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Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, did not significantly reduce the risk of organ failure or death or improve recovery in patients hospitalized with COVID-19 who are at high risk of developing serious complications compared to placebo, according to data presented at the American College of Cardiology's 70th Annual Scientific Session. The researchers, while acknowledging the results were not statistically significant, said they were encouraged by the lower numbers of organ failure and deaths observed in patients treated with dapagliflozin and by favorable safety data.

COVID-19 can lead to multi-organ failure, especially in patients at high risk for severe illness and complications. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial was the first phase III randomized, controlled clinical trial that was initiated to determine whether dapagliflozin could reduce cardiovascular, kidney and respiratory complications or all-cause death and improve recovery (dual primary endpoints), in patients acutely ill and hospitalized with COVID-19.

Dapagliflozin is an SGLT2 inhibitor that was initially developed as a medication to lower blood sugar levels in patients with Type 2 diabetes, but clinical studies have since demonstrated that it also has significant cardiovascular and kidney benefits, regardless of diabetes status.

"We already know that SGLT2 inhibitors provide organ protection in patients with Type 2 diabetes, heart failure and chronic kidney disease, and these are the exact same patients who if they contract COVID-19 are at high risk to be hospitalized with serious illness and develop complications, such as organ failure," said Mikhail Kosiborod, MD, cardiologist at Saint Luke's Mid America Heart Institute, vice president for Research at Saint Luke's Health System in Kansas City, Missouri, and the study's principal investigator. "Accordingly, we wanted to see if dapagliflozin may also help with organ protection in patients with cardiometabolic risk factors who are acutely ill and require hospitalization due to COVID-19."

A total of 1,250 patients admitted with COVID-19 at 95 sites in the U.S., Brazil, Mexico, Argentina, India, Canada and the U.K. between April 2020 and January 2021 were included in the trial. Patients, who also had risk factors for developing serious complications, including high blood pressure, diabetes, atherosclerotic vascular disease, heart failure or chronic kidney disease, were randomized 1-to-1 to dapagliflozin (10 mg) or placebo once daily. Patients started the treatment as soon as possible (and no later than four days following hospital admission) and continued the treatment for a total of 30 days, even if they were discharged from the hospital. Neither the patient nor the clinician or study personnel knew which treatment patients were receiving.

At 30 days, organ failure or death--one of the study's primary endpoints--occurred in 11.2% of patients who were treated with dapagliflozin and 13.8% of patients treated with placebo. Altogether, 6.6% of patients in the dapagliflozin group died during study follow-up versus 8.6% in the placebo group.

Kosiborod said that for every component of organ failure or death endpoint--respiratory, cardiac, kidney failure or death from any cause--the results appeared to be directionally favorable for dapagliflozin as compared to placebo; however, because they did not reach statistical significance, further study is needed.

"Our study generates a hypothesis that dapagliflozin may offer organ protection in acutely ill patients who are hospitalized with COVID-19, but we were not able to prove this beyond a reasonable doubt because patient outcomes rapidly improved during the study period, making it much harder to accrue enough events and reach statistical certainty," Kosiborod said.

Rapid improvements in the standard of care for patients hospitalized with COVID-19 between spring and summer of 2020 resulted in substantial declines in the number of patients with organ failure or death, he explained. For example, the mortality rate in patients hospitalized with COVID-19 in the U.S. decreased from approximately 25% to 5% between April and August of 2020.

The second primary endpoint of recovery, driven mostly by time to hospital discharge, was similar between patients taking dapagliflozin and placebo. Of importance, dapagliflozin was well-tolerated, with no new safety issues identified.

"There were concerns at the beginning of the pandemic about the safety of SGLT2 inhibitors in patients hospitalized with COVID-19, and some groups were recommending discontinuation of these medications in this setting, even in individuals with chronic conditions in which they have known benefits, such as Type 2 diabetes and heart failure. Everyone was doing their best to make recommendations for what they felt was the safest approach in a data-free zone at that time," Kosiborod said. "Our findings show that dapagliflozin is well-tolerated in patients hospitalized with COVID-19, with no new safety issues being observed. This should have implications for clinical practice given that our results do not support discontinuation of SGLT2 inhibitors in this setting, as long as patients are monitored."

Overall, there were numerically fewer serious adverse events in patients receiving dapagliflozin versus placebo, researchers reported. Two non-severe cases of diabetic ketoacidosis were observed in the trial, both in the dapagliflozin group and in patients with prior history of Type 2 diabetes.

"Our study opens the door to asking additional questions," Kosiborod said. "The idea for DARE-19 was quite unorthodox when we started--everyone was concentrating on antivirals and anti-inflammatory drugs, so it is fascinating to hypothesize that SGLT2 inhibitors may provide organ protection in acute illness. This should inform future clinical science and hopefully lead to further investigations."

Older patients hospitalized with acute heart failure who participated in a novel 12-week physical rehabilitation (rehab) program tailored to address their specific physical impairments had significant gains not only in physical functioning but also quality of life and depression compared with those receiving usual care, regardless of their heart's ejection fraction, according to a new study presented at the American College of Cardiology's 70th Annual Scientific Session. Participation in the program, however, did not significantly reduce rehospitalizations during the six-month follow up.

Heart failure, which happens when the heart can't pump blood the way it should because it is too weak or stiff, is the leading cause of hospitalizations in people 65 and older. Many of these patients are never able to return to their previous level of functioning--resulting in reduced independence and increased risk of returning to the hospital or dying.

"These patients have persistently poor outcomes with frequent rehospitalizations, poor quality of life, high rates of dying and high health care costs," said Dalane W. Kitzman, MD, professor of cardiovascular medicine and geriatrics/gerontology at Wake Forest School of Medicine and the study's lead author. "Despite many efforts to improve outcomes in these patients, most studies testing a wide range of medications, devices and strategies have been negative. This suggested to us that we were overlooking an important factor contributing to these poor outcomes, and we suspected the missing factor might be severe physical dysfunction, which is generally not addressed in heart failure management."

In an earlier pilot study, Kitzman and colleagues found that older patients admitted to the hospital with acute heart failure had profound deficits in all domains of physical function, including their balance, mobility and strength, not just in endurance, which would have been expected. Nearly all of these patients (97%) were considered frail or prefrail.

"Even before they are hospitalized, these patients already have lower physical functioning due to both aging and their chronic heart failure, and when their heart failure worsens, their physical function deteriorates further and this can then be exacerbated by the hospital experience and bed rest," Kitzman said. "This sequence of events leading to marked impairments in all domains of physical function and its impact on patient outcomes has been largely overlooked."

With these insights, the REHAB-HF rehabilitation intervention was developed and designed to correct deficits in balance, mobility and strength. REHAB-HF seeks to enhance effectiveness and avoid injuries that can occur when frail older persons undertake traditional cardiac rehab programs that are more focused on endurance. The program was tailored to each patient's specific needs and adjusted to their ability level as they progressed. Unlike traditional cardiac rehab programs that typically start six weeks after a hospitalization, the REHAB-HF program started early--during the patient's hospital stay if possible--and transitioned to three outpatient sessions per week for 12 weeks following hospital discharge. The aim of the current REHAB-HF trial was to evaluate whether this novel rehabilitation program could improve physical function (primary outcome) and rehospitalizations (secondary outcome) when compared to usual care that could include physician-ordered physical therapy or traditional cardiac rehab.

A total of 349 patients across seven different hospitals, including four community hospitals, were enrolled in the study. Patients ranged in age from 60-99 years; over half were women and 49% were from underrepresented racial or ethnic minority groups. Notably, 53% had heart failure with preserved ejection fraction (HFpEF). Overall, they had an average of five comorbidities, most commonly high blood pressure, diabetes, obesity, lung disease and kidney disease, which may also contribute to declines in physical function.

At the three-month follow-up, compared with participants randomized to receive usual care, those in the intervention group had notable and significant improvements in physical functioning and quality of life across all the assessments used. For example, the Short Physical Performance Battery, a standard measure of physical function in older adults, improved by 1.6 units--more than twofold greater than the minimum amount that is meaningful to patients. On the six-minute walk test, they were able to walk 34 meters farther, a large improvement compared to very low function at baseline. Participant scores on the Kansas City Cardiomyopathy Questionnaire, which measures the patient's perception of their health status, and a separate depression survey also showed large improvements. The improvements in physical function in the REHAB-HF intervention group were even greater when compared to the subset of usual care patients who had received traditional physical therapy and/or cardiac rehab as part of their physician's orders, further supporting the effectiveness of the REHAB-HF intervention.

At six months, 83% of patients were still doing their exercises, which Kitzman said bodes well for long-term adherence. However, there were no statistically significant differences in clinical events, including rates of readmission for any reason, with 194 and 213 rehospitalizations occurring in the intervention group and usual care control group, respectively. Heart failure-related hospitalizations were also no different (94 vs. 110) at six months. There were numerically more deaths among people in the rehab group (21 vs. 16), but this was not statistically significant; researchers said this result may have been due to chance.

"The study was not large enough to really look at clinical events. But patient preference surveys show that older patients often value improved function and quality of life independently of rehospitalization and death," Kitzman said. "By improving quality of life and physical functioning, the patient feels better, which is a positive outcome for patients."

Kitzman and his collaborators at Duke University School of Medicine and Thomas Jefferson School of Medicine are now investigating whether certain subgroups of patients (for example, those with HFpEF) saw more benefits, which could inform a subsequent larger trial powered to definitively examine effects on clinical events.

Rivaroxaban, in addition to low-dose aspirin, significantly reduced the occurrence of total severe events of the heart, limb or brain and issues related to other vascular complications in patients with symptomatic peripheral artery disease (PAD) who underwent lower extremity revascularization, a procedure to open blocked arteries in the leg. The findings, presented at the American College of Cardiology's 70th Annual Scientific Session, expand on earlier data and underscore the broad absolute benefits of this strategy in this high-risk patient population, researchers said.

"To our knowledge, this is the first time that the addition of low-dose rivaroxaban to aspirin has been clearly shown to reduce the occurrence of both first and total adverse events in patients with PAD who have undergone lower extremity revascularization but remain at high risk for a heart attack, stroke or recurrent arterial blockage in a limb," said Rupert Bauersachs, MD, director of vascular medicine at the Darmstadt Clinic in Germany and lead author of the study. "The benefits we saw in the trial for first events were statistically significant and entirely consistent with those for total events. Rivaroxaban 2.5 mg twice daily with aspirin should be considered as adjunctive therapy after revascularization to reduce first and subsequent adverse outcomes."

An estimated 10 million U.S. adults and 200 million people worldwide have PAD, which is often associated with leg pain, difficulty walking and poor circulation that can lead to non-healing wounds and a high rate of limb loss. People with PAD are at very high risk for serious complications, including acute limb ischemia--similar to a heart attack or stroke of the leg--that can lead to limb amputation or death if not treated quickly. Patients with symptomatic PAD are commonly treated with procedures to open arteries in the leg to improve symptoms and prevent limb loss, but they remain at very high risk for adverse events. Overall, about 1 in 4 patients with symptomatic PAD require a repeat procedure to open a blocked leg artery.

"There is a need for greater awareness that PAD is a distinct disease state and that patients with PAD have a high risk for cardiovascular adverse events and are generally a very vulnerable population, especially in the post-revascularization setting," Bauersachs said. "Care for these patients is often fragmented because the surgeon who performs the revascularization may not follow them for complications or recurrences. They deserve to receive optimal treatment to reduce the risk of recurrences."

The randomized, double blind, international trial, known as VOYAGER PAD, enrolled 6,564 patients in 34 countries who had PAD and had undergone lower extremity revascularization. The patients' median age was 67 years and 74% were men. Patients were randomly assigned to receive rivaroxaban or a placebo in addition to daily aspirin. The trial was double blinded, meaning that neither the patients nor their doctors knew who was receiving rivaroxaban and who was receiving the placebo. The trial's primary endpoint was timed to the first event of a composite of acute arterial blockage in the leg (called acute limb ischemia), leg amputation due to blood-vessel disease, heart attack, stroke or death due to cardiovascular causes. Another prespecified endpoint was the total number of vascular events, including recurrent primary endpoint events as well as other vascular events like blood clots in the leg veins or lungs or the need for repeat vascular procedures. The median follow-up time was 28 months after patients underwent revascularization.

The research team reported in a late-breaking clinical trial presented at ACC.20/WCC that the trial met its primary endpoint, with a 15% statistically significant reduction in the risk of a first major adverse limb or cardiovascular event seen in patients who received rivaroxaban compared with those who received the placebo. The current study reports on the total number of vascular events with over 4,700 occurring in the 6,564 randomized over three years.

"There were 342 fewer adverse events in the rivaroxaban group than in the placebo group, which translates to an absolute reduction in risk of 12.5%," Bauersachs said. "In a high-risk population, that is a big gain in avoiding the need for patients to come back with vascular complications."

The 6,564 study participants experienced a total of 4,714 vascular events during the study period with 2,301--or about one-third--experiencing at least one vascular event, Bauersachs said.

"So, during approximately three years of follow-up, about 2-3 out of 6 patients with PAD had a vascular event in spite of high utilization of background medical therapy. This overall rate of vascular events is eye-opening and speaks to the high vulnerability of this patient population," Bauersachs said. "First events are just the tip of the iceberg."

A limitation of the study is that the trial was designed to assess the occurrence of first adverse events following lower extremity revascularization, Bauersachs said. Therefore, in a double blinded trial, patients may come off study treatment or go on to other therapies after an event, which can attenuate the observed benefit. Assessment of the total number of adverse events, however, was a prespecified secondary endpoint and despite this limitation, the findings were statistically significant and robust in absolute terms.

In patients who had a coronary stent inserted after experiencing the most severe type of heart attack, the use of a technique that measures blood flow and pressure through a partially blocked artery to determine if a second stenting procedure is needed did not improve outcomes and was more costly than using angiography, or a heart X-ray, alone to guide the procedure, according to research presented at the American College of Cardiology's 70th Annual Scientific Session.

"The strategy of using fractional flow reserve (FFR) to guide the stenting procedure is not superior to the standard technique of using angiography to treat additional partially blocked arteries," said Etienne Puymirat, MD, professor of cardiology at the University of Paris, director of intensive care at the Georges Pompidou Hospital in Paris and principal investigator of the study. "In addition to having no benefit, we have also shown that, based on costs in France, the FFR-guided strategy is more expensive."

Most heart attacks are caused by a blood clot in an artery to the heart that's been narrowed by a buildup of fatty deposits, or plaque. In the most severe type of heart attack, known as a STEMI heart attack, an artery to the heart is completely blocked, causing the death of some heart tissue.

The current study, known as the FLOWER-MI trial, was the first to do a head-to-head comparison of outcomes in STEMI patients with multi-vessel disease who underwent either FFR-guided stenting or stenting guided by angiography alone.

FFR is a measure of blood flow and pressure through a narrowed coronary artery. It is performed during angiography to determine if the stenosis, or narrowing of the artery, is significant and to guide the stenting procedure. Previous studies have shown that STEMI patients treated with FFR-guided stenting had better outcomes than those treated with medication alone, without the insertion of a stent.

Stenting, also known as coronary angioplasty or percutaneous coronary intervention (PCI), is a minimally invasive procedure in which a flexible tube (catheter) is threaded through a coronary artery under local anesthesia. At the site of the blockage, a tiny balloon at the tip of the catheter is inflated to unblock the artery and a stent, a tiny mesh tube coated with medication, is inserted to prop the artery open, restoring blood flow to the heart. Clinicians typically use angiography to assess the extent of blockage in the coronary artery and guide the stenting procedure.

The trial, conducted at 41 centers in France, enrolled 1,171 patients who had a stent inserted into a blocked coronary artery after a STEMI heart attack and who also had a second coronary artery that was at least 50% blocked. The patients' average age was 62 years and 83% were men. Immediately after their first stenting procedure, all patients were randomly assigned to undergo a second stenting procedure in the partially blocked artery, guided either by FFR or by angiography alone. The second procedure was performed within five days of the first during the same hospitalization.

After 12 months, 5.5% of patients in the FFR-guided group had died, had another non-fatal heart attack or had undergone an additional stenting procedure, compared with 4.2% of those in the angiography-guided group, a non-statistically significant difference. Moreover, the FFR-guided procedure was more expensive than the one guided by angiography alone.

The incidence of major adverse cardiovascular events in both groups of patients was considerably lower than the researchers expected, Puymirat said. "These patients were at high cardiovascular risk because of having multi-vessel disease," he said. "Using data from previous trials and registries in this population, we estimated that about 15% of patients would have an adverse event within one year, but in our study the rate was 5% at one year."

The study failed to meet its primary endpoint, a composite of death from any cause, non-fatal heart attack, or urgent need for an additional stenting procedure within 12 months. A secondary endpoint looking at cost-effectiveness favored the use of angiography alone. However, the cost-effectiveness analysis was based on the costs of the two treatment approaches in France and might not be applicable in other countries, Puymirat said.

The researchers will continue to follow the patients in the study for another two years.

This study was simultaneously published online in the New England Journal of Medicine at the time of presentation. The study was funded by a grant from the French Ministry of Health with additional support from Abbott.

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

Puymirat will present the study, "Fractional Flow Reserve-guided Versus Angio-guided Multivessel Revascularization In ST-Elevation Myocardial Infarction Patients. The FLOWER-MI Randomized Trial," on Sunday, May 16, at 10:45 a.m. ET / 14:45 UTC, virtually.

Image fusion is a process that can enhance the clinical value of medical images, improving the accuracy of medical diagnoses and the quality of patient care.

Researchers at the College of Data Science Software Engineering at China's Qingdao University, have developed a new 'multi-modal' image fusion method based on supervised deep learning that enhances image clarity, reduces redundant image features and supports batch processing. Their findings have just been published in KeAi's International Journal of Cognitive Computing in Engineering.

Author Yi Li explains: "Most medical images have unilateral or limited information content; for instance, focus positions vary which can make some objects appear blurred. Having important information scattered across a number of images can hamper a doctor's judgment. Image fusion is an effective solution - it automatically detects the information contained in those separate images and integrates them to produce one composite image."

Researchers are increasingly turning to deep learning to improve image fusion. Deep learning, a subset of machine learning, draws on artificial neural networks that are designed to imitate how humans think and learn. That means it is capable of learning from data that is unstructured or unlabelled.

However much of the current research focuses on the application of deep learning in single image fusion processing. Studies that use it for multi-image batch processing are much rarer.

Li explains: "Medical images have specific practical requirements, including information richness and high clarity. During our study, we used successful image fusion results to build an image-training database. We were then able to use that database to fuse medical images in batches."

Li adds: "Our method also enhances the clarity of MRI, CT and SPECT image fusion, improving the accuracy of medical diagnosis. We have achieved state-of the-art performance in terms of both visual quality and quantitative evaluation metrics. For example, the fused images we produced look more natural, and have sharper edges and higher resolution. In addition, detailed information and features of interest are better preserved."

ATS 2021, New York, NY - A weighted "lottery" designed to increase access to the antiviral drug remdesivir during the May-July 2020 COVID-19 surge for those most affected by the coronavirus, including members of the Black, Latinx and indigenous communities, led to more equitable distribution of the badly needed medication, according to research presented at the ATS 2021 International Conference.

At a time when supplies of COVID-19 medications were scarce, Douglas B. White, MD, MAS, vice chair and professor of critical care medicine, UPMC endowed chair for ethics in critical care medicine and director of the Program on Ethics and Decision Making in Critical Illness, University of Pittsburgh School of Medicine, and colleagues, convened a multi-institution consortium of experts to develop a weighted lottery, in which some patients would be given higher priority for receiving remdesivir while others would be given lower priority.

Consortium members had expertise in bioethics, economics, health disparities, medicine, pharmacy and health law. They assigned more weight to patients from disadvantaged communities and essential workers, and less weight to patients expected to die within a year from a terminal condition and those with severe respiratory failure.

The lottery was implemented at 23 hospitals across the UPMC health system during periods of drug shortage. The team identified eligible patients using an electronic health record- and telephone-based screening system. They calculated the number of potentially eligible patients each week, based on the number of patients who were eligible the previous week. Using the weighting system previously described, a drug allocation team met each day to determine each eligible patient's chance of receiving the drug, and then used a random number generator to run the lottery.

Overall, 61 percent of the available remdesivir was allocated to patients who were from disadvantaged neighborhoods and/or were essential workers. These individuals made up 56 percent of the COVID-19 patient population.

"We showed that in the maelstrom of a pandemic it is possible to deploy an organized allocation strategy that promotes both equity and clinical benefit," said Dr. White.

"This is a major improvement over the first-come, first-served approach that many hospitals have used; that approach is likely to worsen disparities for those with access-to-care barriers. Among those most affected would be persons with disabilities that limit their mobility and those without health insurance, who may delay seeking care due to financial concerns."

He noted that the weighted lottery also allows planners to give priority to certain groups, such as those who are most likely to benefit and those who have been disproportionately affected by the pandemic, such as individuals from hard-hit communities.

"It was our goal from the outset to develop a framework and process that any hospital can use," stated Dr. White. The team also developed a detailed protocol that describes the steps to carry out the lottery, which can be found here.

The researchers concluded that it is best to implement the lottery on a centralized, regional level, rather than hospital-by-hospital. "It is far more efficient to conduct one lottery for many hospitals than have each hospital conduct its own lottery. This approach can simultaneously accomplish fair allocation and rapid learning, because the lottery creates a natural experiment in which some patients receive the scarce drug while others do not. Researchers can use the lottery's registry to assess the effectiveness of the drug." This is described in detail in this article.

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WINSTON-SALEM, N.C. - May 16, 2021 - Heart failure (HF) - when the heart can't pump enough blood and oxygen through the body - affects approximately 6.2 million adults in the United States and is the primary cause of hospitalization in the elderly. Unfortunately, older adults with heart failure often have poor outcomes resulting in reduced quality of life, high mortality and frequent rehospitalizations.

Despite many efforts to improve the prognosis in these patients, most previous studies testing a wide range of interventions were not successful.

Scientists from the Wake Forest, Duke University and Thomas Jefferson schools of medicine tried a different approach - tailoring rehabilitation treatment to the individual and beginning it while the patient was still recovering in the hospital, which is not standard care for these older HF patients.

Using this novel approach, the researchers found that hospitalized older patients with acute heart failure had significant gains in physical function, including balance, mobility, strength and endurance, compared with those receiving usual care, regardless of their heart's squeezing ability (ejection fraction).

The findings are published in the May 16 issue of the New England Journal of Medicine and reported simultaneously at the annual meeting of the American Association of Cardiologists. The study was funded by the National Institute on Aging.

"In an earlier pilot study, we had observed these patients had marked physical dysfunction, with 97% being frail or pre-frail," said the study's lead author, Dalane Kitzman, M.D., professor of cardiovascular medicine and gerontology at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

"And the types of dysfunction were not commonly associated with heart failure - problems with balance, mobility and strength, as well as endurance. One-third could not get out of a chair without using their arms or other assistance and their endurance was twice as bad as similarly aged patients with HF who had not been hospitalized. We also found high rates of depression and cognitive dysfunction, which were usually unrecognized clinically."

Kitzman's team hypothesized that these patients' physical function, which was already compromised due to age and chronic heart failure, worsened and was further exacerbated by their hospital experience and bedrest, and the deficits often persisted after discharge.

To test their theory, they assembled a team of physical-rehabilitation experts to develop the REHAB-HF program, which was specifically designed to meet the unique needs of these patients. The intervention began as early in the hospital stay as possible, transitioned to an outpatient facility for three sessions a week for 12 weeks, and then transitioned to exercise at home, Kitzman said.

This Phase 2 trial included 349 patients, age 65 and older, of whom more than 50% were women and nearly 50% were non-white, at seven medical centers, including four community hospitals.

At three-month follow-up, the scientists found large, statistically significant improvements in physical function as determined through standard measurements of balance, mobility, strength and endurance. Also, rates of frailty and depression declined.

Notably, at six-month follow-up, 83% of patients were still exercising on their own, suggesting they may continue to do so long-term, Kitzman said.

However, at six months there were no statistically significant differences in clinical events such as rates of readmission for any reason, with 194 and 213 rehospitalizations occurring in the intervention group and usual care control group, respectively. Heart failure-related hospitalizations also were no different at six months. There were numerically more deaths among people in the rehab group, but this was not statistically significant and may have been due to chance.

"The study was not large enough to really look at clinical events" Kitzman said. "But by improving quality of life and physical functioning, the patient feels better, which is a positive outcome."

Hamilton, ON (May 15, 2021) - A simple surgery saves patients with heart arrhythmia from often-lethal strokes, says a large international study led by McMaster University.

Researchers found that removing the left atrial appendage -- an unused, finger-like tissue that can trap blood in the heart chamber and increase the risk of clots -- cuts the risk of strokes by more than one-third in patients with atrial fibrillation.

Even better, the reduced clotting risk comes on top of any other benefits conferred by blood-thinner medications patients with this condition are usually prescribed.

"If you have atrial fibrillation and are undergoing heart surgery, the surgeon should be removing your left atrial appendage, because it is a set-up for forming clots. Our trial has shown this to be both safe and effective for stroke prevention," said Richard Whitlock, first author of the study.

"This is going to have a positive impact on tens of thousands of patients globally."

Whitlock is a scientist at the Population Health Research Institute (PHRI), a joint institute of McMaster University and Hamilton Health Sciences (HHS); a professor of surgery at McMaster, the Canada Research Chair in cardiovascular surgical trials, a cardiac surgeon for HHS, and is supported by a Heart and Stroke Foundation career award.

The co-principal investigator of the study is Stuart Connolly who has also advanced this field by establishing the efficacy and safety of newer blood thinners. He is a professor emeritus of medicine at McMaster, a PHRI senior scientist and a HHS cardiologist.

"The results of this study will change practice right away because this procedure is simple, quick and safe for the 15 per cent of heart surgery patients who have atrial fibrillation. This will prevent a great burden of suffering due to stroke," Connolly said.

The study results were fast tracked into publication by The New England Journal of Medicine and presented at the American College of Cardiology conference today.

The study tracked 4,811 people in 27 countries who are living with atrial fibrillation and taking blood thinners. Consenting patients undertaking cardiopulmonary bypass surgery were randomly selected for the additional left atrial appendage occlusion surgery; their outcomes compared with those who only took medicine. They were all followed for a median of four years.

Whitlock said it was suspected since the 1940s that blood clots can form in the left atrial appendage in patients with atrial fibrillation, and it made sense to cut this useless structure off if the heart was exposed for other surgery. This is now proven to be true.

Atrial fibrillation is common in elderly people and is responsible for about 25 per cent of ischemic strokes which are caused when blood clots block arteries supplying parts of the brain. The average age of patients in the study was 71.

"In the past all we had was medicine. Now we can treat atrial fibrillation with both medicines and surgery to ensure a much better outcome," said Whitlock.

He said that the current study tested the procedure during cardiac surgery being undertaken for other reasons, but the procedure can also be done through less invasive methods for patients not having heart surgery. He added that future studies to examine that approach will be important.

Whitlock said the left atrial appendage is a leftover from how a person's heart forms as an embryo and it has little function later in life.

"This is an inexpensive procedure that is safe, without any long-term adverse effects, and the impact is long-term."

Researchers at Rutgers Robert Wood Johnson Medical School are reporting the first instance of COVID-19 triggering a rare recurrence of potentially serious blood clots in people's arms.

The discovery, published in the journal Viruses, improves the understanding of how inflammation caused by COVID-19 can lead to upper extremity blood clots and how best to treat them. The case study is part of a larger Rutgers study of 1,000 hospitalized patients diagnosed with COVID-19 who were admitted and discharged between March and May 2020.

While there have been reports of lower extremity deep vein thrombosis following COVID-19, this is the first study in which COVID-19 triggered a recurrence in the upper arm of an active 85-year-old man who had a prior diagnosis of upper extremity blood clots.

"The patient presented to his primary care physician with complaints of swelling in his left arm and was sent to the hospital for further management where he was diagnosed with an upper arm blood clot and an asymptomatic COVID-19 infection," said Payal Parikh, an assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, who led the study along with Martin Blaser, director of the Center for Advanced Biotechnology and Medicine and a professor at Rutgers Robert Wood Johnson Medical School. "While his oxygen levels were not diminished, he was hospitalized for the management of the upper extremity deep vein blood clot. Often, blood clots are preceded by chronic inflammatory conditions exacerbated by immobility, and rarely do they occur in patients who are otherwise healthy and active at baseline."

Most cases of deep vein thrombosis occur in the legs. Only about 10 percent of blood clots occur in the arms and of those cases only 9 percent recur.

"This is of concern since in 30 percent of these patients, the blood clot can travel to the lung and be possibly fatal," said Parikh. "Other disabling complications include persistent swelling, pain and arm fatigue."

The study suggests that clinicians should consider testing for deep vein thrombosis and COVID-19 in patients who present with complaints of unexplained swelling. People who test positive for COVID-19 should seek medical attention if they have declining oxygen levels, shortness of breath and any unexplained swelling.

"If you have been previously diagnosed with deep vein thrombosis or have chronic medical illness that predisposes you to blood clots, you have a higher risk for recurrence of a deep vein thrombus in the setting of a COVID-19 infection and thus, should be vigilant," said Parikh.

ATS 2021, New York, NY - The use of e-cigarettes is associated with wheezing and shortness of breath in young adults and adolescents, even in those who don't smoke cigarettes or marijuana, according to research presented at the ATS 2021 International Conference.

Alayna P. Tackett, PhD, assistant professor of preventive medicine, University of Southern California Keck School of Medicine, and colleagues conducted a web-based survey of 2,931 adolescents and young adults (average age: 18.9) with questions on the use of e-cigarettes, cigarettes and cannabis, along with self-reported asthma diagnosis and respiratory symptoms, over the previous 30 days. The survey was fielded between August 6 and 30, 2020 among a national convenience sample of youth and young adults aged 14-21 using Lucid™, a survey management company. Recruitment, data collection, and compensation were handled by Lucid and company partners. Statistical analyses were used by the researchers to examine possible relationships among these variables.

They found that, after controlling for age, gender and race/ethnicity, past 30-day e-cigarette use was associated with increased odds of self-reported asthma, wheezing and shortness of breath, compared with survey respondents who reported never using e-cigarettes. This relationship held true, even after statistically controlling for those who said they had ever used cigarettes or cannabis. After controlling for past 30-day cigarette and cannabis use, past 30-day e-cigarette use was no longer associated with asthma--but was still associated with shortness of breath and increased wheezing.

The prevalence of asthma, wheeze and shortness of breath was 24 percent, 13 percent and 20 percent, respectively. Among past 30-day e-cigarette users, 15 percent reported using cigarettes and 37 percent reported cannabis use.

"As more products, including cannabis and various e-cigarette devices, enter the market, assessing respiratory health will be important both where adolescents and young adults receive their health care and in research," said Dr. Tackett. "This preliminary study highlights the need for more longitudinal studies and studies that incorporate objective assessments of respiratory health to further determine the specific respiratory risks from e-cigarettes. We also need to better understand the complex relationships between these products and whether multiple product use is associated with worse respiratory outcomes."

The number of adolescents and young adults who use e-cigarettes continues to increase, with estimates of 5.4 million new users in 2019. E-cigarettes are the most commonly used tobacco product in this age group, but researchers have found it difficult to disentangle the risk of asthma and related respiratory symptoms associated with e-cigarettes due to a high frequency of cigarette and cannabis smoking among e-cigarette users age 14-21.

"Wheeze and shortness of breath are just two indicators of many to assess respiratory health," said Dr. Tackett. "The respiratory system is complex and it may be that measuring respiratory health more frequently through such means as spirometry may help tell us more about the relationship between e-cigarette use, multiple product use and respiratory outcomes."

Dr. Tackett's team is currently conducting two follow-up studies that use objective measurement tools like handheld, home-based spirometry to examine adolescent and young adult reported respiratory symptoms. Those who exclusively use e-cigarettes as well as those who have never used them will be recruited to examine their differences and better understand the relationship between e-cigarette use and respiratory health.

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Session: TP68
Abstract Presentation Time: AVAILABLE ON-DEMAND

ATS 2021, New York, NY - Individuals with asthma who live in redlined neighborhoods have worse lung function than those in locales that excluded Black people and benefited from decades of inequitable wealth accumulation at the expense of Black communities in the United States, according to research presented at the ATS 2021 International Conference.

Alexander Schuyler, MD/PhD candidate, University of Pittsburgh School of Medicine, and Sally Wenzel, MD, director, Asthma & Environmental Lung Health Institute, University of Pittsburgh Medical Center, sought to examine the connection between residence in historically redlined communities and the impact on lung function and asthma outcomes. Redlining is a form of institutional racism and discriminatory mortgage lending practice enacted by the Home Owners' Loan Corporation in the New Deal era that resulted in racialized economic deprivation and segregation. These historically validated and geographically defined mechanisms contribute to current environmental inequities, and, as the authors propose, to worsening asthma outcomes in Black neighborhoods across the U.S.

"Lung health in Black people is impacted by converging legacies of institutional racism, including racist mortgage loaning practices like redlining, and associated environmental inequities," stated Mr. Schuyler. "Racist housing policies have had a long-term negative impact on diseases like asthma. In addition, the clinical and research convention of applying a race correction to lung function measurements may have accentuated these effects, underestimating the impact of racism and environmental inequities on lung health."

Race-based correction for spirometry was constructed in the 1840s by White supremacist physician and enslaver Samuel Cartwright, who used research to justify Black enslavement and to fabricate arguments that Black people were inferior to White people, including having lower lung function. These adjustments continue today, and are considered accepted medical practice. The authors state that the sickest Black patients with asthma may be undertreated because the results of their breathing tests are "adjusted" and may appear to have better lung function than they actually do.

To examine the impact of institutional racism on asthma outcomes, the researchers looked at the lung health of 326 Pittsburgh residents with asthma localized by zip code to determine if they lived in redlined neighborhoods. Patients were identified by the University of Pittsburgh Asthma and Environmental Lung Health Institute at UPMC's patient registry. Study participants were given spirometry lung function tests and questionnaires.

The researchers determined that residence in redlined neighborhoods was independently associated with lower forced expiratory volume (FEV1 -- the maximum amount of air a person can forcibly exhale in one second) after theoretical adjustment for several variables used to "normalize" lung function in research and clinical practice. Supporting these differences, they found that despite no difference in life-threatening asthma episodes, an increased prevalence of co-occurring diseases (co-morbidities) was present in asthmatic adults living in more redlined neighborhoods, independent of race.

"Race is a social construct," said Mr. Schuyler. "We propose that race-based corrections of spirometric values, a multiplicative scaling factor applied to height, age, and sex-adjusted FEV1 and FVC (forced vital capacity--maximum amount exhaled forcefully after breathing in deeply) values on the basis of race, should be abolished. Redlined neighborhoods experience persistently poor air quality, supporting a link with environmental inequality. The use of race-based corrections for spirometric values suggests that observed variations (if any) in lung function across racial groups are related to differential biology when, in fact, disproportionately higher exposure to pollution likely contributed to these differences."

He added, "Clinicians should not use spirometric values alone to make medical decisions, without including the clinical or socioenvironmental context."

The authors explained how spirometric values are adjusted for Black asthma patients: "The equations used to correct spirometric values are generated in reference to a White population. Thus, for this equation White people are artificially assigned a correction factor of 1, while Black people, Asian people, and other racial groups are assigned a correction factor of less than 1. Black people have a correction factor that is typically 85-90% of that used for the White population.

"Applying this correction factor to Black folks compresses the difference between the actual and 'predicted' values in liters to a higher degree than in White people, meaning, in those with severe disease, their lung function appears numerically better than it is. This could lead to clinical decisions to undertreat Black patients. In contrast, there is no recentering of the 'predicted' value in liters in White people. Lower than normal lung function in White people may promote earlier treatment, as they would have lower percent predicted values compared to 'otherwise identical' Black people. Everyone will benefit more if asthma care is driven by the best possible percent predicted values for all people, regardless of race."

Since submitting this ATS 2021 research abstract, Mr. Schuyler and Dr. Wenzel expanded their study to include 1,034 adults with asthma residing in Allegheny County, which includes Pittsburgh. "This gives us a much more detailed view and helps provide better context for each patient." They state that this expanded analysis has helped them determine that residence in redlined neighborhoods, in addition to lower FEV1, is associated with uncontrolled and/or severe asthma. Their additional research also found persistently poor air quality in redlined neighborhoods, linking it strongly with environmental inequity.

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Session: TP16

Abstract Presentation Time: Available On-Demand; 8 a.m. EDT, Friday, May 14, 2021

ATS 2021, New York, NY - While vaping is thought to be a safer alternative to smoking, teens and adults who use e-cigarettes have increased odds of developing asthma and having asthma attacks, according to research presented at the ATS 2021 International Conference.
T

eresa To, PhD, senior scientist in the Child Health Evaluative Sciences program at The Hospital for Sick Children (SickKids), and colleagues sought to determine whether youth and young adults who are current e-cigarette users have increased odds of self-reported asthma and had an asthma attack within the last 12 months.

The researchers used data collected from the 2015-2016 and 2017-2018 cycles of the Canadian Community Health Survey (CCHS), a cross-sectional survey that collects self-reported information about health status, health determinants, and behaviors. They found that 3 percent of survey participants reported e-cigarette use within the previous 30 days, which corresponds to 1 in 32 individuals using e-cigarettes during that time period. Approximately half of e-cigarette users also reported smoking cigarettes daily. One in 8 (13 percent) e-cigarette users had asthma and those with asthma had nearly 24 percent increased odds of having an asthma attack within 12 months.

"To curtail the adverse health effects of vaping we should raise the awareness of the potential harmful health effects of vaping, and develop and implement evidence-based strategies to prevent and reduce e-cigarette use, especially in youth," said Dr. To. "We should also provide means and support to help those who currently vape to quit."

The study included 17,190 individuals aged 12 years and above who participated in the CCHS, in which 3.1 percent reported e-cigarette use in the past 30 days. After making statistical adjustments for other variables that might affect results (confounders), e-cigarette users had 19 percent higher odds of having asthma. Current smokers had 20 percent higher odds of having asthma, while former smokers had 33 percent higher odds. Those who never smoked or used e-cigarettes did not have significant associations with asthma.

"Interestingly, our study found a significantly higher proportion of those who used e-cigarettes reported fair to poor mental health (15 percent) compared to those who did not vape (7 percent)," said Dr. To.

"In addition, those who used e-cigarettes had 60 percent higher odds of self-reported high levels of life stress compared to those who did not. While vaping may not cause stress, it appears that vape cravings may be triggered by stress and anxiety, making it harder for the e-cigarette user to quit. This may be particularly relevant during the pandemic when stress and anxiety are highly prevalent."

"Our findings suggest that e-cigarette use is a modifiable risk factor for asthma to be considered in the primary care of youth and young adults," she concluded.

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Session: TP91

Abstract Presentation Time: On Demand; 8 a.m. EDT, Friday, May 14, 2021

ATS 2021, New York, NY - Having genetic risk variants in the ABO gene might significantly increase the chances of developing COVID-19, and other genes may also increase COVID-19 risk, according to research presented at the ATS 2021 International Conference.

Much about COVID-19 remains a medical mystery, including whether certain genes place individuals at greater risk of contracting the SARS-CoV-2 virus, which causes COVID-19. Ana Hernandez Cordero, PhD, postdoctoral fellow with the Centre for Heart Lung Innovation, University of British Columbia, and colleagues used integrative genomics combined with proteomics to identify these genes.

Genomic research identifies specific genes that may play a role in biological processes such as the development of disease, while proteomics does the same for proteins. Researchers can get a fuller picture of disease processes by integrating tools to investigate both.

"DNA is a big, complex molecule and so, genetic associations alone cannot pinpoint the exact gene responsible for COVID-19," said Dr. Hernandez. "However, by combining COVID-19 genetic information with gene expression and proteomic datasets, we can figure out which genes are driving the relationship with COVID-19."

The researchers combined genetic information with an examination of lung gene expression to identify genetic variants that were controlling gene expression in the lung that were responsible for COVID-19. The researchers identified specific genes' markers that share their effects on gene expression and protein levels with COVID-19 susceptibility. For the analysis, they used bioinformatics to integrate: (1) a genomic dataset obtained from patients who were infected with SARS-CoV-2 as well as non-infected individuals (controls); (2) lung and blood tissue gene expression datasets from clinical populations (non-COVID-19); and (3) a proteome dataset obtained from blood donors (non-COVID-19).

By doing this, they found that several genes responsible for the immune system's response to COVID-19 are also involved in COVID-19 susceptibility. What they discovered was supported by the findings of previous research.

Looking for candidate genes in blood proteins, they were able to go one step further in connecting the effects of genes to susceptibility to COVID-19. Blood proteomics can also help identify markers in the blood that can be easily measured to indicate disease status, and potentially, to monitor the disease.

"By harnessing the power of genomic information, we identified genes that are related to COVID-19," said Dr. Hernandez. "In particular, we found that the ABO gene is a significant risk factor for COVID-19. Of particular note was the relationship between the blood group ABO and COVID-19 risk. We showed that the relationship is not just an association but causal."

In addition to the ABO gene, Dr. Hernandez and colleagues found that people carrying certain genetic variants for SLC6A20, ERMP1, FCER1G and CA11 have a significantly higher risk of contracting COVID-19. "These individuals should use extreme caution during the pandemic. These genes may also prove to be good markers for disease as well as potential drug targets."

Several of the genes identified in the researchers' analysis have already been linked with respiratory diseases. For example, ERMP1 has been linked to asthma. CA11 may also elevate COVID-19 risk for people with diabetes.

Genetic associations for COVID-19 and gene and protein expression were combined using integrative genomics (IG). IG aims to identify mechanisms (for example: gene expression levels) that connect the effects of the genetic code to a complex disease. These methods, although complex, are also fast and their outcomes can help researchers to prioritize candidate genes for in vitro (in the lab) and in vivo (in living organisms) testing.

Dr. Hernandez added, "Our research has progressed since the time that we first conducted this analysis. We have now identified even more interesting candidates for COVID-19 such as IL10RB, IFNAR2 and OAS1. These genes have been linked to severe COVID-19. Their role in the immune response to viral infections and mounting evidence suggest that these candidates and their role in COVID-19 should be further investigated."

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The mysteries of sexual attraction just became a little less mysterious - at least for moths. A team of six American and European research groups including Tufts University has discovered which gene expressed in the brain of the male European corn borer moth controls his preference for the sex pheromone produced by females. This complements a previous study on the gene expressed in the female pheromone gland that dictates the type of blend she emits to attract males. The study was reported today in Nature Communications.

The implications go beyond making a better dating app for bugs. Now scientists can begin to ask why mating signals and mating preferences change in the first place, which is a long-standing paradox since any change could reduce the ability of an organism to successfully mate. Knowledge of these two genes will provide a better understanding of how the pheromones of the 160,000 moth species have evolved.

Of course, one important role for mating preferences is to make sure you are not matching up with a completely different species. The signal sent by females must be preferred by males of the same species to ensure that like mates with like--a mechanism called assortative mating. The European corn borer is interesting because there are two types, called E and Z, with assortative mating within each type. Even though the two types can be mated to each other in captivity, E mostly mates with E, and Z with Z in the field. For this reason, the European corn borer has been used as a model for how one species can split into two, ever since the two pheromone types were first discovered 50 years ago.

"That means we now know - at the molecular level - how chemical matchmaking aids in the formation of new species. Similar genetic changes to pheromone preference could help explain how tens of thousands of other moth species remain separate," said Erik Dopman, professor of biology in the School of Arts and Sciences at Tufts and corresponding author of the study.

Different aspects of the research were conducted by the three co-first authors Fotini Koutroumpa of University of Amsterdam, Melanie Unbehend of the Max Planck Institute for Chemical Ecology, and Genevieve Kozak, a former post-doctoral scholar at Tufts University and now assistant professor at University of Massachusetts, Dartmouth. "Our study's success can be attributed to a team with a common vision and strong sense of humor that helped make the science worthwhile and fun," said Dopman.

One of the surprise discoveries made by the team was that while females may vary their signals in the blend of pheromones they produce, preference in the male is driven by a protein that changes their brain's neuronal circuitry underlying detection rather than affecting the receptors responsible for picking up the pheromones.

Preference for a particular cocktail of pheromones is determined by any of hundreds of variants found within the bab gene of the male. The relevant variants of bab are not in parts of the gene that code for a protein, but in parts that likely determine how much of the protein is produced, which in turn affects the neuronal circuits running from the antennae to the brain. The researchers were able to determine anatomical differences in the male, including the reach of olfactory sensory neurons into different parts of the moth brain, and link them to their attraction to E or Z females.

"This is the first moth species out of 160,000 in which female signalling and male preference genes have both been identified," said Astrid Groot of the University of Amsterdam, who also helped identify the gene controlling the pheromone difference in E and Z females. "That provides us with complete information on the evolution of mate choice and a way to measure how closely these choices are linked to evolving traits and populations."

The ability to predict mating could also help control reproduction in pest insects. The European corn borer is a significant pest for many agricultural crops in addition to corn. In the U.S., it costs nearly $2 billion each year to monitor and control. It is also the primary pest target for genetically modified "Bt corn" which expresses insecticidal proteins derived from the bacterium, Bacillus thuringiensis. While Bt corn remains an effective control of the corn borer moth in the U.S., corn borers in Nova Scotia are now evolving resistance to another variety of Bt corn.

"Our results can help to predict whether Bt resistance could spread from Nova Scotia to the Corn Belt of the U.S., or whether assortative mating could prevent or delay it", said co-author David Heckel at the Max Planck Institute for Chemical Ecology, who also studies how insects evolve resistance to Bt. "Bt corn has enabled a huge reduction in the use of chemical insecticides, and it should be a high priority to preserve its ecological benefits as long as possible."

The COVID-19 pandemic has been shown to have caused a significant strain on the healthcare system and resources in the United States. However, data regarding the impact of the virus on hip fractures, primarily seen in elderly patients, is lacking.

Researchers at Hospital for Special Surgery (HSS) sought to compare characteristics and outcomes of hip fracture patients admitted during the COVID-19 outbreak to patients admitted before the outbreak. They also examined characteristics and outcomes of hip fracture patients with and without the virus. Their findings were presented at the 2021 Spring American Society of Regional Anesthesia and Pain Medicine (ASRA) Annual Meeting.1

"Studying this topic is important because events that stress the healthcare system, like this pandemic, allow us to gain rare insights into what happens to medical care when resources become scarce," said principal investigator Stavros Memtsoudis, MD, PhD, MBA, an anesthesiologist at HSS.

Dr. Memtsoudis and colleagues compared patient and healthcare characteristics, COVID-19 diagnoses and outcomes for hip-fracture patients from March to April 2019 and March to April 2020. Observed outcomes included length of hospital stay, admission to an intensive care unit (ICU), use of mechanical ventilation, 30-day readmission, discharge disposition and postoperative complications.

The number of hip fracture cases during the COVID-19 surge decreased by 50% compared with the same time period during the previous year. "One of the major takeaways from this study was we saw that fractures were more commonly treated nonoperatively, and how outcomes differed," Dr. Memtsoudis noted. During the pandemic, hip fracture patients were discharged earlier and were less likely to be admitted to the ICU.

Other factors did not differ before and after COVID-19, including in-hospital mortality rate, 30-day readmission rate, use of mechanical ventilation, and complication rate.

Hip-fracture patients with COVID-19 stayed in the hospital longer, had higher rates of complications during surgery, increased rates of mortality, and more frequently received nonsurgical treatment.

These results show two main considerations for hospitals. As society begins to return to more normal activities, rates of hip fracture are likely to increase back to pre-COVID-19 levels. Hospitals should be prepared and have plans for treating hip fracture patients with COVID-19, as well as protecting non-COVID-19 patients from exposure.

Additionally, findings that demonstrate shorter length of stay in the hospital, less use of the ICU, and earlier home discharge did not compromise outcomes and deserve further study. This raises the question of whether the strategies of care for hip fracture patients used before the pandemic should be adjusted.

"These results should make us reevaluate our practice going forward to make sure we do not waste resources but also affirm interventions that truly are beneficial," Dr. Memtsoudis concluded.