can be life-threatening reactions to transplants.”
The complications of leukemia, which causes the bone marrow to make too few blood cells or abnormal blood cells, can be triggered by exposure to a pathogen or toxin, requiring the body to ramp up production of new blood cells.

A new Curtin University study has found diet, malaria, substance use and a lack of antenatal care services are linked to one in 10 babies in the Pacific Island region being born preterm and of low birth weight.
Published in leading journal The Lancet Regional Health — Western Pacific, the study reviewed primary studies and reports conducted from the sovereign island states and territories of the region including Fiji, Papua New Guinea, Samoa and Vanuatu.
Lead researcher PhD student Lydia Sandrah Kuman Kaforau, from the Curtin School of Population Health, said the research was the first of its kind in the Pacific Island region.
“Low birth weight, or babies born weighing less than 2500gm, and preterm birth, or those born before 37 weeks, are the main causes of infant and child mortality and morbidity in low and middle-income countries,” Ms Kaforau said.
“While the prevalence and exposures of adverse birth outcomes is well studied in low and-middle-income countries, it is not well known for the Pacific Island region.
“Our study maps the available evidence on the prevalence of low birth weight, preterm birth, and Small for Gestational Age (SGA), as well as their corresponding risks in the region.”
Ms Kaforau said that there were many contributing risk factors to preterm birth and other adverse birth outcomes that could ultimately be avoided.

Eating disorders are associated with an increased risk of people with diabetes developing diabetic retinopathy — a condition that can cause blindness if untreated — according to new research published in the Journal of Diabetes and Metabolic Disorders.
Diabetes is characterised by high concentrations of glucose in the blood, which can in turn lead to tissue damage in several parts of the body including the heart, feet and eyes. The most common eye disease among people with diabetes is retinopathy, where microvascular changes in the retina can result in vision impairment and even blindness. The risk of diabetic retinopathy affects people with all types of diabetes.
Academics from Anglia Ruskin University (ARU) combined data from several studies, with a total of more than 1,100 participants, and found that people with diabetes who were assessed as having an eating disorder were 2.94 times more likely to develop diabetic retinopathy, compared to people with diabetes who did not have an eating disorder.
However, researchers did not find a statistically significant link between binge eating disorder, a condition where a person frequently consumes a large amount of food over a short period of time, and diabetic retinopathy.
Eating disorders considered in the study included anorexia nervosa, a condition where people try and keep their weight as low as possible by reducing their food intake or exercising too much, and bulimia nervosa, where a person attempts to purge food from the body either by vomiting or using laxatives.
Lead author Mike Trott, Research Assistant for ARU’s Vision and Eye Research Institute (VERI) said: “We know there are several factors that can regress or accelerate the progression of retinopathy in people living with diabetes. These include physical activity, which is associated with lower risk, and high blood pressure, which can elevate the risk.
“Our review found a significant positive association between pathological eating disorders and the risk of diabetic retinopathy. The most likely reason for this is poor control of blood sugar levels due to inconsistent food intake or people deliberately not taking insulin as a weight management tactic. Insulin allows the glucose in the blood stream to be converted to energy and subsequently used usefully by the body.
“Practitioners working with people with diabetes should closely monitor eating behaviours so that any abnormal eating behaviour can be addressed swiftly to reduce the risk of diabetic retinopathy and consequent blindness if not treated.”
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Materials provided by Anglia Ruskin University. Note: Content may be edited for style and length.