Body

Researchers at University of California San Diego School of Medicine say the loss of a single gene two to three million years ago in our ancestors may have resulted in a heightened risk of cardiovascular disease in all humans as a species, while also setting up a further risk for red meat-eating humans. The findings are published July 22, 2019 in PNAS.

Atherosclerosis -- the clogging of arteries with fatty deposits -- is the cause of one-third of deaths worldwide due to cardiovascular disease. There are many known risk factors, including blood cholesterol, physical inactivity, age, hypertension, obesity and smoking, but in roughly 15 percent of first-time cardiovascular disease events (CVD) due to atherosclerosis, none of these factors apply.

A decade ago, Nissi Varki, MD, professor of pathology at UC San Diego School of Medicine, with co-author Ajit Varki, MD, Distinguished Professor Of Medicine and Cellular And Molecular Medicine, and colleagues noted that naturally occurring coronary heart attacks due to atherosclerosis are virtually non-existent in other mammals, including closely related chimpanzees in captivity which share human-like risk factors, such as high blood lipids, hypertension and physical inactivity. Instead, chimp "heart attacks" were due to an as-yet unexplained scarring of the heart muscle.

In the new study, the Varkis, and Philip Gordts, PhD, assistant professor of medicine, and others report that mice modified to be deficient (like humans) in a sialic acid sugar molecule called Neu5Gc showed a significant increase in atherogenesis compared to control mice, who retain the CMAH gene that produces Neu5Gc.

The researchers -- members of the Glycobiology Research and Training Center and/or the Center for Academic Research and Training in Anthropogeny at UC San Diego -- believe a mutation that inactivated the CMAH gene occurred a few million years ago in hominin ancestors, an event possibly linked to a malarial parasite that recognized Neu5Gc.

In their findings, the research team said human-like elimination of CMAH and Neu5Gc in mice caused an almost 2-fold increase in severity of atherosclerosis compared to unmodified mice.

"The increased risk appears to be driven by multiple factors, including hyperactive white cells and a tendency to diabetes in the human-like mice," said Ajit Varki. "This may help explain why even vegetarian humans without any other obvious cardiovascular risk factors are still very prone to heart attacks and strokes, while other evolutionary relatives are not."

But in consuming red meat, humans are also repeatedly exposed to Neu5Gc, which researchers said prompts an immune response and chronic inflammation they call "xenosialitis." In their tests, human-like mice modified to lack the CMAH gene were fed a Neu5Gc-rich, high-fat diet and subsequently suffered a further 2.4-fold increase in atherosclerosis, which could not be explained by changes in blood fats or sugars.

"The human evolutionary loss of CMAH likely contributes to a predisposition to atherosclerosis by both intrinsic and extrinsic (dietary) factors," wrote the authors, "and future studies could consider using this more human-like model."

In previous work, the Varkis and colleagues have shown that dietary Neu5Gc also promotes inflammation and cancer progression in Neu5Gc-deficient mice, suggesting that the non-human sugar molecule, which is abundant in red meat, may at least partially explain the link between high consumption of red meat and certain cancers.

Interestingly, the evolutionary loss of the CMAH gene appears to have produced other significant changes in human physiology, including reduced human fertility and enhanced ability to run long distances.

Children born to women on HIV therapy containing the drug dolutegravir since conception have a slightly higher risk of neural tube defects, compared to children born to women on regimens of other antiretroviral drugs. The findings are from a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health, and were presented at the 10th International AIDS Society Conference in Mexico City by Rebecca Zash, M.D., of Beth Israel Deaconess Medical Center in Boston. The study also appears online in the New England Journal of Medicine.

Neural tube defects are abnormalities affecting the brain and spinal column. The NICHD-funded study began in 2014 to track birth outcomes, including neural tube defects, among children born to women on antiretroviral therapy for HIV infection in eight hospitals in Botswana. The country changed its treatment guidelines in 2016 to recommend drug combinations containing dolutegravir for all adults, including pregnant women. In 2018, a preliminary analysis of the study data suggested a potential risk for neural tube defects among infants whose mothers began receiving dolutegravir around the time of conception. At the International AIDS Society Conference, the researchers reported the full analysis of the study data collected through March 2019.

For women on dolutegravir since conception, five neural tube defects occurred out of 1,683 births (.3%). For women on the drug efavirenz since conception, there were three cases of neural tube defects out of 7,959 births (.04%). For women on any HIV treatment regimens that did not contain dolutegravir, there were 15 neural tube defect cases out of 14,792 births (.1%). Overall, the researchers found a .2% difference in risk for children born to women on dolutegravir since conception, which they described as small, but significant.

Families living with extremely rare neurodegenerative diseases finally received an answer to the cause of their illnesses, thanks to a researcher's hunch and decades of improvements in DNA sequencing technology.

Four different rare diseases are all caused by the same short segment of DNA repeated too many times, a mutation researchers call noncoding expanded tandem repeats. Researchers suspect variations of this type of mutation may cause other diseases that have thus far evaded diagnosis by genetic testing.

Treatment strategies for many genetic diseases are complicated by the fact that different mutations can cause the same disease. For example, Parkinson's disease can be caused by unique mutations in at least five different genes. Cystic fibrosis can be caused by over 1,000 different mutations in the same gene.

Researchers are excited because instead of finding unique mutations in specific genes, they identified the same mutation in different areas of the genome causing different diseases.

Genetic cause of rare diseases evaded diagnosis

"Because the mutations causing the diseases are so similar, in the future, all these patients might benefit from the same treatment," explained Dr. Hiroyuki Ishiura, M.D./Ph.D., assistant professor from the University of Tokyo Hospital and first author of the recent research paper published in Nature Genetics.

"Gene silencing techniques [which inactivate previously active genes] are a possible treatment. We cannot know the result, but we believe such strategies may help patients in the future," said Dr. Shoji Tsuji, M.D./Ph.D., project professor from the University of Tokyo Hospital, a corresponding author of the recent research paper.

The research team focused on patients with adult-onset neurodegeneration, showing symptoms like cognitive impairment, uncontrolled movement, loss of balance, weakness in the arms and legs, or difficulty swallowing.

The genetic cause of one disease with those symptoms, fragile X tremor/ataxia syndrome, was identified in the early 2000s as three letters of the genetic code, CGG, being repeated dozens or hundreds of times on the X chromosome. Noncoding expanded tandem repeat mutations can be caused by any letters of the genetic code repeated an unusual number of times anywhere in the genome.

Researchers had a hunch that the same CGG repeat mutation might cause three other rare diseases with similar symptoms and clinical test results. But since patients with those other diseases had normal X chromosomes, researchers had no idea where in the genome the potential CGG repeat mutations might exist.

High-tech scavenger hunt

Previous generations of DNA sequencing technology required researchers to know where in the genome to look for a mutation. Searching for CGG repeat mutations on all 46 chromosomes in the human genome was extremely difficult and laborious.

The new approach that researchers designed relies on modern next-generation genome sequencing and clever data analysis.

Researchers sequenced patients' and healthy people's entire genomes in short, overlapping but broken stretches. Collaborators, including Professor Shinichi Morishita, a computational biologist from the Department of Bioinformatics and Systems Biology, developed a new computer program to sort all of those short sequences and search for ones made of just CGG over and over again.

Using a standard sequence of the entire healthy human genome, the computer program could pin down those short segments containing CGG repeat mutations to particular genetic neighborhoods. Researchers narrowed down their search to anywhere in the genome where patients had a large number of CGG repeats and healthy people had none.

With that information, researchers then knew where to sequence a long stretch of DNA to specifically identify the gene and where in the gene the patients' CGG repeat mutations exist.

Rare diseases share common symptoms

All four rare neurological diseases that the research team studied are caused by CGG repeat mutations in distant, seemingly unrelated areas of the genome.

One of the diseases is currently only known in a single family.

"We cared for this family starting 10 years ago, so it was a long puzzle for us to find the correct diagnosis," said Ishiura.

Efforts are ongoing to study genomes identified through the genetic analysis of people who are healthy despite having the same CGG repeat mutations. Such cases are extremely rare.

The researchers hope that their studies on rare neurodegenerative diseases might lead to insights into more common diseases caused by other types of noncoding tandem repeat mutations, including amyotrophic lateral sclerosis (ALS), also known as motor neuron disease or Lou Gehrig's disease.

WASHINGTON, DC (July 22, 2019): A change in the care protocol of patients undergoing weight-reduction operations exceeded its desired effect by cutting postoperative hospital stays in half, reducing postoperative hospital readmissions by 38 percent, and reducing the amount of opioids the patients were sent home with by 95 percent, according to study results from a large bariatric and metabolic surgery center in Charleston, S.C.

The objective of implementing the new care regimen, called an Enhanced Recovery After Surgery (ERAS) protocol, was to shorten the number of days patients spend in the hospital after their operations and to prescribe fewer opioid pain medications, said Charles K. Mitchell Jr., MD, FACS, FASMBS, of Roper St. Francis Bariatric and Metabolic Services, who presented the results at the American College of Surgeons (ACS) Quality and Safety Conference 2019, concluding today in Washington, D.C.

"My concern was that patients were going to go back to the emergency room and needed to be seen again because we were sending them home too quickly or were not managing their pain properly, but the opposite was true," Dr. Mitchell said. "Our readmission rates actually dropped almost 40 percent with the implementation of this protocol."

Specifically, the hospital readmission rate went from 5 percent before implementing ERAS to 3.1 percent afterward. Likewise, the average length of stay (LOS) in the hospital after a bariatric operation went from 3.3 days to 1.5 days, and the average in-hospital, per-patient morphine equivalents, which is a measure of pain-relieving medication administered, went from 89.1 to 4 mg. The study evaluated patient outcomes for the year before and the year after the institution adopted the ERAS protocol in December 2016.

Roper St. Francis was invited to adopt the Employing New Enhanced Recovery Goals for Bariatric Surgery (ENERGY) project because it ranked as an outlier with regard to hospital length of stay within the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP). MBSAQIP is a nationwide joint initiative of the ACS and the American Society of Metabolic and Bariatric Surgery (ASMBS) that tracks outcomes at bariatric surgery centers with the goal of identifying best practices and improving low-performing centers.

"The cost implications are quite positive," Dr. Mitchell said, not only because of the shorter hospital stays, fewer readmissions, and less pain medications, but also due to the types of pain medication used. "Some programs will implement these protocols and they'll use very expensive pain medications such as intravenous Tylenol (acetaminophen) or Exparel suspension," Dr. Mitchell said. Exparel suspension is liposomal bupivacaine, a local anesthetic that, once injected, can last at least 24 hours. "We decided that strategy was cost prohibitive, so we administered 0.25 percent bupivacaine as a local anesthetic and Tylenol tablets." The cost of that combination at Dr. Mitchell's institution was $6.24 for the first 24 hours postoperatively compared with approximately $672 for three doses of IV Tylenol and one vial of Exparel, Dr. Mitchell noted.

Implementing the program involved more than adopting new practices. "Anytime you start an enhanced recovery after surgery protocol, the first thing you have to get people to understand is that it's not just an order set; it's a completely different mindset," Dr. Mitchell said.

The ERAS protocol involves intense preoperative patient education about a pain-management plan that eliminates the patient-controlled analgesia (PCA) pump and avoids routine administration of opioids, which can cause constipation or nausea. It also involves training the nursing staff to give multimodal pain medication according to the protocol rather than providing opioids to relieve a patient's pain upon request.

"Before the protocol, 96 percent of our surgical patients received opioids either upon induction of anesthesia or during the case. That number now is zero," Dr. Mitchell said. "One hundred percent of patients received opioids after their operations by way of a PCA pump with morphine or dilaudid before we started this protocol, and now we have, depending on the month, somewhere between 55 and 70 percent who receive no opioids during their hospital stay."

Obese patients commonly take pain medication for arthritis before they have bariatric operations, but in this study population, Dr. Mitchell noted, "Almost all of those patients were not given any extra narcotics to go home with after their procedures." Their postoperative pain management care did not deviate from the protocol, and all patients resumed their home pain management regimen at discharge.

Beyond pain management, the ERAS protocol also has patients up, out of bed, and walking, as well as taking liquids by mouth, within six hours after their operations. Since the bariatric surgical team adopted the ENERGY ERAS protocol, other surgical services in the health system have shown interest in adopting an ERAS protocol, Dr. Mitchell said.

People who follow the paleo diet have twice the amount of a key blood biomarker linked closely to heart disease, the world's first major study examining the impact of the diet on gut bacteria has found.

Researchers from Edith Cowan University (ECU) compared 44 people on the diet with 47 following a traditional Australian diet.

The research, published in the European Journal of Nutrition, measured the amount of trimethylamine-n-oxide (TMAO) in participants' blood.

High levels of TMAO, an organic compound produced in the gut, are associated with an increased risk of heart disease, which kills one Australian every 12 minutes.

Impact on gut health

The controversial Paleo (or 'caveman') diet advocates eating meat, vegetables, nuts and limited fruit, and excludes grains, legumes, dairy, salt, refined sugar and processed oils.

Lead researcher Dr Angela Genoni said that with the diet's growing popularity, it was important to understand the impact it could have on overall health.

"Many Paleo diet proponents claim the diet is beneficial to gut health, but this research suggests that when it comes to the production of TMAO in the gut, the Paleo diet could be having an adverse impact in terms of heart health," she said.

"We also found that populations of beneficial bacterial species were lower in the Paleolithic groups, associated with the reduced carbohydrate intake, which may have consequences for other chronic diseases over the long term."

Reduced intake of whole grains to blame

She said the reason TMAO was so elevated in people on the Paleo diet appeared to be the lack of whole grains in their diet.

"We found the lack of whole grains were associated with TMAO levels, which may provide a link between the reduced risks of cardiovascular disease we see in populations with high intakes of whole grains," she said.

The researchers also found higher concentrations of the bacteria that produces TMAO in the Paleo group.

"The Paleo diet excludes all grains and we know that whole grains are a fantastic source of resistant starch and many other fermentable fibres that are vital to the health of your gut microbiome," Dr Genoni said.

"Because TMAO is produced in the gut, a lack of whole grains might change the populations of bacteria enough to enable higher production of this compound.

"Additionally, the Paleo diet includes greater servings per day of red meat, which provides the precursor compounds to produce TMAO, and Paleo followers consumed twice the recommended level of saturated fats, which is cause for concern.

Dr Angela Genoni initially presented her findings at the Nutrition Society of Australia Conference last year. This is the first time the findings have been published in a peer-reviewed journal.

Miami Beach, FL--A new study, presented today at the Society of NeuroInterventional Surgery's (SNIS) 16th Annual Meeting, found that non-internal carotid artery (non-ICA) site of occlusion, the use of a balloon-guided catheter, and better collateral grade were all independent predictors of the first pass effect (FPE).

FPE occurs when a complete revascularization is achieved after a single attempt with mechanical thrombectomy. Prior research has already shown that FPE is associated with significantly higher rates of a good clinical outcome.

The study, Predictors of the First Pass Effect with Neurothrombectomy for Acute Ischemic Stroke, analyzed data from 984 patients treated at 55 sites. Results showed that FPE was achieved in 40% of patients and that rates of mortality at 90 days were lower in the FPE group compared to the non-FPE group (12% vs 19%).

"By understanding more about the factors that influence a good clinical outcome, we can reach our goal of helping all stroke patients survive and thrive," said Dr. Ashutosh Jadhav, MD, Ph.D., lead author of the study and associate professor of Neurology and director of the Stroke Institute at the University of Pittsburgh in Pittsburgh, Pennsylvania. "This study suggests that more knowledge of these predictors may influence our choice of thrombectomy device and technique."

Known as two of the most lethal cancers, ovarian and pancreatic cancer are often called silent killers since they rarely have early symptoms. As a result, they frequently go undetected until they're too late to effectively treat.

Cancer scientists at Houston Methodist and The University of Texas MD Anderson Cancer Center have been vigilant about looking for more effective late-stage treatments and may have found one.

In a study published online July 22 in the journal Clinical Cancer Research, co-corresponding authors Stephen T.C. Wong, Ph.D., from Houston Methodist Cancer Center and Samuel Mok, Ph.D., from The University of Texas MD Anderson Cancer Center report that they have found a new type of immunotherapy to try in the fight against these two deadly malignancies.

Wong, Mok, and colleagues developed a monoclonal antibody to block the action of a protein secreted by the cells surrounding and supporting tumors in ovarian and pancreatic cancers, called MFAP5. This protein is found at high levels in patients with both these cancers and associated with decreased survival rates.

"We found that blocking MFAP5 enhances the effectiveness of chemotherapy treatments and suppresses tumor growth in ovarian and pancreatic cancers, as well as inhibits progression of these two cancers in mice," said Wong, who is also professor of systems medicine and bioengineering at the Houston Methodist Research Institute. "This new immunotherapy drug targets supporting cells surrounding a tumor rather than just the tumor cells alone. This tumor microenvironment contains newly developed blood vessels and fibrous connective tissue - created through the processes of angiogenesis and fibrosis - that feed and support the tumor."

The MFAP5 protein has been shown to trigger the formation of these surrounding elements that supply and stimulate the tumor, influencing how it grows and spreads. Blocking it prevents new blood vessels and excess tissue from forming within the microenvironment, thereby cutting off the tumor's blood supply and support.

Mok, who is an endowed professor of gynecologic oncology and reproductive medicine at MD Anderson explains, "MFAP5 promotes fibrosis in ovarian and pancreatic cancers, and fibrosis promotes progression, chemoresistance and reduces survival of people with these cancers. By blocking this secretory protein with an antibody, we can treat the tumor by targeting multiple cellular types - fibroblasts and blood vessels -- in the tumor microenvironment."

Now that they have demonstrated the feasibility of using their monoclonal antibody to target MFAP5 as a new cancer treatment regimen, the researchers are in the process of designing and generating a humanized anti-MFAP5 antibody for further development as a therapeutic agent to treat ovarian and pancreatic cancers. Wong said they expect to have it ready by the end of the year for efficacy and toxicity testing, followed by a Phase I clinical trial in the following year.

"The convergence of biological science, computational science, and engineering has allowed us to achieve such translational discovery," Wong said.

Ann Arbor, July 22, 2019 - A new study in the American Journal of Preventive Medicine, published by Elsevier, reveals a unique and strong association between firearm ownership and the risk of domestic homicides. For each 10 percent increase in household gun ownership rates, the findings show a significant 13 percent increased incidence of domestic firearm homicide. The homicide risk differed across victim-offender relationships, with nondomestic firearm homicide rising only 2 percent among firearm owners.

"While personal protection is a commonly cited reason for owning a gun, our research shows that firearm ownership also confers significant risks to loved ones, as they are more likely to be killed if there is a gun in the household," said lead investigator Aaron J. Kivisto, PhD, School of Psychological Sciences, University of Indianapolis, Indianapolis, IN, USA. "Our findings highlight the importance of firearm removal in protecting victims of domestic violence, the majority of whom are women."

The investigators looked at annual homicide rates in all 50 US states from 1990 through 2016, across a variety of victim-offender relationships, including homicides of intimate partners, other family members, acquaintances, and strangers. Data were drawn from the US Census, Bureau of Labor Statistics, National Institute on Alcohol Abuse and Alcoholism, and Federal Bureau of Investigation's Uniform Crime Report. They examined whether state-level household gun ownership rates were uniquely associated with homicide rates within specific victim-offender relationships.

Researchers noted significant variations across states in the rate of gun-owning households in the US, ranging from 10.4 percent to 68.8 percent. Differences were observed by regions; for example, higher rates were found in states in the south and west, whereas lower firearm ownership was observed in the Northeast region. The study demonstrated that the incidence of domestic firearm homicide was significantly higher in states at the top end of the spectrum. Nearly one in three homicides was classified as domestic with higher domestic firearm homicide rates observed in southern states and lower rates occurring in the northeast. Approximately half of all homicide victims were classified as friends/acquaintances.

"In states at the top quartile of household firearm ownership, there was a 64.6 percent increased incidence rate of domestic firearm homicide, relative to states in the lowest quartile of gun ownership. By contrast, these comparisons did not reveal significant differences for nondomestic firearm homicide rates," explained Professor Kivisto.

The results point to the need to more fully understand the role of firearms across the diverse social and relational dynamics implicated in acts of fatal gun violence. As the number of deaths caused by firearm violence continues to rise in the US, researchers have started to examine potential causal factors, one of which is the number of households with firearms. Past research has consistently pointed to an association between state-level gun ownership and rates of firearm mortality, including suicides and homicides. The results of this study suggest that the risks of gun ownership on homicide rates are relatively specific to domestic homicides, which the study defined as the homicide of an intimate partner or other family member.

The findings should help guide suggested avenues for future policy, practice, and research initiatives. Professor Kivisto noted, "While some federal laws are in place that are aimed at reducing domestic firearm violence, not enough has been done to enforce them at the federal level. States that have enacted legislation to prohibit individuals at high risk of intimate partner violence from possessing firearms and requiring them to relinquish any they currently own, have a lower incidence of domestic firearm homicide."

BOSTON - Medical consensus once supported daily use of low dose aspirin to prevent heart attack and stroke in people at increased risk for cardiovascular disease (CVD). But in 2018, three major clinical trials cast doubt on that conventional wisdom, finding few benefits and consistent bleeding risks associated with daily aspirin use. Taken together, the findings led the American Heart Association and American College of Cardiology to change clinical practice guidelines earlier this year, recommending against the routine use of aspirin in people older than 70 years or people with increased bleeding risk who do not have existing cardiovascular disease.

Aspirin use is widespread among groups at risk for harm including older adults and adults with peptic ulcers - painful sores in the lining of the stomach that are prone to bleeding that affect about one in ten people. In a research report published today in Annals of Internal Medicine, researchers from Beth Israel Deaconess Medical Center (BIDMC) report on the extent to which Americans 40 years old and above use aspirin for primary prevention of cardiovascular disease.

"Although prior American Heart Association and American College of Cardiology guidelines recommended aspirin only in persons without elevated bleeding risk, the 2019 guidelines now explicitly recommend against aspirin use among those over the age of 70 who do not have existing heart disease or stroke," said senior author Christina C. Wee, MD, MPH, a general internist and researcher at BIDMC and Associate Professor of Medicine at Harvard Medical School. "Our findings suggest that a substantial portion of adults may be taking aspirin without their physician's advice and potentially without their knowledge."

Using data from the 2017 National Health Interview Survey (NHIS), a nationally representative survey of U.S. households conducted before the release of the new guidelines, Wee and colleagues characterized aspirin use for primary prevention of CVD. The team found that about a quarter of adults aged 40 years or older without cardiovascular disease - approximately 29 million people - reported taking daily aspirin for prevention of heart disease. Of these, some 6.6 million people did so without a physician's recommendation.

Concerningly, nearly half of adults 70 years and older without a history of heart disease or stroke reported taking aspirin daily. The authors noted that a history of peptic ulcer disease - another contraindication for the routine use of aspirin - was not significantly associated with lower aspirin use as one would have expected.

"Our findings show a tremendous need for health care practitioners to ask their patients about ongoing aspirin use and to advise them about the importance of balancing the benefits and harms, especially among older adults and those with prior peptic ulcer disease," said lead author Colin O'Brien, MD, a senior internal medicine resident at BIDMC and fellow at Harvard Medical School.

Coauthor, Stephen Juraschek, MD, PhD, a primary care physician at BIDMC, cautions that "these findings are applicable to adults who do not have a history of cardiovascular disease or stroke. If you are currently taking aspirin, discuss it with your doctor to see if it is still needed for you."

DALLAS - July 19, 2019 - Ever stand up too quickly and see stars? Fainting from low blood pressure can be dangerous for astronauts as well as for patients. With the 50th anniversary of the Apollo 11 moon landing approaching, UT Southwestern Medical Center researchers are publishing heart-related space research that helps us to understand the problem of low blood pressure.

The study, now in Circulation, is the first to examine this condition - called orthostatic intolerance - during daily activities when the astronauts returned home. The researchers found that exercise regimens during space flight, followed by saline injections after landing, were sufficient to prevent the condition from occurring.

Cardiologist Dr. Benjamin Levine led the study and has worked in space research for three decades. Dr. Levine is a Professor of Internal Medicine at UT Southwestern and Director of the Institute for Exercise and Environmental Medicine, a collaboration between UT Southwestern and Texas Health Presbyterian Hospital Dallas.

"Doing an hour or more of daily exercise was sufficient to prevent loss of heart muscle, and when it was combined with receiving hydration on their return, the condition was prevented entirely," said Dr. Levine. "We expected to see up to two-thirds of the space crew faint. Instead, no one fainted."

The researchers used an unusual tool, a small blood pressure cuff on each astronaut's finger, to measure blood pressure and every heartbeat. These measurements were taken during multiple 24-hour periods before, during, and after six months of spaceflight. Twelve astronauts were involved, eight men and four women.

A similar condition is also diagnosed in patients as Postural Orthostatic Tachycardia Syndrome (POTS), which is predominantly found in women. The dizziness that it causes is life-changing and can be debilitating. Dr. Levine helped one Dallas patient return to a normal life:

This treatment is just one of the ways medicine, heart research, and space travel have connected throughout Dr. Levine's work. The successful moon landing in 1969 was an early influence on his career.

"Like most kids in the 1960s, everyone gathered around to watch the broadcast in black and white. For a kid interested in science, this was the pinnacle of life," said Dr. Levine. "The space program always had a strong pull for me. I liked to think about the limits of human capacity and what could be."

That early interest led Dr. Levine into space research within the field of cardiology, and he began working with the space shuttle program in 1991.

"We put a catheter in an astronaut's heart - it was former UT Southwestern faculty member Dr. Drew Gaffney -- and sent him into space. It was probably the most expensive right-heart catheterization ever," Dr. Levine reminisced. "Much of our early research was devoted to understanding why astronauts faint when they return from space. Now, we can prevent it from happening."

A biologist at Louisiana State University conducted a pioneering research study that could help us to better understand the role of dopamine in stress resilience in humans through analyzing wild songbirds. This study could lead to increased prevention and treatment of stress-related disorders.

Dopamine is a chemical in the brain that is important for learning and memory. Department of Biological Sciences Assistant Professor Christine Lattin, and colleagues conducted this study of wild songbirds showing that dopamine is important in responding to chronic stressors, which can help wildlife conservation efforts in response to environmental stressors such as habitat destruction, natural disasters, extreme weather events and increases in predation.

Lattin, who is the lead author on the study published in Nature's Scientific Reports, applied a biomedical imaging technology called Positron Emission Tomography, or PET, scans that are used commonly on humans but rarely on wild animals to quantify dopamine receptors in house sparrows.

"This study is exciting because it is the first time PET scans have been used in wildlife to quantify dopamine receptors in the brain. Developing this technique has opened the door to being able to scan animals and release them back into the wild," she said. "We need to know how these wild birds are coping with stressors and responding to changes to the environment so we can understand how to best protect them."

In addition to the biomedical imaging, Lattin and colleagues tracked changes in the birds' body mass and hormone levels, and observed their behavior using a remotely operated video camera to study wild house sparrows' response to captivity over four weeks. The birds were scanned after being brought in to the lab and then again four weeks later. By using PET scans, they were able to study how the stress of captivity affected the birds over time.

They found that one type of dopamine receptor decreased over time during captivity, which suggests that birds became less resilient to stress over time. The greater the decrease in dopamine receptors, the more they exhibited anxiety-related behaviors such as feather ruffling. All of the wild birds also decreased body mass.

"These physiological, neurobiological and behavioral changes suggest that songbirds are not able to habituate to captivity, at least over short periods of time. It is very important that scientists studying stress in wildlife find more ways to study them in their natural habitat," Lattin said.

This research complies with all existing laws and regulations and the Ornithological Council's Guidelines for the Use of Wild Birds in Research.

Study finds chest X-rays contain 'hidden' information that can be harvested with artificial intelligence to predict long-term mortality

BOSTON - The most frequently performed imaging exam in medicine "the chest X-ray" holds 'hidden' prognostic information that can be harvested with artificial intelligence (AI), according to a study by scientists at Massachusetts General Hospital (MGH). The findings of this study, to be published in the July 19, 2019 issue of JAMA Network Open, could help to identify patients most likely to benefit from screening and preventive medicine for heart disease, lung cancer and other conditions.

AI technology automates many aspects of our daily lives, such as your smartphone's speech-recognition function, photo tagging on social media, and self-driving cars. AI is also responsible for major advances in medicine; for example, several groups have applied AI to automate diagnosis of chest X-rays for detection of pneumonia and tuberculosis.

If this technology can make diagnoses, asked radiologist Michael Lu, MD, MPH, could it also identify people at high risk for future heart attack, lung cancer, or death? Lu, who is director of research for the MGH Division of Cardiovascular Imaging and assistant professor of Radiology at Harvard Medical School, and his colleagues developed a convolutional neural network, a state-of-the-art AI tool for analyzing visual information, called CXR-risk. CXR-risk was trained by having the network analyze more than 85,000 chest X-rays from 42,000 subjects who took part in an earlier clinical trial. Each image was paired with a key piece of data: Did the person die over a 12-year period? The goal was for CXR-risk to learn the features or combinations of features on a chest X-ray image that best predict health and mortality.

Next, Lu and colleagues tested CXR-risk using chest X-rays for 16,000 patients from two earlier clinical trials. They found that 53% of people the neural network identified as "very high risk" died over 12 years, compared to fewer than 4% of those that CXR-risk labeled as "very low risk." The study found that CXR-risk provided information that predicts long-term mortality, independent of radiologists' readings of the x-rays and other factors, such as age and smoking status.

Lu believes this new tool will be even more accurate when combined with other risk factors, such as genetics and smoking status. Early identification of at-risk patients could get more into preventive and treatment programs. "This is a new way to extract prognostic information from everyday diagnostic tests," says Lu. "It's information that's already there that we're not using, that could improve people's health."

Bottom Line: An observational study of pregnant women in Northern California suggests marijuana use before and during pregnancy has increased over time. The study of nearly 277,000 women in Kaiser Permanente Northern California included 367,403 pregnancies from 2009 to 2017. The women reported marijuana use on questionnaires as part of standard prenatal care. The authors report marijuana use in the year before pregnancy increased from 6.8% of women in 2009 to 12.5% in 2017, and marijuana use during pregnancy increased from 1.95% to 3.38%. Daily use of marijuana in the year before pregnancy increased from 1.17% in 2009 to 3.05% in 2017, and daily use during pregnancy increased from 0.28% to 0.69%. A limitation of the study is that the results may not be generalizable to women outside of California or those without access to health care.

Authors: Kelly C. Young-Wolff, Ph.D., M.P.H., Kaiser Permanente Northern California, Oakland, and coauthors

(doi:10.1001/jamanetworkopen.2019.6471)

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.

PHILADELPHIA - Cells dispose of harmful "trash" through autophagy, a normal and necessary process in which aggregated proteins and dysfunctional structures are handled. If any part of this fails, waste builds up inside cells, eventually killing them. According to a new study from the Perelman School of Medicine at the University of Pennsylvania, as cells age, their ability to shed harmful refuse declines. The findings suggest that the deterioration of autophagy in aged neurons--cells that never replicate and are as old as the bodies they inhabit--could be a risk factor for a suite of neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis), Alzheimer's, and Parkinson's.

Using live-cell imaging of neurons from young and aged mice, Erika Holzbaur, PhD, a professor of Physiology, and first author Andrea Stavoe, PhD, a postdoctoral fellow in Holzbaur's lab, published their study this week in eLife. The importance of autophagy was recognized in 2016 with the Nobel Prize in Physiology or Medicine.

"The current thinking among scientists is that a decline in autophagy makes neurons more vulnerable to genetic or environmental risks," Holzbaur said. "What motivates our line of research is that most neurodegenerative diseases in which a deterioration of autophagy has been implicated, such as ALS, and Alzheimer's, Huntington's and Parkinson's diseases, are also disorders of aging,"

At the start of autophagy, a component within the cell, called an autophagosome, engulfs misfolded proteins or damaged structures to be degraded, essentially sequestering this waste in a biological trash bag. The autophagosome then fuses with a second cellular structure, called a lysosome, that contains the enzymes needed to breakdown the garbage, allowing the components to be recycled and reused. This elegant waste-removal stream is what keeps neurons healthy, but in its absence, neurons eventually die due to the buildup of unattended refuse.

"Think city streets during a sanitation workers strike," Stavoe said.

The team assessed rates of autophagy in mouse neurons during aging and identified a significant decrease in the number of autophagosomes produced, along with pronounced defects in the structure of autophagosomes produced by neurons from aged mice.

While early stages of autophagosome formation were unaffected, they found frequent stalling in their formation in aged mice, while the ones that did form were misshapen. These defects may allow the trash to accumulate at neuronal synapses. Stavoe notes that in other studies autophagosomes with misformed membranes have been observed in deceased human brain tissue from donors with neurodegenerative disease.

Importantly, turning on the protein WIPI2B in aged mice restores autophagosome formation in aged neurons, bringing the autophagy garbage-hauling process back online. This rescue is dependent on the level of activation of WIPI2B, providing insight into the biological regulation of autophagosome formation.

On the other hand, when researchers took WIPI2B out of young neurons, autophagosome formation stalled. "This stunning and complete rescue of autophagy using one protein suggests a novel therapeutic target for age-associated neurodegeneration," Stavoe said.

Healthcare in low- and middle-income countries is poorly prepared for the increasing number of high blood pressure (ie hypertension) disorders. More than two-thirds of all people affected go without treatment. Researchers led by the Harvard T.H. Chan School of Public Health, the University of Göttingen and the Medical Faculty of Heidelberg have discovered this. The study appeared in The Lancet.

The research team analysed the healthcare of hypertension in 44 countries of the Global South. Using a model known as "cascade methodology", they determined how well the health systems of the various countries are adapted. This method works like a stepped waterfall: a cascade of data shows step-by-step where patients are lost from health systems. First, the researchers determined how many people suffer from high blood pressure. Based on this, they determined how many of those patients were examined, diagnosed and treated each time. Finally, they analysed how many patients successfully controlled the disease with medication.

"Hypertension is already most prevalent in regions belonging to the Global South, particularly sub-Saharan Africa, as well as Central and South Asia," says Pascal Geldsetzer, postdoctoral research fellow at Harvard T.H. Chan School of Public Health and first author of the study. "Our study shows not only that care for hypertension in these countries is severely inadequate, but also where exactly patients are being lost in the treatment system."

The results: less than half of those affected are diagnosed with high blood pressure. Only 30 percent of these patients are treated and only one tenth have the disease under control. "High blood pressure can be treated relatively well and cheaply," says Sebastian Vollmer, Professor of Development Economics at the University of Göttingen. "Undiagnosed or untreated hypertension, on the other hand, is a considerable risk for the people affected and can lead to significant complications, including death." Till Bärnighausen, Professor of Global Health at Heidelberg University Hospital and Medical Faculty of Heidelberg, adds: "High blood pressure is already one of the major widespread diseases in the Global South and is becoming increasingly common as the populations in these countries age. This study provides important insights for policy-makers about where in the treatment chain for hypertension the greatest problems currently lie."

In order to improve the health systems of the countries concerned, the authors look at what worked in health systems that are managing to provide care. Costa Rica, Bangladesh, Brazil, Ecuador, Kyrgyzstan and Peru are good examples.