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Scientists at the Institute of Pharmacy at Martin Luther University Halle-Wittenberg (MLU) have developed new delivery vehicles for future gene therapies. A team of researchers led by Dr Christian Wölk are using artificial fats to transport DNA into cells. The scientists demonstrate how well this technique works in a study conducted in collaboration with pharmacists from the University of Marburg. The study has been published in "Biomaterials Science".

Gene therapy is the only treatment for people with diseases caused by genetic defects. In theory, a defective gene is replaced by a healthy one, thus eliminating the cause of the disease. Congenital immunodeficiencies, congenital blindness and sickle cell anaemia could all be treated in this way. Even cancer cells could be rendered harmless through genetic modification. However, the treatment method has suffered many practical setbacks and, up until now, only six gene therapies have been approved in Europe.

In addition to producing the required gene sections, one of the biggest hurdles is transporting the DNA into the cell and to its destination in the body. The few gene therapies approved to date use modified viruses to do this. These viruses infect the cell and introduce the DNA. However, this method entails risks since the viruses can trigger a violent immune reaction. They are also very costly and time-consuming to produce.

Dr Christian Wölk's junior research group at the Institute of Pharmacy at MLU under the leadership of Prof Andreas Langner is therefore working on a new system for introducing DNA into the body's cells. "Non-viral systems are very appealing because they are easy to produce," says Wölk. The only drawback is that their effect diminishes over time and they must be re-administered. His research group uses liposomes, fat bubbles that are already used as carriers for various other drugs. They combine with nucleic acids in the DNA to form so-called lipoplexes. They fuse to the cell membrane and release their content into the cell.

The pharmacists in Halle have developed four artificial fats (lipids) that are suitable for DNA transport. One, the lipid DiTT4, is now entering the next phase of preclinical trials. If these trials are successful, clinical studies on humans will follow. "The most recent studies have been very promising," says Wölk. The lipid is able to encapsulate nucleic acids, protect them from enzymatic degradation and introduce them very efficiently into cells. According to pharmacist Julia Giselbrecht, one important aspect of the technique is that it does not require co-lipids. "This advantage enables simple, reproducible production, which is necessary for later clinical applications." Along with Dr Shashank R. Pinnapireddy from the University of Marburg, Giselbrecht is the lead author of the study which has been published in Biomaterials Science.

However, there are still a few challenges to overcome. For example, researchers still need to clarify which cells DiTT4 releases its load into when it is injected directly into the body. Therapies that have already been approved usually modify the cells outside the body before injecting them into the body. However, because DiTT4 is so compatible with blood components, systemic application would be possible, explains Giselbrecht.

Wölk is therefore confident that the lipids developed in Halle will be used for gene therapies in the future. "We are convinced the system works," says Wölk. In addition to Philipps University Marburg, the University of Leiden is also participating in the research project. Wölk is also planning to conduct research on the subject at the University of Leipzig.

The gastroenterology team at Henri-Mondor AP-HP Hospital and University Paris-Est Créteil, led by Professor Iradj Sobhani, together with teams from Inserm and the Institut Pasteur Molecular Microbial Pathogenesis Unit (U1202), led by Professor Philippe Sansonetti - holder of the Microbiology and Infectious Diseases Chair at the Collège de France -, have demonstrated that an imbalance in the gut microbiota, also known as "dysbiosis", promotes the onset of colorectal cancer. The teams, operating as the "Oncomix" group since April 2016, demonstrated that transplanting fecal flora from patients with colon cancer into mice caused lesions and epigenetic changes characteristic of the development of a malignant tumor.

The pilot study, funded by the French National Cancer Institute and promoted by the Paris Public Hospital Network (AP-HP) as part of a hospital program for clinical cancer research (PHRC-K), led to the development of a non-invasive blood test which identifies the epigenetic phenomenon associated with dysbiosis. The test was validated in 1,000 individuals. These findings were published in the journal Proceedings of the National Academy of Sciences (PNAS) on November 11, 2019.

Sporadic colorectal cancer can develop in patients without any known risk factors. It occurs as a result of complex interactions between individuals and their environment. The increasing incidence of this condition reflects negative environmental developments, which can trigger alterations to the genetic and epigenetic DNA of host cells, thereby promoting the onset of sporadic colorectal cancer.

Several studies have investigated the role of the microbiota as a mediator of these interactions. The team in the Gastroenterology Department at Henri-Mondor AP-HP Hospital and University Paris-Est Créteil, together with a team composed of members from Inserm and the Institut Pasteur Molecular Microbial Pathogenesis Unit (U1202), and the Chair in Microbiology and Infectious Diseases at the Collège de France, demonstrated in mice that the epigenetic mechanism triggered by some bacteria in the microbiota contributes to the onset or promotion of sporadic colorectal cancer. They subsequently validated their findings in humans.

The 136 mice in the study were transplanted with either fresh stools from nine patients with sporadic colorectal cancer or fresh stools from nine patients with no colon disorders. The procedure was carried out at Henri-Mondor AP-HP Hospital. The colons of the mice were examined 7 and 14 weeks after the human fecal microbiota transplant. The teams particularly investigated the number and development of aberrant crypt foci (or ACF, a type of precancerous lesion), the microbial profile and damage to colonic DNA. They also took into account the animals' food intake, weight and blood indicators.

A link between fecal dysbiosis (an imbalance in gut bacteria composition) and the genetic and epigenetic DNA signature in the animals' tissues was identified using statistical tests. Mice who had received fresh stools from patients with sporadic colorectal cancer developed precancerous lesions known as aberrant crypt foci (ACF) without any significant genetic changes to the colon, but they had a greater number of hypermethylated genes - which have been significantly linked to the incidence of ACF in the colonic mucosa.

After verifying links between fecal dysbiosis and DNA anomalies (methylation) in the patients with sporadic colorectal cancer who took part in the fecal transplants, a pilot study was carried out in humans with the aim of developing a simple, reproducible blood test that can be used for early-stage diagnosis of colorectal tumors in asymptomatic patients. Prospective validation of the test was performed on 1,000 asymptomatic patients who were due to be given a colonoscopy. To identify the bacteria involved, their entire bacterial genome was sequenced. The level of hypermethylation of three genes was defined as a cumulative methylation index (CMI). The patients were classified according to their CMI (positive or negative). An analysis identified a positive CMI as a predictive factor for the onset of sporadic colorectal cancer.

This research shows that the microbiota of subjects with sporadic colorectal cancer induces precancerous colonic lesions in animals by the hypermethylation of a small number of genes. The CMI and/or methylating bacteria could therefore be used as diagnostic markers for this type of cancer. These initial findings will need to be evaluated and confirmed in a clinical trial.

Children born to women on HIV therapy containing the drug efavirenz were 2 to 2.5 times more likely to have microcephaly, or small head size, compared to children born to women on regimens of other antiretroviral drugs, according to an analysis funded by the National Institutes of Health. The children with microcephaly also had a higher risk for developmental delays, compared to children with normal head size.

The study was conducted by Paige L. Williams, Ph.D., of the Harvard T.H. Chan School of Public Health, and colleagues. It appears in The Lancet.

"Our findings underlie the importance of having alternatives to combination therapy with efavirenz for pregnant women with HIV," said study author Rohan Hazra, M.D., chief of the Maternal and Pediatric Infectious Disease Branch of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, which provided funding for the study.

Researchers analyzed data from a follow-up study of more than 3,000 infants born to women on HIV therapy during pregnancy. In this earlier study, the children's head circumferences were measured periodically from 6 months of age through 5 to 7 years of age.

For the current study, investigators used two classification systems to rank the children's head growth. The first classification system combined standards developed by the U.S. Centers for Disease Control and Prevention for children under 3 years of age with Nellhaus Charts, an older set of standards for children over 3 years of age. For the second classification system, the researchers consulted Nellhaus Charts from birth to age 18.

Based on Nellhaus standards, children whose mothers were on regimens containing the drug efavirenz were more than twice as likely to have microcephaly, compared to children whose mothers were on other regimens. According to the combined Nellhaus-CDC standards, children exposed to efavirenz in the womb were around 2.5 times as likely to have microcephaly. Children with microcephaly according to Nellhaus standards also scored lower on standardized tests of child development at ages 1 and 5 years.

Of the 141 children exposed to efavirenz in the womb, 14 (9.9%) had microcephaly, compared to 142 of 2,842 who were not exposed to efavirenz (5%).

The researchers noted that exposure to all other types of HIV therapies was not associated with a higher risk of microcephaly.

New Rochelle, NY, November 18, 2019--A new study has shown that the majority of women (82.5%) and men (65.1%) working at an academic medical center reported at least one incident of sexual harassment by staff, students, and faculty during the previous year. Similarly, a substantial proportion of women (64.4%) and men (44.1%) who worked with patients reported experiencing sexual harassment from patients or their families within the prior year, according to the study published in Journal of Women's Health, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. Click here to read the full-text article on the Journal of Women's Health website through December 18, 2019.

The study is entitled "#MedToo: A Large-Scale Examination of the Incidence and Impact of Sexual Harassment of Physicians and Other Faculty at an Academic Medical Center." It was coauthored by Emily Vargas, PhD, Sheila Brassel, Lilia Cortina, PhD, Isis Settles, PhD, timothy Johnson, MD, and Reshma Jagsi, MD, DPhil.

The researchers systematically examined the prevalence of recent sexual harassment among a large sample of physicians and other faculty currently practicing in an academic medical center. The study included multiple potential sources of harassment, including other faculty, staff, and students, as well as patients and patients' families. In addition, the study focused on the outcomes of sexual harassment and found a negative association between sexual harassment and physician mental health, job satisfaction, sense of safety at work, and intentions to look for new employment.

In the accompanying Editorial entitled "Sexual Harassment Is an Occupational Hazard," Sabine Oertelt-Prigione, MD, PhD, Radboud University Medical Center (Nijmegen, The Netherlands) and Universitätsmedizin (Berlin, Germany), concludes that "sexual harassment appears as a highly prevalent phenomenon, that impacts the entire workforce and has serious health and occupational consequences." Employers have a legal duty to devote personnel and economic resources to such an impactful phenomenon, she states. "It is time to move the discourse from an individualized to an institutional level, from single cases to collective action."

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children's National Hospital faculty.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children's National and the study's senior author, presented the teams' findings Nov. 8, 2019, during a second-annual symposium jointly held by Children's National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children's National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings.

According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person's immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person's missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body's infection-fighting white blood cells, the Children's National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3).

Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

Three patients were treated for active CMV, and the T-cells resolved their viremia.

Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.

Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses.

"These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections," says Michael Keller, M.D., a pediatric immunologist at Children's National and the lead study author. "Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients."

What The Study Did: Whether natural premature menopause and premature menopause that results from surgery to remove a woman's ovaries before age 40 are associated with increased risk of developing cardiovascular diseases was the focus of this observational study.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Pradeep Natarajan, M.D., M.M.Sc., of Massachusetts General Hospital in Boston, is the corresponding author.

(doi:10.1001/jama.2019.19191)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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Media advisory: The full study is linked to this news release. This study is being released to coincide with a session on cardiovascular disease in women at the American Heart Association's Scientific Sessions 2019.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2019.19191?guestAccessKey=8f4e1663-2889-4cf6-bb95-dc63cceabfe4&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=111819

What The Podcast Is About: Oscar-winner, recording artist and filmmaker Barbra Streisand, who helped create a namesake Women's Heart Center at Cedars-Sinai in Los Angeles, and Noel Bairey Merz, M.D., the center's director, discuss cardiovascular disease in women, which often presents differently and may not be diagnosed.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Embed this link to provide your readers free access to the article that links to the podcast  This link will be live at the embargo time https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2019.15736?guestAccessKey=cd1655ef-83b5-4891-89fc-6b00ba622e1c&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=111819

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Media advisory: The podcast and related articles linked below are being published to coincide with a session on cardiovascular disease in women at the American Heart Association's Scientific Sessions 2019. To contact Dr. Bairey Merz email Sally Stewart at sally.stewart@cshs.org and to contact Barbra Streisand email Rupa Balasubramanian at rupa@fundamental-inc.com.

Boston, Mass. - Cardiovascular disease is a major cause of death among homeless adults, with mortality rates that are substantially higher than the general population. However, little is known about whether there are differences in care between homeless and non-homeless adults and whether any such differences contribute to disparities in cardiovascular outcomes. Understanding these patterns is critically important from a public health perspective, particularly given the growing homeless population in the United States and rising rates of acute hospitalization among homeless adults.

In a new retrospective study published today in JAMA Internal Medicine, a team of researchers led by Rishi Wadhera, MD, MPP, MPhil, an investigator in the Smith Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center (BIDMC), found that there are indeed striking disparities in in-hospital care and mortality between homeless and non-homeless adults. The study found homeless adults were significantly less likely to receive important diagnostic or therapeutic procedures for urgent cardiovascular conditions and generally had higher in-hospital death rates compared with non-homeless adults.

"Our findings illustrate an urgent need for public health and policy efforts to support safety-net hospitals and other hospitals that care for high numbers of homeless individuals, in order to reduce disparities in hospital-based care and improve health outcomes for this vulnerable population," said Wadhera.

Wadhera and colleagues evaluated whether there were differences in intensity of care (e.g. diagnostic or therapeutic procedures) and death rates among homeless and non-homeless adults hospitalized for urgent cardiovascular conditions, including heart attack, stroke, cardiac arrest and heart failure. Using the State Inpatient Databases of the Healthcare Cost and Utilization Project, they analyzed more than 1.8 million hospitalizations across 525 hospitals between 2010 and 2015, focusing on three states with large homeless populations - Massachusetts, Florida, and New York.

Wadhera and team found that only 55 percent of homeless patients hospitalized for a very dangerous type of heart attack, ST-elevation myocardial infarction, underwent percutaneous coronary intervention to treat this condition. In contrast, 76 percent of non-homeless adults with the same type of heart attack received this procedure. Similarly, homeless individuals hospitalized for cardiac arrest or stroke also received lower intensity procedural care and experienced higher mortality rates compared to their non-homeless counterparts.

For example, in the cardiac arrest cohort, homeless adults were 7.5 percent less likely to undergo coronary angiography and 4.7 percent less likely to undergo percutaneous coronary intervention, compared to non-homeless adults. Among adults hospitalized with stroke, homeless individuals were 6 percent less likely to undergo cerebral angiography than non-homeless individuals. Similarly, mortality rates among homeless persons hospitalized with stroke and cardiac arrest were 2.6 percent and 18.7 percent higher, respectively, than non-homeless individuals.

"One important finding from our study was that even in the same hospital, homeless patients seem to be clinically treated differently than non-homeless patients," said Wadhera. "For example, we found that among adults hospitalized for a heart attack, homeless individuals were less likely to receive a coronary angiography and percutaneous coronary intervention, than non-homeless adults hospitalized for a heart attack at the same site of care. Further work is needed to understand whether implicit biases or stigma influence how clinicians deliver care to homeless patients or whether there are clinical reasons behind these differences in care."

Should you take omega-3 pills? Or try to have two to servings of omega-3 rich fish a week, as the American Heart Association recommends? It may seem a bit murky if you follow headlines about nutrition and health.

That's why researchers at the Intermountain Healthcare Heart Institute continue to research the potential benefits and risks of this popular supplement, especially when it comes to prostate cancer risk and heart health.

The Intermountain research team presented two new studies about omega-3s at the 2019 American Heart Association Scientific Sessions in Philadelphia on Nov. 17, 2019.

In one study, the Intermountain research team identified 87 patients who were part of the Intermountain INSPIRE Registry and had developed prostate cancer. These patients were also tested for plasma levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are two common omega-3 fatty acids.

When compared to a matched control group of 149 men, the researchers found that higher omega-3 levels were not linked with elevated prostate cancer risk.

Viet T. Le, MPAS, PA, researcher and physician assistant at the Intermountain Healthcare Heart Institute, said they undertook this study in light of findings from a 2013 paper from the Journal of the National Cancer Institute that suggested a possible link between higher omega-3 plasma levels and the development of prostate cancer, one that has been debated since publication.

"If I'm recommending omega-3 for my patients to save their hearts, I want to make sure I'm not putting them at risk for prostate cancer," said Le. "Our study found no evidence of a link between the two."

In the second study presented at the 2019 American Heart Association Scientific Sessions, the Intermountain researchers looked at 894 patients undergoing coronary angiography (a test that shows how blood flows through the arteries in the heart).

These patients had no prior history of heart attack or coronary artery disease, however upon their first angiogram, about 40% of those patients had severe disease and about 10% had three-vessel disease, Le said.

Researchers also measured patients' plasma levels of omega-3 metabolites, including DHA and EPA. Those patients were then followed to see who had subsequent heart attack, stroke, heart failure, or who died.

Researchers found that patients who higher rates of omega-3 metabolites had lower risk of those follow up adverse effects regardless of whether they had severe disease or not on their initial angiogram.

"This study is important because we looked at how omega-3 helps patients who have already developed disease, and its effects on survival - both in getting to the first angiography to be diagnosed (vs. having a heart attack or worse before even knowing they have heart disease) and thereafter," said Le.

"While a seeming association between higher plasma omega-3 levels and the findings of severe heart disease upon initial angiogram might raise alarms that omega-3 isn't beneficial, they did live to see a doctor and get diagnosed," Le added. "And we saw a link between higher levels of omega-3 and their survival rate thereafter."

Researchers from the Intermountain Healthcare Heart Institute in Salt Lake City have identified new mutations in a gene commonly associated with non-ischemic dilated cardiomyopathy (NIDC), a disease that weakens the heart muscle, making it more difficult to adequately circulate blood to meet the body's needs.

Patients with NIDC struggle because the heart's ability to pump blood is decreased, as the heart's main pumping chamber, the left ventricle, is enlarged and dilated.

Unlike other kinds of heart conditions, NIDC often isn't related to or a symptom or sign of a known cardiovascular disease or disease risk factor. While researchers have known that genetic factors play a role in non-ischemic dilated cardiomyopathy, that role isn't entirely known.

In a new study presented to heart experts from around the world, researchers from the Intermountain Healthcare Heart Institute have identified 22 mutations in 27 of 229 NIDC patients in a gene called TITIN - 15 of them not previously discovered.

These discoveries depended on applying advanced "whole exome sequencing". These TITIN mutations are of a type called "truncating variants", or TTN-tv for short, which are linked with the development of cardiomyopathy and heart failure.

"Truncating mutations in TITIN are common in NIDC, so we wanted to know: if we find one, should we be more, or less worried about the patient's prognosis? The answer is yes," said Jeffrey L. Anderson, principal investigator of the study and distinguished clinical and research physician at the Intermountain Healthcare Heart Institute.

In the study, the DNA samples of the 229 Intermountain patients diagnosed with NIDC were analyzed. Researchers also identified lifestyle, environmental and other disease factors documented in the medical records that are associated with heart problems, like high blood pressure, diabetes, a history of alcohol or drug abuse, or previous chemotherapy treatment. Patients were evaluated when they first presented and then were followed for five years.

Patients with a TTN-tv mutation more often had severe cardiomyopathy at presentation, and by five years they were less likely to have recovered (11% of those with a mutation vs. 30% of those without).

These patients also were more likely to have shown progressive disease, such as a heart transplant, implant of a permanent heart assist device, or death if they had a TTN-tv mutation (41%) than if they didn't (25%).

TTN-tv mutation patients also commonly were found to have non-genetic predisposing factors, suggesting that these other factors may act in concert with genetic factors to precipitate heart failure.

Findings from the study were presented at the 2019 American Heart Association Scientific Sessions in Philadelphia on Nov. 17, 2019

"What we think is that, in many cases, people go along just fine with one of these mutations, but then other environmental and lifestyle or disease factors kick in, and it tips them over into non-ischemic dilated cardiomyopathy," said Dr. Anderson. "We think non-ischemic dilated cardiomyopathy is the result, in many cases, of a combination of genetic predisposing factors and environmental or other disease factors."

"Currently, physicians don't routinely test patients with NIDC for all of these known and new TTN-tv gene mutations, and there's no specific genetic treatment for the disease," said Dr. Anderson.

"However, if patients were to be tested and identified as having a disease-predisposing mutation, physicians could then be more aggressive about monitoring them and treating them with known heart failure drugs and devices," he added. "If we test patients for one of these disease-related mutations, we can identify them and also affected family members whose disease is more likely to occur and then progress so we can be better on top of prevention and treatment measures."

The largest-ever clinical trial of a medication for pediatric cardiology patients found that an oral drug significantly improved exercise capacity in adolescent patients with severe, congenital single-ventricle heart defects. A study leader says the physiologic benefits represent a milestone in the care of those who have undergone the Fontan procedure, a palliative operation for single-ventricle disease.

"Exercise capacity is a surrogate for morbidity and mortality outcomes in children with single-ventricle congenital heart disease. It is our hope that an improvement in exercise capacity will translate into better long-term outcomes," said pediatric cardiologist David J. Goldberg, MD, of the Cardiac Center at Children's Hospital of Philadelphia (CHOP) and co-principal investigator of the multicenter Fontan Udenafil Exercise Longitudinal Assessment Trial (FUEL). The principal investigator of the trial, also from CHOP's Cardiac Center, was Stephen Paridon, MD.

Goldberg reported the FUEL Trial results today at the 2019 Scientific Sessions of the American Heart Association in Philadelphia and was the lead author of an article published concurrently in the journal Circulation.

The Phase 3 randomized, double-blind, placebo-controlled clinical trial, sponsored by Mezzion Pharma Co., Ltd., enrolled 400 male and female participants aged 12 to 18 years old from 30 centers in the United States, Canada and South Korea within the Pediatric Heart Network.

"This study of udenafil provides the first evidence of clinical benefit for a medication in this unique population of children with single-ventricle heart disease," said Goldberg.

Patients born with single-ventricle heart defects have a severely underdeveloped pumping chamber in their hearts. A series of complex childhood surgeries culminating in the Fontan procedure has greatly improved survival of patients with single-ventricle disease. However, the surgical corrections do not provide normal blood circulation, and survivors have low cardiac output and long-term complications. Among those complications is exercise intolerance, associated with increased morbidity and mortality.

The researchers reported that participants in the FUEL trial had statistically significant improvements in oxygen consumption and other measures of exercise capacity during moderate levels of activity. There was also a numeric improvement in oxygen consumption at peak exercise, although this did not achieve statistical significance. "These benefits in exercise capacity reflect better circulatory function, and should correlate with better long-term circulatory health for patients who have undergone the Fontan procedure," said Goldberg.

The patients who took udenafil tolerated the treatment well, with side effects limited to those previously known from phosphodiesterase type 5 inhibitors, more commonly including headache, facial flushing, abdominal pain, nosebleed and erection (among males).

A related trial, the FUEL Open-Label Extension (FUEL OLE) Trial is currently proceeding, with the goal of measuring treatment tolerability and safety over a longer period for this patient population. In the meantime, added Goldberg, "For the many patients with heart disease worldwide now living with Fontan physiology, these trial results represent a big step in the right direction."

While Intermittent fasting may sound like another dieting craze, the practice of routinely not eating and drinking for short periods of time has shown again to lead to potentially better health outcomes.

In a new study by researchers at the Intermountain Healthcare Heart Institute in Salt Lake City, researchers have found that cardiac catheterization patients who practiced regular intermittent fasting lived longer than patients who don't. In addition, the study found that patients who practice intermittent fasting are less likely to be diagnosed with heart failure.

"It's another example of how we're finding that regularly fasting can lead to better health outcomes and longer lives," said Benjamin Horne, PhD, principal investigator of the study and director of cardiovascular and genetic epidemiology at the Intermountain Healthcare Heart Institute.

Findings from the study will be presented at the 2019 American Heart Association Scientific Sessions in Philadelphia on Saturday, November 16, 2019.

In the study, researchers asked 2,001 Intermountain patients undergoing cardiac catheterization from 2013 to 2015 a series of lifestyle questions, including whether or not they practiced routine intermittent fasting. Researchers then followed up with those patients 4.5 years later and found that routine fasters had greater survival rate than those who did not.

Because people who fast routinely also are known to engage in other healthy behaviors, the study also evaluated other parameters including demographics, socioeconomic factors, cardiac risk factors, comorbid diagnoses, medications and treatments, and other lifestyle behaviors like smoking and alcohol consumption.

Correcting statistically for these factors, long-term routine fasting remained a strong predictor of better survival and lower risk of heart failure, according to researchers.

The Intermountain Healthcare Heart Institute has the opportunity to closely study intermittent fasting because a large portion of its patients do it regularly: a significant portion of Utah's population belongs the Church of Jesus Christ of Latter-day Saints, whose members typically fast the first Sunday of the month by going without food or drink for two consecutive meals, and thus not eating for the period of about a day.

While the study does not show that fasting is the causal effect for better survival, these real-world outcomes in a large population do suggest that fasting may be having an effect and urge continued study of the behavior.

"While many rapid weight loss fasting diets exist today, the different purposes of fasting in those diets and in this study should not be confused with the act of fasting," said Dr. Horne. "All proposed biological mechanisms of health benefits from fasting arise from effects that occur during the fasting period or are consequences of fasting."

Dr. Horne has previously conducted studies about risk of diabetes and coronary artery disease in patients and found that rates are lower in patients who practice routine intermittent fasting. Those studies were published in 2008 and 2012 and suggested that the decades-long development of those chronic diseases may be ameliorated by long-term routine fasting.

Why long-term intermittent fasting leads to better health outcomes is still largely unknown, though Dr. Horne said it could be a host of factors. Fasting affects a person's levels of hemoglobin, red blood cell count, human growth hormone, and lowers sodium and bicarbonate levels, while also activating ketosis and autophagy - all factors that lead to better heart health and specifically reduce risk of heart failure and coronary heart disease.

"With the lower heart failure risk that we found, which is consistent with prior mechanistic studies, this study suggests that routine fasting at a low frequency over two thirds of the lifespan is activating the same biological mechanisms that fasting diets are proposed to rapidly activate," Dr. Horne noted.

Researchers speculate that fasting routinely over a period of years and even decades conditions the body to activate the beneficial mechanisms of fasting after a shorter length of time than usual.

Typically, it takes about 12 hours of fasting for the effects to be activated, but long-term routine fasting may cause that time to be shortened so that each routine faster's daily evening/overnight fasting period between dinner and breakfast produces a small amount of daily benefit, they noted.

Further studies are on-going that will answer this question and other questions related to possible mechanisms of effects on development of chronic disease and survival. Additional research will also examine potential psychological effects of fasting and potential effects on appetite and perception of hunger.

Fasting is not for everyone. Researchers caution that pregnant and lactating women should not fast, as well as young children and frail older adults. People who have received an organ transplant, who have a suppressed immune system, who are experiencing acute or severe chronic infections, and those with eating disorders should also not fast.

People diagnosed with chronic diseases - especially those who take medications for diabetes, blood pressure, or heart disease - should not fast unless under the close care and supervision of a physician because of the severe adverse effects that medications in combination with fasting can cause, including as hypoglycemia.

PHILADELPHIA -- Women who are diagnosed with peripartum cardiomyopathy (PPCM) during late pregnancy or within a month following delivery are more likely to experience restored cardiac function and improved outcomes compared to those who are diagnosed later in the postpartum period, according to a new study from Penn Medicine. The findings underscore the need for increased awareness and monitoring of heart failure symptoms, particularly among black women, who, on average, are diagnosed significantly later than white patients, researchers found.

Authors say the findings, which will be published in Hypertension and presented at the American Heart Association's 2019 Scientific Sessions, may explain the striking disparities in outcomes between white and black patients with PPCM. In a previous study, published in JAMA Cardiology, the team found black women were only about half as likely to return to normal levels of cardiac function and took twice as long to do so.

"Our findings demonstrate that important racial disparities exist not only in the outcomes of patients with PPCM, but in the timing of diagnosis and baseline level of cardiac function," said the study's lead author Jennifer Lewey, MD, MPH, director of the Women's Cardiovascular Health Program and co-director of the Pregnancy and Heart Disease Program at Penn Medicine. "Cardiomyopathy is the leading cause of maternal mortality in the postpartum period, and while we recommend increased monitoring for peripartum cardiomyopathy in all patients, it's particularly important in black women. Earlier diagnoses of PPCM may help to prevent the poor outcomes and expedite their recovery to normal cardiac function."

PPCM, which affects at least one in 2,000 pregnancies in the United States, is a rare, potentially life-threatening form of heart failure in which the heart muscle becomes weak--often during the final month of pregnancy or in the first few months after delivery. Although the majority of patients, about 60 to 70 percent, experience a recovery to normal cardiac function, about 13 percent of patients experience severe, persistent cardiac dysfunction and can require a heart transplant or left ventricular assist device (LVAD), a mechanical pump that helps the left ventricle pump blood to the rest of the body.

Hypertensive disorders of pregnancy (HDP), such as gestational hypertension (high blood pressure noted in the latter part of pregnancy) and preeclampsia (a dangerous complication characterized by high blood pressure), are the strongest risk factors for PPCM. Previous studies have noted that patients with HDP and, ultimately, PPCM may fare better than those who do not develop HDP prior to PPCM. The studies suggest that if HDP contributes to the development of PPCM, the resolution of postpartum high blood pressure and restoration of normal blood vessel formation could accelerate one's recovery to normal cardiac function. However, several studies have demonstrated that no such relationship exists.

To further examine how HDP and the timing of diagnosis impact patient outcomes, the Penn team conducted a retrospective study of 220 patients diagnosed with PPCM. Although women with HDP are diagnosed with PPCM earlier in the postpartum period, researchers found that women with HDP and PPCM experienced similar rates of left ventricular ejection fraction (LVEF) as those without HDP (68 percent and 63 percent, respectively). However, they found that patients who were diagnosed with PPCM more than a month after the delivery had significantly lower rates of cardiac recovery than those who were diagnosed earlier (54 percent vs. 70 percent). Patients who received an early diagnosis generally had higher baselines of cardiac function, likely contributing to the improved outcomes, authors suggest.

Additionally, researchers found that the majority of white patients with PPCM and HDP were diagnosed within a week of delivery. However, black patients with PPCM and HDP were most likely to be diagnosed between one and five months postpartum, with a small percentage diagnosed even beyond the five-month mark.

"While we are still investigating the factors--such as genetics and socioeconomic status--that lead to later diagnosis in this population, we hope our findings help to increase awareness of the need for proactive monitoring," said the study's senior author Zoltan Arany, MD, PhD, a professor of Cardiovascular Medicine at Penn.

Lewey will present her research at 1:30 pm ET on Saturday, November 16, in Zone 2 of the Science and Technology Hall at the Pennsylvania Convention Center in Philadelphia.

A high-fat, low-carbohydrate diet like the Keto regimen has its fans, but influenza apparently isn't one of them.

Mice fed a ketogenic diet were better able to combat the flu virus than mice fed food high in carbohydrates, according to a new Yale University study published Nov. 15 in the journal Science Immunology.

The ketogenic diet -- which for people includes meat, fish, poultry, and non-starchy vegetables -- activates a subset of T cells in the lungs not previously associated with the immune system's response to influenza, enhancing mucus production from airway cells that can effectively trap the virus, the researchers report.

"This was a totally unexpected finding," said co-senior author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular and Developmental Biology, and an investigator of the Howard Hughes Medical Institute.

The research project was the brainchild of two trainees -- one working in Iwasaki's lab and the other with co-senior author Visha Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. Ryan Molony worked in Iwasaki's lab, which had found that immune system activators called inflammasomes can cause harmful immune system responses in their host. Emily Goldberg worked in Dixit's lab, which had shown that the ketogenic diet blocked formation of inflammasomes.

The two wondered if diet could affect immune system response to pathogens such as the flu virus.

They showed that mice fed a ketogenic diet and infected with the influenza virus had a higher survival rate than mice on a high-carb normal diet. Specifically, the researchers found that the ketogenic diet triggered the release of gamma delta T cells, immune system cells that produce mucus in the cell linings of the lung -- while the high-carbohydrate diet did not.

When mice were bred without the gene that codes for gamma delta T cells, the ketogenic diet provided no protection against the influenza virus.

"This study shows that the way the body burns fat to produce ketone bodies from the food we eat can fuel the immune system to fight flu infection," Dixit said.

When the electronic health record is programmed to automatically flag and create orders for patients needing cancer screenings, doctors are significantly more likely to order them, a new Penn Medicine study shows. However, the study showed that the other part of the equation -- patients following through on those screenings -- was unaffected by the increase in orders.

"Cancer screening involves both the clinician recommending and ordering it as well as the patient taking action to schedule and complete it. Our study found nudges can be very influential, but for cancer screening they likely need to be directed to both clinicians and patients," said Mitesh Patel, MD, MBA, the director of the Penn Medicine Nudge Unit and the senior author of the study published today in JAMA Network Open.

Currently, primary care physicians have to remember to manually check the electronic health record (EHR) to determine whether a patient is eligible for a cancer screening. Then, they must discuss it with the patient and put in an order, if need be. Because of physicians' busy schedules and limited time with patients, this can get lost in the shuffle, especially as the day goes along, as previous research by Patel and this study's lead author, Esther Hsiang, MD, MBA, showed.

To alleviate some of that strain and guide primary care doctors to get more patients screened, Hsiang, a researcher in the Nudge Unit at the time of this study, and Patel evaluated a nudge implemented by the University of Pennsylvania Health System that involved programming the EHR to check whether patients were due for colorectal or breast cancer screenings. This check occurred while patients met with a medical assistant, who kicks off visits with some of the routine steps, such as checking vital signs. Once the medical assistant finished their tasks, the EHR prompted them to accept or decline a screening order. If accepted, the order would be set up so that the doctor would be reminded to discuss it with the patient and sign off on it, involving no further technical effort.

"Clinicians are increasingly being asked to do more with a fixed amount of time with a patient," Hsiang explained. "By directing the intervention to medical assistants, this reduced the burden on busy clinicians to respond to alerts and instead gave them more time to have a discussion with their patients about screening."

With the nudge in place at three different practices in the health system from September 2016 until the end August 2017, screening order rates for breast cancer jumped by 22 percent compared to practices without the nudges. Overall, of all patients due for a screening in those practices, nearly 88 percent had one ordered. For colorectal cancer, the order rate jumped by nearly 14 percent compared to the other practices, with 82 percent of overdue patients, total, having a screening ordered.

In spite of these gains, there was almost no change in the rates of patients who actually followed through and completed their screenings.

"Once cancer screening is ordered, the patient still has to take several steps to complete it," Patel explained. "That includes scheduling an appointment, sometimes conducting prep -- such as bowel prep for a colonoscopy -- and then going to the appointment. These several steps can add up to high hurdles, especially if patients have lower motivation to begin with. Future interventions should test ways to nudge patients to complete cancer screenings."

That's exactly what Patel is working on now, developing a new study to test nudges for both parties while also attempting to eliminate or alleviate some of the hurdles to completing screenings.

And while the study only focused on two specific types of cancer, these nudges have a wider potential.

"Since EHRs are used by more than 90 percent of physicians, this is a really scalable approach," Patel said. "It is likely that it could be successful for other types of screening."