Culture

Before undergoing surgery, patients often go through a number of tests: blood work, sometimes a chest X-ray, perhaps tests to measure heart and lung function.

In fact, about half of patients who had one of three common surgical procedures done in Michigan between 2015 and the midway point of 2019 received at least one routine test beforehand.

That's according to new research in JAMA Internal Medicine from a collaboration between the University of Michigan-based Michigan Program on Value Enhancement (MPrOVE) and the Michigan Value Collaborative, a statewide initiative that focuses on improving medical and surgical quality.

Yet plenty of evidence suggests that preoperative testing is often unnecessary for low-risk surgeries.

At best, it's costly and doesn't usually improve outcomes for patients. At worst, it can lead to more invasive testing and delay surgery, which can create complications that could have been avoided if the tests weren't done.

"There aren't that many areas in medicine where the data is pretty definitive that something is low-value," says Lesly Dossett, M.D., the division chief of surgical oncology at Michigan Medicine and the co-director of MPrOVE, "but preoperative testing before low-risk surgeries is certainly one of them."

How testing started -- and why it continues

In the latter half of the 19th century, modern surgery was still in its infancy.

Anesthesia was new, and even minor surgeries were not routine. So researchers used tests to assess their patients' physical health and measure their risk of complications during operations.

"There was probably a time when some of the testing did reduce adverse events," Dossett says. "But now there's been so many advances in surgery -- complication rates are so low that a lot of these tests are not necessarily helpful anymore."

Others agree with her.

Professional organizations ranging from the American College of Surgeons and the Society of General Internal Medicine to the American Society of Anesthesiologists have identified routine preoperative testing as a low-value type of care that should be reduced whenever possible.

In 2012, the American Board of Internal Medicine Foundation even launched an initiative called the Choosing Wisely campaign that promotes conversations between health care providers and patients about unnecessary medical tests and procedures.

But, almost a decade later, preoperative tests continue to be ordered.

Of about 40,000 patients in the U-M study who had surgery to either remove the gall bladder, repair a groin hernia, or remove cancerous breast tissue, close to a third underwent two or more tests beforehand, and about 13% had three or more.

The most common tests were a complete blood count, an electrocardiogram and a basic metabolic panel, all of which aren't inherently necessary before these surgeries.

"It's one thing to say that this is well recognized in the literature," says Hari Nathan, M.D., Ph.D., who happens to be the division chief of hepato-pancreato-biliary surgery at Michigan Medicine as well as the director of the MVC, "but it's a different thing to put it in the hands of the clinicians who are at the bedside in an easy-to-read, easy-to-understand and convenient-to-carry-around format."

Patients who had a complete medical history and physical done during a visit that was separately billed were more likely to have had preoperative testing as were those who were older or had more than one medical condition.

"I could see those two latter factors being in the background, hypothetically giving some pressure to do more testing," says Nicholas Berlin, M.D., M.P.H., a plastic surgery resident at Michigan Medicine and the first author of the study. "That's not to suggest there's an age threshold or a comorbidity that requires preoperative testing every single time. There's not."

A small number of people who fall into these categories may actually benefit from having these tests done, although it's difficult to know exactly how many based on this data, the researchers say. Yet, when they adjusted their model to account for that issue, they still found overuse of testing.

The data also revealed wide variations in testing, not only between the 63 hospitals studied but also within health systems for the same procedures, pointing to the need for more research to drill down further into the origins of the problem.

"We have more work to do on our end to figure out what's driving these differences within and between hospitals," says Berlin, who's also a National Clinician Scholar at the University of Michigan Institute for Healthcare Policy and Innovation. "This is signaling to other projects in the future between MPrOVE and statewide quality collaboratives that use more of an on-the-ground approach."

Value added statewide

This study represents one of the first partnerships between the Michigan Value Collaborative and MPrOVE, a joint venture of IHPI and Michigan Medicine that tries to optimize patient care, improve quality and demonstrate the value of care at Michigan Medicine through research and analytics.

In the past, MPrOVE has worked to reduce preoperative visits and tests such as EKGs before cataract surgery at Michigan Medicine, but its leaders wanted to expand the scope of their research to include other procedures and more hospitals.

The MVC was an ideal partner to do so: Funded by Blue Cross Blue Shield of Michigan, the initiative allows more than 90 hospitals and 40 physician organizations in Michigan to compare their data and identify best practices as well as opportunities for improvement.

"It's something that's squarely in MVC's strike zone and fits very well with MPrOVE's mission," Nathan says, "It just made sense for us to work together on this."

Limiting preoperative testing is one of two signature projects for the MVC, and Nathan has already started meeting with area health systems to tackle the issue.

"Some hospitals routinely send patients through a preoperative clinic, which represents a way to move the needle here in a very targeted way, just by influencing what gets ordered in the setting of that clinic," he says. "At other hospitals, there is no such clinic, and the individual surgeons and/or anesthesiologists are ordering tests, so that might require a different approach in order to get more adherence to guidelines."

"But I love seeing variation because when we see variation, that means there's an opportunity to learn from one another," he adds.

One of the challenges in reducing preoperative testing is that it generates revenue for hospitals, which means there's not a financial incentive to do less of it, Dossett says. But Nathan says that, based on his interactions with local health systems, he believes there's an appetite for change in this area.

"At the end of the day, we all recognize that as a society, we need to find ways to curb health care costs," he says. "That's in everybody's interest. Even if, on your balance sheet, you think it makes sense to do more tests just to make money, as health care providers and as a nation, it does not make sense. It is unsustainable. When we talk to our members, everybody gets that."

The experimental heart failure drug omecamtiv mecarbil reduced heart failure hospitalizations by a greater margin among patients with more severely reduced ejection fraction, a measure indicating severe impairment in the heart's pumping ability, compared with those who had moderately reduced ejection fraction, according to research presented at the American College of Cardiology's 70th Annual Scientific Session.

Omecamtiv mecarbil works by improving the ability for heart muscle cells to contract and operates through a different biological pathway than any of the current heart failure medications. The research is an extended analysis of data from GALACTIC-HF, a trial involving more than 8,200 participants that found omecamtiv mecarbil significantly improved outcomes in terms of a composite of cardiovascular death or heart failure events among patients with heart failure with reduced ejection fraction. The new analysis focused on how patient outcomes varied based on the level of severity of their reduced ejection fraction.

"This is a drug that will potentially help the very group of patients that are most difficult to care for," said John R. Teerlink, MD, a cardiologist at the University of California, San Francisco and the San Francisco VA Medical Center, and the study's lead author. "While the results from GALACTIC-HF show omecamtiv mecarbil brought improvements overall, these new findings point to a group of patients with more severe heart failure in whom there is even greater benefit."

Heart failure is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body. The trial investigated omecamtiv mecarbil in patients with heart failure with an ejection fraction of less than or equal to 35%. Ejection fraction is a measure of the amount of oxygen-rich blood that the heart pushes out with each heartbeat (50-70% is considered normal).

As previously reported, the GALACTIC-HF trial met its primary endpoint, which was a composite of time to first heart failure event or death due to cardiovascular causes, and the benefit was predominantly driven by reductions in heart failure events, with no significant improvement in the rate of death from cardiovascular causes compared to placebo. An additional benefit, according to Teerlink, is that when compared with other commonly used heart failure medications, omecamtiv mecarbil did not adversely affect blood pressure, heart rate, potassium concentrations or renal function, even when used alongside current heart failure medications. In addition, there was no increase in cardiac ischemic or ventricular arrhythmic events.

"The good news is omecamtiv mecarbil can be added on to a patient's treatment regimen at any time, because it doesn't interact with any of the commonly used heart failure therapies in terms of adverse effects," Teerlink said. "While it doesn't provide a benefit in terms of reducing cardiovascular death, it can provide its benefit in terms of reducing heart failure hospitalizations virtually anywhere in the treatment process."

In the new analysis, researchers found that the relative and absolute benefits from omecamtiv mecarbil significantly improved with progressively lower ejection fraction. Patients in the two lowest quartiles in terms of ejection fraction had a 15-17% reduction in the risk of dying from cardiovascular causes or being hospitalized with heart failure, compared to 8% for the entire patient population. In the lowest quartile, the absolute risk reduction was 7.4 per 100 patient years, meaning that treating fewer than 12 patients with omecamtiv mecarbil would result in preventing one cardiovascular death or heart failure hospitalization.

"That's a very important and clinically meaningful finding, particularly given that patients with low ejection fraction tend to be at the highest risk and the hardest to treat," Teerlink said.

The study did not show a clear benefit of omecamtiv mecarbil among patients with ejection fraction higher than about 30%. The researchers plan to further investigate this finding to determine whether a subset of these patients may benefit from the therapy. Additional studies are underway to examine whether having atrial fibrillation or other conditions in addition to heart failure may affect outcomes from the drug.

One of the enduring mysteries of the COVID-19 pandemic is why most children tend to experience fewer symptoms than adults after infection with the coronavirus. The immune system response that occurs in the rare cases in which children experience life-threatening reactions after infection may offer an important insight, a Yale-led study published in the journal Immunity suggests.

While many children infected with the virus are asymptomatic or go undiagnosed, about one in 1,000 children experience multi-system inflammatory response (MIS-C) four to six weeks after confirmed infection with SARS-CoV-2, the virus that causes COVID-19. The condition is marked by a variety of symptoms, including fever, abdominal pain with vomiting and/or diarrhea, rash, and cardiovascular and neurological problems. If diagnosed early, the condition is readily treatable with immune suppressants such as steroids. If left untreated, however, it can be fatal.

"Why does this happen when there is no virus or anti-viral response still present and in kids? And why is it only occurring in youth?" asked Carrie Lucas, an assistant professor of immunobiology at Yale and corresponding author of the new study.

In an exhaustive analysis, Lucas and her lab tested blood from children with MIS-C, adults with severe COVID symptoms, as well as healthy children and adults. They found that children with MIS-C had immune system signatures distinct from other groups.

Specifically, the children with MIS-C had high levels of alarmins, molecules that make up part of the innate immune system which is mobilized quickly to respond to all infections. Other research findings have suggested that a child's innate immune system response may be stronger than those of adults, one possible explanation for why they generally experience milder symptoms than adults after infection.

"Innate immunity may be more active in children who are infected with virus," Lucas said. "But on the flip side, in rare cases it may get too revved up and contribute to this inflammatory disease."

Children diagnosed with MIS-C were also found to have a marked elevation of certain adaptive immune responses, which are defenses to combat specific pathogens -- such as the virus causing COVID-19 -- and that typically confer immunological memory. But instead of being protective, the responses produced in these affected children appear to attack a variety of host tissues, a hallmark of autoimmune diseases.

Lucas speculates that the initial immune response in these rare cases triggers a cascade that damages healthy tissue, which in turns makes the tissue more susceptible to attack by autoantibodies.

In the meantime, the peculiar immune system signatures of MIS-C could help in the diagnosis and early treatment options of children at high risk of the disorder, Lucas said.

Inserm teams led by Laurent Reber (Infinity, Toulouse) and Pierre Bruhns (Humoral Immunity, Institut Pasteur, Paris) and French company NEOVACS have developed a vaccine that could induce long-term protection against allergic asthma, reducing the severity of its symptoms and thus significantly improving patient quality of life. Their research in animals has been published in the journal Nature Communications.

Asthma is a chronic disease affecting around 4 million people in France and 340 million worldwide. Allergic asthma is characterized by inflammation of the bronchial tubes and respiratory discomfort caused by the inhalation of allergens, most often dust mites. This exposure to dust mites and other allergens leads to the production of antibodies called immunoglobulin E (IgE) and type 2 cytokines (such as interleukin-4 (IL-4) and IL-13) in the airways. This leads to a cascade of reactions resulting in hyperresponsiveness of the respiratory tract, overproduction of mucus, and eosinophilia (when there are too many eosinophils, a type of white blood cell, in the airways).

Inhaled corticosteroids are the gold standard for controlling asthma. However, in the case of severe asthma, this treatment is not enough. The use of therapeutic monoclonal antibodies that target IgE or the IL-4 and IL-13 pathways is then required. However, these are costly and require the long-term or even lifelong administration of injections.

To overcome this problem, researchers from Inserm, Institut Pasteur, and the company NEOVACS, have developed a conjugate vaccine, called a kinoid, by coupling the recombinant cytokines IL-4 and IL-13 with a carrier protein called CRM197 (a non-pathogenic mutated form of the diphtheria toxin, used in many conjugate vaccines).

The preclinical results (in animal models) show that this vaccine induces the sustained production of antibodies specifically directed against IL-4 and IL-13. Indeed, six weeks after the first injection of the conjugate vaccine, 90% of the mice presented high levels of antibodies. Over one year after primary immunization, 60% of them still had antibodies capable of neutralizing IL-4 and IL-13 activity.

The researchers also showed an effect on asthma symptoms: the vaccine was able to strongly decrease levels of IgE, eosinophilia, mucus production and airway hyperresponsiveness in a model of dust mite allergic asthma. This study therefore suggests both the prophylactic and therapeutic efficacy of the vaccine in this model of asthma and no adverse effects were observed in the animals.

The research team's findings will now need to be tested in a clinical trial setting.

Patients with heart failure with preserved ejection fraction who took the antifibrotic drug pirfenidone saw a significant reduction in a marker of heart muscle scarring compared with patients who received a placebo, based on findings from an early-phase trial presented at the American College of Cardiology's 70th Annual Scientific Session.

"Observational data suggests that heart muscle scarring, or fibrosis, is an important disease process for heart failure prognosis," said Chris Miller, MD, a cardiologist and National Institute for Health Research Clinician Scientist at the University of Manchester and Manchester University NHS Foundation Trust and the study's lead author. "With cardiac MRI, we were able to select a group of patients in whom fibrosis appears to be important and then reduce that scarring. While further investigation is needed, it suggests that fibrosis is an effective treatment target."

Heart failure means that the heart is no longer able to pump blood around the body properly, causing shortness of breath, swelling and fatigue. In about half of patients with heart failure, the forward pumping function of the heart, or ejection fraction, is normal. This is called heart failure with preserved ejection fraction, or HFpEF. While heart failure can involve multiple factors, scarring of the heart muscle is thought to be an important contributing factor in up to two-thirds of patients with HFpEF. This new trial suggests clinicians could one day use a personalized approach to prevent or reverse scarring in those individuals, thereby slowing the progression of heart failure, Miller said.

Pirfenidone is currently approved for treating adults with idiopathic lung fibrosis, or scarring in the lungs that makes it hard to breathe. While the mechanism of action has not been fully established, the drug is thought to work by inhibiting biological processes involved in scar formation. Preclinical studies suggest pirfenidone can both reduce scar tissue formation and reduce existing scarring in the heart.

Researchers enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated natriuretic peptides (markers of fluid retention). Eligible patients underwent cardiac MRI scanning. Those who had evidence of scarring in the heart muscle, as indicated by an extracellular volume (a measurement of heart muscle scaring) of 27% or greater, were randomly assigned to take pirfenidone or a placebo daily. In total, 94 patients were randomized, with 47 assigned to each treatment group.

At one year, patients underwent a second cardiac MRI to measure change in heart muscle extracellular volume, the primary endpoint. Extracellular volume declined by 1.21% on average in patients who took pirfenidone compared with those receiving placebo, a reduction Miller said was likely to be clinically significant.

"Based on the data we have from previous observational studies, this amount of change in fibrosis could translate into a significant reduction in death and hospitalization for heart failure, but further work is needed to determine this," Miller said.

The study also found evidence that fluid retention, measured using natriuretic peptides, improved in patients who took pirfenidone compared to those receiving placebo.

"The associated reduction in natriuretic peptides provides support for heart scarring having a causal role in heart failure and being an efficacious therapeutic target," Miller said. "Hopefully this work can lead to further development of therapeutics that target heart fibrosis and scarring, and a phase three trial to see if pirfenidone improves patient outcomes."

The most common adverse events were nausea, insomnia and rash.

The study was funded by the National Institute for Health Research (UK). The investigational medicinal product was gifted by Roche Products Limited. Immunoassay testing equipment and materials were gifted by Roche Diagnostics International Limited. Neither company had any role in study design or conduct, including data collection, management, analysis and interpretation; preparation, approval of, and the decision to submit the abstract/manuscript.

Patients with heart failure with reduced ejection fraction (HFrEF) did not have better health outcomes if they took sacubitril/valsartan combination therapy compared with valsartan alone, according to new data presented at the American College of Cardiology's 70th Annual Scientific Session.

Heart failure, a leading cause of hospitalization among adults over age 65, is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body, causing fatigue and shortness of breath. For patients with severe heart failure, treatment options are limited to a mechanical heart pump or heart transplant. Doctors have sought ways to slow the progression of severe heart failure to delay the need for these invasive options.

The U.S. Food and Drug Administration has approved sacubitril/valsartan for treatment of heart failure, but the major clinical trial that led to the drug combination's approval, called PARADIGM-HF, had relatively few participants with New York Heart Association (NYHA) Class IV heart failure, the most severe form of the disease. The new trial, called LIFE, was designed to determine whether sacubitril/valsartan is superior to valsartan alone in patients with severe HFrEF.

The trial found no significant improvements with the combination drug when compared with valsartan in terms of the primary endpoint: change in heart failure severity as measured by the area under the curve for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The results also showed no difference in terms of clinical outcomes, though results for some secondary and tertiary endpoints favored valsartan, including a finding that patients taking valsartan were significantly less likely to experience hyperkalemia (elevated potassium levels).

"The results of the LIFE trial show that sacubitril/valsartan is not superior to valsartan for lowering NT-proBNP levels in patients with advanced heart failure," said Douglas L. Mann, MD, Lewin Distinguished Professor of Cardiovascular Disease at Washington University School of Medicine and the study's lead author. "This is important because the type of heart failure patients studied in the LIFE trial were sicker than the patients in PARADIGM-HF. Although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan."

For the trial, researchers enrolled 335 patients with advanced heart failure as defined by having reduced pumping capacity with an ejection fraction of less than 35% (a measure of the heart's squeezing ability for which a value of 50-70% is considered normal) as well as other physiological and functional markers of severe heart failure. Participants were randomly assigned to take either sacubitril/valsartan or valsartan alone for 24 weeks.

About one-third of patients assigned to take sacubitril/valsartan were unable to tolerate the combination drug at the full dose used in previous trials due to side effects including hypotension (low blood pressure and dizziness) and worsening renal function. These patients took a reduced dose.

"Patients with advanced heart failure are a very difficult group of patients to treat. It has been widely assumed that sacubitril/valsartan would be effective in all patients with heart failure," Mann said. "I think the drug works very effectively in patients with milder heart failure, but the results of the LIFE trial indicate that there is no evidence that sacubitril/valsartan is better than valsartan for more advanced heart failure, and there appears to be less hyperkalemia with valsartan."

The combination of sacubitril/valsartan is thought to work in part by reducing the size of the heart and improving its pumping ability.

"We make the assumption that all heart failure patients are the same and therefore will respond the same to all therapies. However, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the end organ changes that occur in the heart and kidneys. These end organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure. This is one of the lessons we learned from the LIFE trial," Mann said.

The study was limited by its relatively short duration, Mann said. In addition, the sample size fell short of the planned enrollment of 400 patients since the trial was stopped early in response to the COVID-19 pandemic.

The likelihood of people surviving COVID-19 in UK hospitals has been improving over time, a new study has found.

Research published in The Lancet Respiratory Medicine by the ISARIC Coronavirus Clinical Characterisation Consortium found that in-hospital mortality declined from 32% at the start of the first wave (Mar-Apr 2020) to 16% at the end of the first wave (Jun-Jul 2020).

In their study of 63,972 adults admitted to 247 UK hospitals the researchers found reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. This improvement was found to be associated with adoption of steroids as a newly proven treatment and improvements in respiratory support and critical care use, in part reflecting improved clinical knowledge.

Dr Annemarie Docherty, Senior Clinical Lecturer at the University of Edinburgh and a Consultant in Intensive Care Medicine, said: "The risk of death for people admitted to hospital with covid-19 was extremely high at around one in three at the beginning of the first wave, and consistently improved over subsequent months. Part of this improvement can be explained by differences in the people who were admitted to hospital, and how sick they were. Further reduction in the risk of death can be explained by improvements in care of covid-19 patients with treatments such as dexamethasone and better use of advanced respiratory support."

Professor Calum Semple, Professor of Child Health and Outbreak Medicine at the University of Liverpool and Co-Lead of ISARIC4C, said: "This is good news in a week where there is some anxiety about how new variants will impact upon the roadmap out of lock down. We now understand better how changes in patient characteristics and improvement in medical care have led to improved survival in UK hospitals. The discovery of what works and as importantly what does not work was only possible because of prepared research capacity that was put in place by the investigators collaborating at Universities of Liverpool, Edinburgh, Imperial College, and Oxford with NIHR support."

Professor Chris Whitty, Chief Medical Officer and co-lead of the National Institute for Health Research, said: "This National Institute for Health Research (NIHR) supported research provides evidence that frontline clinicians and healthcare professionals learnt and adapted to COVID-19 to improve patient care. Many of those healthcare professionals also facilitated research into treatments, such as dexamethasone, which was vital to the improvement in mortality described in this paper. These improvements are testament to the hard work of many."

The work is the latest result from ISARIC - a global network of clinicians and scientists who have been preparing to prevent disease and death from severe outbreaks since 2012 in readiness for a pandemic such as this. The ISARIC4C study is led by researchers from Liverpool, Edinburgh and Imperial College London and is principally funded by grants from the National Institute for Health Research (NIHR) and UK Medical Research Council.

A group of Brazilian and Portuguese researchers observed a correlation between the presence of lead in the organism and a microRNA (miRNA) that could be associated with the mechanisms that regulate DNA methylation, a physiological process required to control gene expression and ensure that genes function properly.

The alterations were detected in blood cells from workers in automotive battery plants, which use lead as a raw material. Curiously, lead levels in blood samples from 85 volunteers – averaging 20 micrograms per deciliter of blood (20 µg/dl) – were lower than the acceptable ceiling defined in Brazilian law (60 µg/dl).

The study was supported by FAPESP and reported in an article published in Frontiers in Genetics. The authors are affiliated with the Federal University of São Paulo (UNIFESP), the Federal University of the ABC (UFABC), Anhembi Morumbi University, and the University of São Paulo (USP) in Brazil, and the New University of Lisbon (UNL) in Portugal. The study was part of a project funded by FAPESP.

“What all the studies conducted to date suggest, albeit incipiently, is that low-level exposure to lead isn’t necessarily associated with a lack of adverse effects but may correlate with molecular events that precede the events that are well-established in the literature as deriving from chronic lead poisoning, such as neurological and hematological problems,” said Gustavo Rafael Mazzaron Barcelos, last author of the article. Barcelos is a professor at UNIFESP’s Institute of Health and Society (ISS) in Santos, São Paulo state.

Although low doses did not correlate directly with health problems, he added, the DNA alterations should serve as a warning. “These levels cannot be considered safe. It would be great if lead exposure levels could be minimal, but a whole industrial system depends on production of lead. We need good public policy to minimize exposure, which we’ve been observing systematically in Brazil for decades,” Barcelos said.

In Brazil, any lead exposure exceeding 60 µg/dl must be reported to the SUS, the national health service, and the social security authorities. In China, research has shown that local workers have higher blood lead levels, averaging around 40 µg/dl.

“We analyzed DNA methylation, one of the epigenetic changes that occur mainly in promoter regions, which control gene functions. When methylation in these regions undergoes such changes, protein synthesis may become dysregulated, potentially causing problems. There’s evidence that lead exposure can inhibit DMNT1, the enzyme responsible for controlling DNA methylation. In the samples we analyzed, we found an abundance of miR-148a, a miRNA that targets the gene for DMNT1,” said Marilia Ladeira de Araújo, first author of the article. The study was part of her PhD research at ISS-UNIFESP. She performed part of the analysis while working as a research intern at UNL’s Medical School with a scholarship from FAPESP.

Detection

In a previous study, the group had detected an overall decrease in DNA methylation in the same worker cohort, using samples taken at plants in the state of Paraná. Reported in the Journal of Toxicology and Environmental Health, Part A, the study was part of the master’s research of Paula Pícoli Devóz at the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP). Devóz is also a co-author of the latest published study.

The researchers then decided to look for biomarkers of reduced DNA methylation, identifying several miRNAs that could be associated with this event. They observed a significant increase in miR-148a, noted in the literature as being associated with DNA damage, inflammatory processes, and oxidative stress, all of which may correlate with the development of multifactor pathologies such as neurodegenerative diseases and cancer, for example.

“The advantage of using miR-148a as a biomarker of epigenetic disturbances induced by lead exposure is that these alterations in its expression may precede various cellular disorders, such as oxidative stress and cell death,” Barcelos said. “We don’t yet know whether a decrease in DNA methylation has adverse effects. We analyzed the overall status of this parameter in DNA as a whole, but we now know it’s a potential biomarker of this condition.”

As soon as the pandemic is over, he plans to continue the research by collecting more samples from the same cohort over a relatively long period to see if the effects of low-level exposure persist and how the organism can adapt to it.

The article “Association between miR-148a and DNA methylation profile in individuals exposed to lead (Pb)” is at: www.frontiersin.org/articles/10.3389/fgene.2021.620744/.

Journal

Frontiers in Genetics

DOI

10.3389/fgene.2021.620744

Researchers at the University of California, Davis, have found a link between traffic-related air pollution and an increased risk for age-related dementia, including Alzheimer's disease. Their study, based on rodent models, corroborates previous epidemiological evidence showing this association.

Alzheimer's disease is the most common cause of age-related dementia and the sixth leading cause of death in the United States. More than 5 million Americans currently live with Alzheimer's disease -- a number that is expected to triple by 2050 as the population ages. Health care costs for those patients are predicted to grow from $305 billion in 2020 to $1.1 trillion by 2050.

UC Davis toxicologist Pamela Lein, senior author of the study recently published in Environmental Health Perspectives, said their findings underscore the urgent need to identify factors that contribute to the onset and progression of Alzheimer's to develop effective preventive measures for reducing the individual and societal burden of this disease.

Lein worked with UC Davis atmospheric scientist Anthony Wexler and first author Kelley Patten, while she was a doctoral student in the UC Davis graduate group for pharmacology and toxicology, to develop a novel approach to study the impacts of traffic-related air pollution in real time. Researchers set up a rodent vivarium near a traffic tunnel in Northern California so they could mimic, as closely as possible, what humans might experience from traffic-related air pollution.

"This approach was a creative way to get at the question of what impacts air pollution has on the brain in the absence of confounding factors such as socioeconomic influences, diet, etc.," Lein said. "It's important to know if living close to these roadways poses a significant risk to the human brain as it ages."

Exposure outcomes on the aging brain

The researchers exposed male and female rats for up to 14 months to filtered air or polluted air drawn from the tunnel and delivered it to animals unchanged in real time. The subjects were divided into two groups: wild type rats and those that express Alzheimer's disease risk genes that are relevant to humans.

Testing was conducted in 3-, 6-, 10- and 15-month-old animals using hyperspectral imaging, behavioral testing and neuropathologic measures to quantify the expression of Alzheimer's disease characteristics.

"We saw that traffic-related air pollution accelerated Alzheimer's disease characteristics not only in the animals who express the risk gene (which we anticipated) but also in the wild type rats," Lein said. "We didn't anticipate that. The big, exciting discovery is that traffic-related air pollution is a risk factor for late-onset Alzheimer's disease. This is important because this pollution is everywhere and could explain the increased number of people impacted by Alzheimer's disease across the world."

What remains unclear is which component of that pollution is predominately responsible for the effects on the brain. There are gases, particulate matter, road dust, tire wear, vibration and noise involved in traffic-related air pollution.

"The next set of studies is to try and tease apart specific components of traffic-related air pollution that drive these Alzheimer's disease traits," Lein said. "Or is it the collective mix that causes the damage?"

Fine particles (PM 2.5) in the polluted air at the study site were below federal regulatory limits, but ultrafine particles, which are not regulated, were detected in the brains of exposed animals.

"The Environmental Protection Agency only regulates down to the PM 2.5 level, but the bulk of this traffic-related air pollution is ultrafine particulate matter," Lein said. "These studies provide incentive to re-evaluate the current regulatory standards and suggest that current ones are not protective of the aging brain."

The study shows traffic-related air pollution can deliver a double whammy, decreasing the time of onset of Alzheimer's disease characteristics and accelerating disease progression. While personal factors can change an individual's risk for Alzheimer's disease (exercise, smoking, diet), people are often poor about sticking to a plan to decrease their risk factors.

"There's a lot of data that shows if you can regulate risk factors through policy at a population level, you have a more significant public health impact than if you try to regulate them at the individual level," Lein said. "If we could make some progress in identifying which component in traffic-related air pollution is causing these effects, then scientists can approach legislators to develop scientifically based regulations. Even if we can delay onset of Alzheimer's disease by five years, we could potentially save our health care system an enormous amount of money."

This study is one of four published papers to come out of the research site to date. A prior study, published in Translational Psychiatry focused on the developing brain and found a link between traffic-related air pollution and an increased risk for changes in brain development relevant to neurodevelopmental disorders such as autism.

In patients receiving therapeutic hypothermia after suffering out-of-hospital cardiac arrest, those who were cooled below 31 degrees Celsius (about 88 degrees Fahrenheit) for 24 hours showed no difference in terms of death or poor neurological outcomes at six months compared with patients receiving guideline-recommended cooling of 34 C (about 93 F). These findings are part of a study presented at the American College of Cardiology's 70th Annual Scientific Session.

Therapeutic hypothermia is a procedure in which a person's body is cooled far below normal body temperature. It has been shown to improve survival and reduce brain damage in people who have been resuscitated but remain comatose after suffering cardiac arrest (when the heart stops pumping effectively). Current guidelines for therapeutic hypothermia recommend cooling the body to 32-36 C for 24 hours. The new study found no benefit from a deeper cooling to 31 C.

"The results of our trial do not support the use of moderate therapeutic hypothermia of 31 C to improve neurological outcomes in comatose survivors of out-of-hospital cardiac arrest," said Michel R. Le May, MD, interventional cardiologist at the University of Ottawa Heart Institute and the study's lead author. "These findings do not support changing the current guidelines; we need to look for other strategies that can improve outcomes for these patients who currently have a poor prognosis."

The trial enrolled 367 patients treated for out-of-hospital cardiac arrest at the University of Ottawa Heart Institute between 2013-2020. All patients had been successfully resuscitated, as indicated by a return of blood pressure, but remained comatose. Participants were cooled with an endovascular device that uses temperature-controlled saline-filled balloons inserted near the heart via a vein to alter a patient's body temperature. For half of the patients, the endovascular device was set to cool the body to 31 C and for the other half the device was set to 34 C. Once the target temperature was achieved, the temperature was maintained for 24 hours before the patient was warmed up to normal body temperature at a rate of 0.25 degrees per hour.

The trial is the first to use a randomized, double-blind approach for testing different target temperatures for therapeutic hypothermia. Physicians overseeing the treatment were prevented from seeing the temperature setting by a shield placed over the temperature display on the endovascular machine. Nurses were aware of the temperatures but maintained separate charts to maintain blinding among the treating physicians.

The study's primary endpoint, a composite of death or poor neurological outcome at six months, occurred in 48% of those cooled to 31 C and 45% of those cooled to 34 C, a difference that was not statistically significant. There was also no significant difference between groups in terms of the rate of death or the rate of poor neurological outcome when these outcomes were assessed individually. The researchers examined outcomes by sex, age and other variables but found no significant differences in any subgroups analyzed.

Patients cooled to 31 C on average had a longer stay in the cardiac intensive care unit, which Le May said may reflect the fact that both the cool-down and warm-up periods lasted longer for these patients due to the lower target temperature.

Other researchers have assessed whether different temperatures or durations of therapeutic hypothermia can improve outcomes, but these previous studies have similarly demonstrated no improvement over current guidelines. Moving forward, Le May suggested brain monitoring approaches could be used to inform which strategies may be best suited for each patient's particular situation.

"It may be useful to pool all these studies together and try to figure out if there is a particular temperature that's more suitable in particular cases," Le May said. "We also have to find better, noninvasive tools to assess the brain and perhaps turn our attention toward a more personalized way of treating these patients. This would allow us to select the protocol that optimizes the benefit for a particular patient."

Le May said that many key elements influencing survival after out-of-hospital cardiac arrest come into play before the patient reaches the hospital, including whether bystanders administer basic CPR, how quickly paramedics arrive on the scene and how quickly patients are transferred to specialized cardiac centers. Focusing on these factors could offer opportunities to further improve survival, he said.

The study was conducted at a single center, which may limit its generalizability but was helpful in ensuring consistent treatment protocols, Le May said.

Patients with chronic kidney disease and Type 2 diabetes who took the experimental drug finerenone were about 30% less likely to develop the heart rhythm disorder atrial fibrillation (AFib) than those taking a placebo, according to data presented at the American College of Cardiology's 70th Annual Scientific Session.

Last year, researchers reported that the trial, called FIDELIO-DKD, met its primary endpoint showing a significant benefit of finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, in terms of a composite of sustained decrease in kidney function, kidney failure and renal death. The new analysis reveals that patients derived these benefits regardless of their history with AFib and suggests that taking finerenone also reduced the rate of new-onset AFib.

"Finerenone can lower the risk of development of atrial fibrillation in patients with chronic kidney disease and diabetes and can be used as a therapeutic strategy to delay its onset," said Gerasimos Filippatos, MD, from the National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital in Athens, Greece, and the study's lead author. "It can also protect the heart and the kidney from further damage caused by chronic kidney disease and diabetes in these patients with or without pre-existing atrial fibrillation."

Chronic kidney disease, diabetes and AFib are major public health concerns worldwide. Patients with chronic kidney disease and diabetes face an increased risk of developing AFib because these conditions can cause changes in the heart's structure and electric signaling, leading to fast and erratic heart rhythms. During preclinical studies, finerenone was reported to slow these structural changes.

FIDELIO-DKD randomly assigned 5,674 patients with chronic kidney disease and diabetes to take finerenone or a placebo and tracked outcomes for a median of 2.6 years. The primary endpoint was a composite of kidney failure, renal death or sustained decrease in estimated glomerular filtration rate (a measure of kidney function) of 40% or more from baseline. The key secondary outcome included death by loss of heart function, nonfatal heart attack, nonfatal stroke or hospitalization for heart failure.

As previously reported, finerenone significantly lowered the risk of kidney events by 18% and the risk of cardiovascular events by 14% compared with placebo. For the new analysis, researchers assessed outcomes among patients with and without a history of AFib or atrial flutter (about 8% of participants had AFib or atrial flutter at the start of the trial) and the risk of patients developing AFib or atrial flutter during the study.

The results found the primary and secondary endpoints were significantly lower in patients taking finerenone regardless of their AFib status at the start of the study.

"The previously-reported kidney and heart protection with finerenone applied equally to patients with and without pre-existing atrial fibrillation," Filippatos said.

In addition, new-onset AFib or atrial flutter was reported in 3.2% of patients taking finerenone and 4.5% of those taking a placebo, a significant difference in favor of finerenone.

Researchers said that previous findings from preclinical studies have suggested that finerenone may help reduce scarring and thickening of the heart tissue, possibly through its action of blocking mineralocorticoid receptors, a type of protein molecule present on many cell types in the heart and kidney that has been shown to be especially abundant in patients with AFib.

"Preventing or delaying the onset of atrial fibrillation in patients with chronic kidney disease and diabetes is particularly important since having atrial fibrillation can worsen chronic kidney disease and having diabetes can worsen atrial fibrillation symptoms," Filippatos said. "Treatment in these patients can also be challenging because they are prone to developing blood clots [which can lead to stroke] and bleeding. Finerenone has the potential to reduce the burden of atrial fibrillation in these patients."

Filippatos said that larger studies focused specifically on new-onset AFib would be needed to confirm the findings. Because participants underwent heart rhythm tests only once per year in FIDELIO-DKD, Filippatos said it is possible that researchers missed asymptomatic AFib or cases that were not apparent from tests. A separate trial is currently underway to examine finerenone's effects in patients with less severe chronic kidney disease and diabetes.

A subgroup of patients who experienced an out-of-hospital cardiac arrest (OHCA) that did not respond to standard advanced cardiac life support (ACLS), were immediately transported to a cardiac care center, and placed on a device similar to a heart-lung bypass machine were more likely to have survived with good brain function six months later than similar patients who received standard care at the site where the OHCA occurred. The study was presented at the American College of Cardiology's 70th Annual Scientific Session.

"This study--the largest randomized clinical trial that has been conducted to address this question--shows that a hyperinvasive approach is a feasible and effective treatment strategy for OHCA," said Jan Blohlávek, MD, PhD, professor of medicine at Charles University in Prague, Czech Republic, and lead author of the study.

Although the primary endpoint (six-month survival with good brain function as assessed by a validated scale for measuring cerebral performance after a cardiac arrest) was not met, the trial was stopped prematurely because the hyperinvasive approach showed efficacy in subgroups of patients.

Cardiac arrest occurs when a sudden malfunction of the heart's electrical system causes the heart to begin beating very erratically, which interrupts blood flow to the heart and brain. According to the Centers for Disease Control and Prevention, about 375,000 people have an OHCA every year in the U.S. The survival rate after an OHCA is about 12%. To survive, the patient must receive immediate cardiopulmonary resuscitation (CPR) to increase blood flow to the heart and brain and an electrical shock from a defibrillator to stop the abnormal heart rhythm.

The study involved 256 patients who experienced a witnessed OHCA. The patients' median age was 57 years and 92% were men. About 45% had high blood pressure and 20% had a history of coronary artery disease. They were randomly assigned to receive either standard advanced cardiac life support or hyperinvasive support.

Patients in the standard-care group (the S group) were treated at the site where the OHCA occurred with manual CPR, defibrillation, medications to reverse the cardiac arrest and other elements of usual care for a cardiac arrest. Patients in the hyperinvasive group (the H group) received mechanical CPR using a device that provided automatic chest compression and were transported immediately to a cardiac center where--if their heartbeat was not restarted en route--they were placed on an extracorporeal membrane oxygenation (ECMO) machine. This machine temporarily takes over the work of the heart and lungs by infusing fresh oxygen into the blood and pumping blood to the body's organs and tissues.

After six months, 31.5% of patients in the H group and 22% of those in the S group had survived with good brain function, a difference that was not statistically significant. As secondary outcomes, Blohlávek and his colleagues looked at the proportion of patients in each group who had recovered neurological and cardiac function at 30 days after the OHCA. In the H group, 34.7% had good neurological function at 30 days, compared with 22.7% in the S group, a statistically significant difference. Recovery of cardiac function was similar in the two groups.

The main benefit of the hyperinvasive approach was evident in a subgroup of patients who were resuscitated for more than 45 minutes; 20 patients in the H group survived, compared with six in the S group. Moreover, four of the six survivors in the S group had been crossed over to the H group and had therefore received hyperinvasive rather than standard treatment.

The study design allowed emergency medical staff at the scene and at the hospital to switch (or "crossover") patients randomly assigned to the S group to the H group or vice versa. Patients assigned to the H group could be switched to the S group if hyperinvasive intervention would likely be futile. The overall crossover was low; of the 256 patients enrolled in the study, 11 (8.3%) randomly assigned to the S group were switched to the H group, while nine (7.2%) randomly assigned to the H group were switched to the S group. However, because the study used a rigorous form of analysis known as "intention to treat," patients who crossed over were still counted as part of the group they had been randomly assigned. According to Blohlávek, in patients who crossed over from the S group to the H group, 40% survived with normal neurological outcomes, while none of the patients survived in a switch from the H group to the S group.

The study's data safety and monitoring board--an independent group of experts whose job was to review the study data at prespecified intervals--decided to stop the study after 256 subjects had been enrolled, when it became clear that survival and neurological recovery were superior in the H group, Blohlávek said. For this reason, the study did not reach its prespecified enrollment target of 570 patients.

Patient survival in the S group, at 22%, was more than twice as high as the researchers had expected. "A byproduct of training the emergency medical teams to conduct the hyperinvasive protocol is that they also achieved extraordinarily good results among patients who received standard [advanced cardiac life support]," Blohlávek said.

The study has implications for practice, based on the findings that the hyperinvasive approach was most beneficial for patients who were resuscitated for more than 45 minutes and that, among patients who were resuscitated for a shorter time, the number of neurologically intact survivors was similar in both groups, Blohlávek said.

"Timely transport to a hospital and treatment with ECMO should be considered for patients whose hearts do not regain spontaneous activity with standard advanced cardiac life support," Blohlávek said. "However, this may be viable only in circumstances where there is absolutely optimal prehospital care, including the ability to have a bystander perform chest compressions at the scene of the arrest with direction via telephone from the emergency dispatch center, and the ability to quickly transport the patient to a dedicated cardiac center where highly trained specialists are available."

The ocean is a big place with many deep, dark mysteries. Humans have mapped no more than 20% of the sea, and explored less. Even the kelp forests of Southern California -- among the best studied patches of ocean on the planet -- hide species not yet described by science.

Now, UC Santa Barbara's Thomas Turner has published a paper in the journal Zootaxa describing four new species of sponges. These novel specimens weren't dredged from the murky depths or found on some distant seamount, but collected locally from popular dive spots. The study brings Turner's new species count to five, and the scientist believes there may be dozens yet to discover and describe along the West Coast.

Turner, an associate professor in the Department of Ecology, Evolution, and Marine Biology, collected hundreds of samples by hand from dives he conducted all around Southern California. He made sure to photograph each sponge in its natural habitat, documentation that will provide a wealth of information not otherwise available once a specimen goes into a collection. Back in the lab, he got to work analyzing their anatomy and sequencing their genes.

In 2020, Turner described his first new species of sponge using these molecular techniques: Galaxia gaviotensis, which he found just west of Santa Barbara. He suggested the common name Gaviota galaxy sponge. "Like a galaxy, the type species of the genus is packed with a diversity of stars," he wrote, referring to the shape of its spicules, microscopic objects that provide structural support to many sponges.

The four species in the new paper appear to a layperson as nondescript beige patches on kelp forest rocks. At first, Turner couldn't even tell what order they belonged to. But while the simple creatures can be hard to distinguish visually, their genomes can reveal their differences. So this is where Turner focused his efforts.

"When I got the DNA, and I was shocked to learn that they were in Scopolinida, which is almost entirely tropical," he said. Species in this order were unknown from the west coast. In fact, no one had documented Scopolinid sponges anywhere in the eastern Pacific.

And laypeople have certainly come across at least two of these species. "They live out in the open; divers have been swimming past them for decades," Turner said. He even found pictures of one of them on the citizen science app iNaturalist. "They're all over Southern California, super common. Just no scientist has ever picked one up and looked at it to try to figure out what it was."

When naming a new species, a scientist often try to highlight a salient characteristic of the organism. This is challenging to do for a bunch of beige splotches. So Turner named two after the locations where he found them: S. goletensis, for the town of Goleta; and S. kuyamu, for the village of Kuyamu, a community of Barbareño Chumash that once stood onshore at the site where the sponge was discovered. Based on their genomics, Turner concluded that these two are sister species, more closely related to each other than any other known sponges.

Turner coined the name S. jali for the third species after the patterns on its surface, which reminded him of a jali, a latticed screen common in Indo-Islamic architecture. He named the final species after Nausicaä, a character in the Hayao Miyazaki film "Nausicaä of the Valley of the Wind." The film is about humans and nature, he explained, and a lot of the weird organisms in the fictional world filter and clean the environment like a sponge. In fact, sponges are unique in consuming even viruses and bacteria, he added; many other filter feeders forgo these minute morsels in favor of much larger plankton.

Sponges diverged from all other animals over 600 million years ago, with the major subgroups parting ways not long after that. "So, the amount of independent evolution within sponges is comparable to that within all other animals," explained Turner. Because they diverged from other animals so long ago, they can potentially tell scientists a lot about our origins.

The animals have also caught the attention of biomedical researchers. Given how porous they are, sponges are much more intertwined with their external environment than any other animal. As a result, they have to actively manage their bacterial and viral loads. This has led sponges and their microbiota to produce a lot of antimicrobial and even anti-cancer compounds, Turner said.

Despite their long evolutionary history, most sponges have retained similarities like a simple body plan and filter-feeding lifestyle. Sponges' simplicity and similarity has long vexed scientists, who used to classify life based on morphology: the form and function of organisms. "For basically 200 years, taxonomists have struggled to figure out how to classify the sponges because they offer so few morphological characteristics," Turner remarked.

Only in the past few decades have researchers straightened out the different orders of sponges. "A taxonomic order is a pretty big group of animals," Turner continued. "For example, cats, dogs and walruses are all in the same order: Carnivora."

Taxonomy is never carried out just for taxonomists. It's done to lay a foundation for researchers in other fields to build upon. "Trying to conduct research without taxonomy is kind of like if you went to the Library of Congress and there weren't any librarians, and all the books were just in a big pile," Turner said. "There's plenty of information there, but you can't do anything with it. The taxonomist's job is the librarian's job: to organize all that information so that everyone else can study it."

Ecologists are often at a loss when it comes to sponges, Turner explained, simply because the taxonomy and systematics haven't been done to figure out what's what. That's the situation that greeted Turner when sponges first caught his interest a few years ago.

"I was diving recreationally in the kelp forest here, and I was seeing all these sponges," he recalled. "I couldn't tell what they were; I didn't know what was important to them; I couldn't tell what was different from one to another; and I was getting really frustrated." Finally, he decided that someone needed to straighten this out, and it might as well be him.

Turner's experience as a scientific diver combined with his background in genomics made him perfectly suited to begin sorting out the taxonomy and systematics of West Coast sponges. Since 2018 he has collected about 800 specimens. The four species in this paper, plus the one from 2020, are just the beginning of his work describing perhaps 100 new species and adding critical information to hundreds of others.

DNA sequencing offers a path forward to understanding these animals, but there's still a lot of painstaking morphological analysis in Turner's future. That's because, by combining these two methodologies, he can bridge the gap between modern molecular biology and our historical reliance on physiology. "That is the only way out of this morass that we're in regarding sponge taxonomy," Turner said, "combining the morphology with the genetics."

Unfortunately, many sponge specimens were preserved in ways that did not safeguard the animals' DNA. This will make it a challenge to bring old collections into the era of molecular biology. In that light, Turner is applying for funding to investigate how to extract DNA from old sponge samples.

As perhaps the only sponge taxonomist on the U.S. Pacific coast, Turner also intends to continue his research on the region's sponges. He plans to start sequencing the whole genomes of sponges he's collected, looking for patterns of molecular evolution to try and sort out what makes one different from another, and what that can tell us about their ecology and evolution. His research is supported by The Southern California Bight Marine Biodiversity Observation Network (SCB MBON), a long-term collaboration led by UC Santa Barbara's Robert Miller. The results should elucidate the roles these animals play in their ecosystems.

"It's all about building a foundation that lots of other people can hopefully build upon," he said, "and establishing a new direction for marine study in California wherein people can use sponges in their research."

Alcohol appears to have an immediate--or near-immediate--effect on heart rhythm, significantly increasing the chance that an episode of atrial fibrillation (AFib) will occur, according to new data presented at the American College of Cardiology's 70th Annual Scientific Session.

The data revealed that just one glass of wine, beer or other alcoholic beverage was associated with twofold greater odds of an episode of AFib occurring within the next four hours. Among people having two or more drinks in one sitting, there was a more than threefold higher chance of experiencing AFib. Using an alcohol sensor placed on participants' ankles, which passively monitored alcohol intake, the investigators found that every 0.1% increase in inferred blood alcohol concentration over the previous 12 hours was associated with an approximate 40% higher odds of an AFib episode. Evidence from those sensors also demonstrated that the total alcohol concentration over time also predicted the chance AFib would occur.

"Alcohol is the most commonly consumed drug in the world, and there is still a lot we don't understand about what it does to our bodies and, in particular, our hearts," said Gregory M. Marcus, MD, cardiologist and professor of medicine at the University of California, San Francisco, and the study's lead author. "Based on our data, we found that alcohol can acutely influence the likelihood that an episode of AFib will occur within a few hours, and the more alcohol consumed, the higher the risk of having an event."

AFib is the most common heart rhythm disorder. It is often characterized by a rapid, chaotic and fluttery heartbeat. Marcus said that people can experience a range of symptoms. Some may not feel anything, while others are overcome with severe shortness of breath, fatigue, fainting or near fainting spells and a disconcerting sensation that the heart is beating out of control. AFib also results in costly use of health care services, including visits to the emergency department, hospitalizations and procedures each year. Over time, AFib can lead to heart failure, stroke and dementia if untreated.

Researchers enrolled 100 patients with paroxysmal or intermittent AFib, which tends to go away within a short period of time (unlike chronic AFib). Patients in the study were 64 years old on average; the majority were white (85%) or male (80%). Past medical history, medications and lifestyle habits were assessed through chart reviews and patient interviews. Each participant was fitted with a wearable heart monitor that continuously tracked their heart rhythm and an ankle sensor to objectively detect when more than two to three drinks were consumed on a given occasion. Participants were asked to press a button on the heart monitor each time they had an alcoholic drink. Finger stick blood tests measuring alcohol consumption in the previous few weeks were also used to corroborate self-reported drinking events. Because researchers used repeated measurements from the same individual, they served as their own control over time. Overall, more than half (56) had an episode of AFib during the four-week study.

"Patients have been telling us that alcohol is a trigger for AFib for a long time, but it's been hard, if not impossible, to study because there is a critical temporal relationship that requires a real-time assessment of alcohol intake and heart rhythm," Marcus said. "This is the first study to objectively demonstrate and quantify the real-time relationship between alcohol consumption and AFib episodes. While this study was limited to people with intermittent AFib, it's reasonable to extrapolate the fact that in many people alcohol may be the main trigger for an initial episode."

Marcus said there may be other factors--such as race/ethnicity, sex, genetics or other environmental exposures--that influence alcohol's effect on the heart in various ways and need to be studied. In addition, people often pair alcohol with foods that are high in sodium, while some pour a drink because they feel stressed, so there may be other things that play a role. The findings also run counter to previous reports about the potentially protective role of alcohol on heart health when used in moderation.

"There is conventional wisdom that alcohol is 'good' or 'healthy' for the heart, based on observational studies, but that relates to coronary heart disease and heart attack. These new data present an interesting conundrum regarding the overall risks versus benefits of alcohol in moderation," Marcus said. "But the data is very clear that more is not better when it comes to alcohol; those who drink more have a higher risk of heart attack and death."

Marcus added that this situation is a perfect example where precision medicine may play a clinically relevant role to help identify which patients are at high risk for alcohol-related AFib. Those who are not at high-risk of the harmful effects of alcohol might yet benefit from moderate alcohol consumption as another way to potentially protect them from coronary blockages and disease.

The general recommendation for daily alcohol consumption is no more than one standard alcoholic beverage a day for women and two for men.

"Still, when patients ask me what they can do to avoid an AFib episode, I tell them the evidence suggests that they should minimize, if not completely eliminate, alcohol. But we have to consider quality of life as well, which is both relevant to arrhythmia symptoms and the opportunity to enjoy a glass of wine once in a while for some. So, it's not as simple as instructing everyone to avoid alcohol," Marcus said.

As far as next steps, Marcus and his team will look at how these results, which are limited to those with intermittent AFib, may apply to the general population. They also hope to identify other factors that may influence the relationship between alcohol and AFib, including genetics.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism.

Marcus will be available to the media in a virtual press conference on Monday, May 17, at 12:15 p.m. ET/ 16:15 UTC.

Marcus will present the study, "Acute Alcohol Consumption and Discrete Atrial Fibrillation Events," on Monday, May 17, at 10:45 a.m. ET / 14:45 UTC, virtually.

On Sept. 9, 2018, astronomers spotted a flash from a galaxy 860 million light years away. The source was a supermassive black hole about 50 million times the mass of the sun. Normally quiet, the gravitational giant suddenly awoke to devour a passing star in a rare instance known as a tidal disruption event. As the stellar debris fell toward the black hole, it released an enormous amount of energy in the form of light.

Researchers at MIT, the European Southern Observatory, and elsewhere used multiple telescopes to keep watch on the event, labeled AT2018fyk. To their surprise, they observed that as the supermassive black hole consumed the star, it exhibited properties that were similar to that of much smaller, stellar-mass black holes.

The results, published today in the Astrophysical Journal, suggest that accretion, or the way black holes evolve as they consume material, is independent of their size.

"We've demonstrated that, if you've seen one black hole, you've seen them all, in a sense," says study author Dheeraj "DJ" Pasham, a research scientist in MIT's Kavli Institute for Astrophysics and Space Research. "When you throw a ball of gas at them, they all seem to do more or less the same thing. They're the same beast in terms of their accretion."

Pasham's co-authors include principal research scientist Ronald Remillard and former graduate student Anirudh Chiti at MIT, along with researchers at the European Southern Observatory, Cambridge University, Leiden University, New York University, the University of Maryland, Curtin University, the University of Amsterdam, and the NASA Goddard Space Flight Center.

A stellar wake-up

When small stellar-mass black holes with a mass about 10 times our sun emit a burst of light, it's often in response to an influx of material from a companion star. This outburst of radiation sets off a specific evolution of the region around the black hole. From quiescence, a black hole transitions into a "soft" phase dominated by an accretion disk as stellar material is pulled into the black hole. As the amount of material influx drops, it transitions again to a "hard" phase where a white-hot corona takes over. The black hole eventually settles back into a steady quiescence, and this entire accretion cycle can last a few weeks to months.

Physicists have observed this characteristic accretion cycle in multiple stellar-mass black holes for several decades. But for supermassive black holes, it was thought that this process would take too long to capture entirely, as these goliaths are normally grazers, feeding slowly on gas in the central regions of a galaxy.

"This process normally happens on timescales of thousands of years in supermassive black holes," Pasham says. "Humans cannot wait that long to capture something like this."

But this entire process speeds up when a black hole experiences a sudden, huge influx of material, such as during a tidal disruption event, when a star comes close enough that a black hole can tidally rip it to shreds.

"In a tidal disruption event, everything is abrupt," Pasham says. "You have a sudden chunk of gas being thrown at you, and the black hole is suddenly woken up, and it's like, 'whoa, there's so much food -- let me just eat, eat, eat until it's gone.' So, it experiences everything in a short timespan. That allows us to probe all these different accretion stages that people have known in stellar-mass black holes."

A supermassive cycle

In September 2018, the All-Sky Automated Survey for Supernovae (ASASSN) picked up signals of a sudden flare. Scientists subsequently determined that the flare was the result of a tidal disruption event involving a supermassive black hole, which they labeled TDE AT2018fyk. Wevers, Pasham, and their colleagues jumped at the alert and were able to steer multiple telescopes, each trained to map different bands of the ultraviolet and X-ray spectrum, toward the system.

The team collected data over two years, using X-ray space telescopes XMM-Newton and the Chandra X-Ray Observatory, as well as NICER, the X-ray-monitoring instrument aboard the International Space Station, and the Swift Observatory, along with radio telescopes in Australia.

"We caught the black hole in the soft state with an accretion disk forming, and most of the emission in ultraviolet, with very few in the X-ray," Pasham says. "Then the disk collapses, the corona gets stronger, and now it's very bright in X-rays. Eventually there's not much gas to feed on, and the overall luminosity drops and goes back to undetectable levels."

The researchers estimate that the black hole tidally disrupted a star about the size of our sun. In the process, it generated an enormous accretion disk, about 12 billion kilometers wide, and emitted gas that they estimated to be about 40,000 Kelvin, or more than 70,000 degrees Fahrenheit. As the disk became weaker and less bright, a corona of compact, high-energy X-rays took over as the dominant phase around the black hole before eventually fading away.

"People have known this cycle to happen in stellar-mass black holes, which are only about 10 solar masses. Now we are seeing this in something 5 million times bigger," Pasham says.

"The most exciting prospect for the future is that such tidal disruption events provide a window into the formation of complex structures very close to the supermassive black hole such as the accretion disk and the corona," says lead author Thomas Wevers, a fellow at the European Southern Observatory. "Studying how these structures form and interact in the extreme environment following the destruction of a star, we can hopefully start to better understand the fundamental physical laws that govern their existence."

In addition to showing that black holes experience accretion in the same way, regardless of their size, the results represent only the second time that scientists have captured the formation of a corona from beginning to end.

"A corona is a very mysterious entity, and in the case of supermassive black holes, people have studied established coronas but don't know when or how they formed," Pasham says. "We've demonstrated you can use tidal disruption events to capture corona formation. I'm excited about using these events in the future to figure out what exactly is the corona."