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May 4, 2020 -- A study at Columbia University Mailman School of Public Health found that long-term buprenorphine treatment is associated with improvements in health care outcomes. Compared to individuals who discontinued buprenorphine, those with continuous treatment had significantly lower rates of prescription opioid use and opioid-related events, including medically treated overdoses in the follow-up period. The results are published in the May issue of the journal Health Affairs.

"Buprenorphine is an effective medication for the treatment of opioid addiction, yet until now studies were not designed to establish a minimum duration of treatment for opioid use disorder needed to achieve improved clinical outcomes," said Hillary Samples, PhD, postdoctoral research fellow in the Department of Epidemiology, Columbia University Mailman School of Public Health. "As a result of limited evidence, health plans and care guidelines set potentially restrictive treatment standards."

The researchers analyzed health insurance claims data to compare patients with continuous buprenorphine treatment to those who discontinued 6-9 months after initiating medication with the goal of extending evidence from clinical trials, which are typically limited to 3 to 6-month periods. In addition, the National Quality Forum defines 180 days (6 months) as the minimum duration of pharmacotherapy for opioid use disorder treatment, and quality measures are often used by federal and state agencies or health plans to set treatment standards.

Compared to 4,433 adults who discontinued buprenorphine 6-9 months after beginning treatment, individuals with continuous treatment had significantly lower risk of all-cause inpatient (?52%) and emergency department (?26%) services, opioid-related hospital services (?128%), overdose events (?173%), and opioid prescriptions (?120%) as well as a significantly lower rate of prescription opioid use (?124%) in the follow-up period than in the treatment period.

The greatest decreases were found for overdose events, opioid-related inpatient and emergency department services and prescription opioids use. "The pattern of results indicates that longer-term buprenorphine treatment more effectively protects patients from adverse clinical outcomes," said Samples.

"Overall, our findings suggest a need for broader efforts to increase long-term access to care and extend standards and guidelines for minimum treatment duration," noted Samples. "While guidelines can lead to improvements in care and patient outcomes, they can also have unintended consequences, such as forming the basis for managed care practices that limit access to longer-term treatment."

Heart disease patients taking evolocumab in addition to a statin to achieve extremely low levels of cholesterol do not show increased incidence of neurocognitive impairments, including memory loss or reduction in executive functions (mental skills), while at the same time have a decrease in recurrent cardiovascular events such as stroke and heart attack, according to a study published in the Journal of the American College of Cardiology that examined the cognitive function of the entire FOURIER cohort at two years.

Statins are used to reduce low-density lipoprotein cholesterol (LDL-C), or bad cholesterol, and prevent heart disease and stroke. However, some high-risk patients need to take PCSK9 inhibitors combined with a maximally tolerated statin or other lipid-lowering therapies to reduce their LDL-C even more. While prior research has shown that heart disease patients do not experience adverse neurocognitive effects when taking PCSK9 inhibitors with statin to treat bad cholesterol, until now there has not been a large-scale trial to investigate the impact of using evolocumab and statin to achieve very low LDL-C levels on patient-reported cognition.

Researchers in this study looked at the self-reported Everyday Cognition study results from 22,655 patients in the original FOURIER trial, which was completed after a median duration of 2.2 years. The percentage of patients who reported cognitive decline at the end of the study was similar for placebo vs. those taking evolocumab, both for total score 3.6% vs. 3.7%, respectively, and for subdomains (memory 5.8% vs. 6% and total executive function 3.6% vs. 3.7%, respectively). The proportion reporting cognitive decline was similar in patients who achieved very low LDL-C levels (

"These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab, while simultaneously reducing recurrent cardiovascular events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients," said Robert P. Giugliano, MD, SM, corresponding author of the study and senior investigator of the TIMI Study Group at Brigham, Women's Hospital and Professor of Medicine at Harvard Medical School in Boston.

The patient-reported outcomes of this comprehensive study in over 22,000 patients build upon the results of the EBBINGHAUS trial, which demonstrated evolocumab added to background statin did not affect cognitive performances using a validated battery of neurocognitive tests performed serially in a subset of 1,204 patients enrolled in the FOURIER trial.

FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and LDL-C levels ≥70 mg/dL despite statin. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition scale.

This study has several limitations, including a healthy volunteer bias in the cognitive survey responders, the relatively younger age of the participants, and the low proportion of patients with a history of stroke.

"It is unclear if this expectation of safety can be extrapolated to periods of greater than three years, or to patients who are older than 75 years, are at very high ASCVD risk, or with a history of ischemic or hemorrhagic stroke," said Jennifer G. Robinson, MD, MPH, professor of epidemiology and medicine at the University of Iowa, in an accompanying editorial. "An altered safety profile may influence the potential for a net cardiovascular risk reduction benefit from the addition of PCSK9 mAbs. Longer follow-up and more diverse trial populations are needed."

PITTSBURGH, May 4, 2020 - It's no secret that America has an ever-worsening drug addiction problem, but how much does a person's birth year come into play?

Researchers at the University of Pittsburgh Graduate School of Public Health show that the generation a person was born into -- Silent Generation, Baby Boomer, Generation X or Millennial -- strongly predicts how likely they are to die from a drug overdose, and at what age. These results appear today in Nature Medicine.

"Sociological imprinting marks a person born in a given time," said senior author Donald Burke, M.D., who holds the Jonas Salk Chair of Population Health and is dean emeritus of Pitt Public Health. "It reflects attitudes they encountered right at the time of adolescence, and attitudes about drug use -- those stay for a lifetime."

Up until now, research into the demographics of drug use has focused more on age, finding that midlife is the riskiest time for drug-related death, but Burke and colleagues saw that the year a person was born also has a large effect.

For the study, lead author Hawre Jalal, Ph.D., assistant professor of health policy and management at Pitt Public Health, analyzed 661,565 drug overdose deaths reported by the Centers for Disease Control and Prevention from 1979 to 2017, plotting death rate as a function of both age and either birth year or generation.

The data clearly showed that the overdose epidemic emerged abruptly among the Baby Boomers, shifted youth-ward for Generation X, and then soared to new heights among the Millennials. These phases map onto the previously identified drug waves that came with the waxing and waning popularity of prescription opioids, heroin and fentanyl, each in turn.

Peering within each generation, Jalal and colleagues saw a steady march toward greater overdose risk at younger ages for each successive birth year, which they found quite surprising.

"There's no reason why the lines should be fanning like this," Jalal said. "If you look at breast cancer, for example, or any other mortality curves, they don't look like that."

It's not clear why this is happening, Jalal said, but the pattern is too clean to chalk up to chance. And an overall rise in drug overdose deaths -- although that is happening in the background of these data -- does not explain away the results presented in this study.

Burke uses an analogy borrowed from infectious diseases to explain the progressive shift of drug overdose deaths to younger ages.

"There is an epidemic going on. And just like an infectious disease, there is a transmission," said Burke, also a professor in Pitt Public Health's Department of Epidemiology. "In this case, it propagates from older to younger age groups."

Burke hopes that the highly regular patterns uncovered in this analysis will give policy makers a tool for testing whether their measures to curb drug overdose deaths are working over the long term -- any effective intervention should disrupt the pattern.

What The Viewpoint Says: Changes in ophthalmology practices after the COVID-19 pandemic are discussed in this article.

Authors: David W. Parke II, M.D., of the American Academy of Ophthalmology in San Francisco, is the author.

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

(doi:10.1001/jamaophthalmol.2020.2004)

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

They know it's addictive. They know it's linked to dangerous and even fatal lung diseases. And they know it delivers far more nicotine than the cigarettes it's supposed to replace.

But the social aspects of vaping drives young people to use Juul and other e-cigarettes, according to nearly two-thirds of teens and young adults in a new study. Less than 5% say the availability of fruity flavors drives use of e-cigarettes by members of their generation, and only 10% say that addiction does.

The findings, published in a research letter in JAMA Pediatrics, come from a text-message-based survey of teens and young adults between the ages of 14 and 24 conducted by the University of Michigan's MyVoice study.

The survey was conducted before the 2019 epidemic of vaping-associated lung injury, and long before suggestions that COVID-19 might pose a greater risk to people who smoke or vape. It was also conducted before the federal ban on sales of all vaping products to people under the age of 21, and on the sale of fruit-flavored vaping pods, but not vaping liquids.

But it still sheds light on what kinds of messaging and interventions might be needed to reduce e-cigarette use in in youths, says senior author Tammy Chang, M.D., M.P.H., M.S., an assistant professor of family medicine at Michigan Medicine, U-M's academic medical center.

"It's not just about the flavors, it's about understanding the motivations for using these products, and their attitudes toward risk," says Chang, a member of the U-M Institute for Healthcare Policy and Innovation. "They're more savvy than we think they are, and they're using it because it's about being cool and about the experimentation that happens naturally in adolescence. Reducing teen and young adult use of these products, especially under current policies, will require an evidence-based approach."

Assessing knowledge and attitudes

The survey used "juuling" as the term for the activity of using Juul and other e-cigarettes. It asked a nationally representative sample of teens and young adults four questions, and allowed them to answer however they liked. In all, 1,129 young people answered - 92% of those who have volunteered to receive occasional text surveys from the MyVoice study.

In all, 79% of the respondents said they think juuling is dangerous, and another 7% said it might be. Nearly 72% believe it can lead to use of other substances, including cigarettes and other drugs, and one in four of the rest of the respondents said that people who juul already use other substances.

Georgia Wood, the lead author and undergraduate student at U-M, said: "These findings are critically important because it describes the lived experiences of youth related to Juul, which has been missing. This is the kind of information we need to create policies and programs that work. Youth are depending on us to do that."

"For policymakers and public health officials who want to focus prevention and cessation messages on the health risks, or who think that bans on flavors will be the answer, these data show that ship has sailed," says Chang. "We need to use what we now know about what drives youth behavior, and put teeth behind the enforcement of sales bans as we have with alcohol."

Chang notes that other research has shown that vaping spiked among young people in the past few years, just as smoking of cigarettes had gone down to record low levels. "The message about the dangers of smoking tobacco was just getting through, and then vaping came along and we may now have a whole new generation addicted to nicotine," she says.

Younger vs. older youths

The study broke respondents up by age group. While 14- to 17-year olds were somewhat more likely to have heard of Juul, 84% of the 18-24-year-olds also had heard of it. Young respondents were also somewhat more likely to say that social factors were the main reason that people their age use e-cigarettes, but 58% of older respondents also said this.

The two age groups were about the same in their perceptions of danger from vaping, including nicotine intake, physical health effects and addiction. The same was true for their opinions about whether vaping leads to use of other substances.

Chang notes that more research needs to be done on how to help young people cut down on or stop using e-cigarettes, especially given the fact that nicotine replacement products like gums and patches are not approved for people under 18. In the meantime, young people can talk to health providers about whether those products are right for them.

Future directions

More research is needed on the effects of bans on sales of vaping products to people under 21, and sales of flavored pods, Chang says -- as well as on the effect of the COVID-19 pandemic on access to vape shops that sell the bulk liquids used in non-pod devices. So is more research on patterns of cigarette use by young people, after these changes, she adds.

Meanwhile, enforcement of those new rules will become more important, she says.

"As a society, we need to do the baseline job of cutting back on the potential supply of nicotine in all its forms to young people, while allowing adults who use vaping as a means of reducing cigarette use to continue to have access," she says. "We need to focus on penalizing those who sell these products to people under 21, in any setting and any form, so that we can keep an addictive drug out of the hands of adolescents who are naturally seeking to experiment as part of their development."

At the same time, vaping-related messaging to young people as early as middle school should focus on social factors, Chang says. This could include positive identity development that focuses on individual strengths instead of the need to be cool or belong to a social group that emphasizes vaping.

"We need to start our conversations with youth from this perspective - and start it early," she says.

Verticillium wilt among olive trees is one of the most devastating diseases for olive trees and one of the main plant health problems in the olive sector. The disease is caused by a fungus called Verticillium dahliae that is in infected soils, takes over root systems and blocks the vascular systems until the plant dies. These effects produced by the disease are similar to those of a severe drought.

An article published by the University of Cordoba, the University of Valencia and the Institute of Sustainable Agriculture of the Spanish National Research Council demonstrated that the infection, for which there is no effective cure, is much more complex than previously assumed. The study looked into the dynamics of the microbiome of infected roots and concluded that the infection process involves many more participants: although the disease is controlled by the verticillium fungus initially, it is not carried out by one sole species, but rather by a community of microorganisms that attack the tree.

As pointed out by researcher Antonio Rodríguez Franco from the Department of Biochemistry and Molecular Biology at the University of Cordoba, the results suggest that olive tree withering caused by Verticillium wilt "should be understood as a biological process of systems in which complex interactions take place."

According to the research results, there are several open fronts in this microscopic war declared by Verticillium but fought by other organisms as well.

Several kinds of fungi, bacteria and protozoa work in partnership in order to attack the tree. Also coming into play is an array of opportunistic microbes, such as nematodes and amebas, that though they do not participate in the infection initially, they feed off of substances that help defend the olive tree to counter the attack. Lastly, beneficial fungi that up to that point had a symbiotic relationship with the tree's roots, change sides and become harmful to the plant.

Broadly speaking, these are the dynamics in the battle, whose final result is the wilting of thousands of olive trees in the Mediterranean basin. All this has been explained in detail after analyzing RNA samples and performing a metatranscriptomic study of different samples.

The results, as pointed out by the author, could contribute to focusing future treatment on alleviating a disease that has increased over the past few years due to intense planting in infected soils. As for now, however, there are still many questions to be answered, such as how genes are involved in the plant's defense processes and why some olive tree species are immune to infection.

PHILADELPHIA - Activating the G protein-coupled estrogen receptor (GPER) - a receptor found on the surface of many normal and cancer tissues - has been shown to stop pancreatic cancer from growing, but may also make tumors more visible to the immune system and thus more susceptible to modern immunotherapy. Researchers at the Perelman School of Medicine at the University of Pennsylvania and Penn's Abramson Cancer Center observed the effects of GPER activation in human and mouse pancreatic cancer models and published their findings in Cellular and Molecular Gastroenterology and Hepatology today.

For most cancer types, including pancreas, women generally have better outcomes than men. Although the reasons for this are only now emerging, researchers have known for decades that there is a link between the body's sex hormones and some types of cancer, especially those arising in reproductive tissues such as breast and prostate. However, the idea that cancers in non-reproductive tissues might also be influenced by sex steroid hormones has only recently been considered.

Building on their research showing the anti-cancer activity of GPER in melanoma models, Todd W. Ridky, MD, PhD, an assistant professor of Dermatology at Penn and the study's senior author, and his lab, examined whether GPER activators may also inhibit other cancer types.

"We know that activating GPER in melanoma models stops the growth of cancer cells and make the tumors themselves more immunogenic, so we wanted to find out what would happen if we selectively activated GPER other tumor types. In this study we examined several pancreatic cancer models and found that synthetic small molecule GPER activators potently inhibited pancreatic cancer cells, and simultaneously rendered the tumor cells more sensitive to other anti-cancer therapies," Ridky said.

For this study, the Ridky lab worked with the Penn Pancreatic Cancer Research Center (PCRC), directed by study co-author Ben Z. Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research. Using new PCRC mouse pancreatic cancer models, the multidisciplinary team was able to show GPER's impact on pancreatic cancer growth. In some models, GPER activation inhibited growth and made tumors more sensitive to anti-PD-1 immunotherapy, pointing to the translational potential of improving the efficacy of existing treatments in a cancer type where PD-1 inhibitors have not historically been very effective.

The use of GPER activators is a novel idea in cancer therapy, and has a key difference from most anti-cancer agents. Nearly all current cancer drugs act to block the activity of cellular proteins that are needed by not only the cancer cells, but also by normal cells. As a result, most cancer drugs are associated with major toxicity. In contrast, the estrogenic analog used in the Penn study activates GPER. This approach mirrors something that naturally occurs in the body, as GPER is already present and normally activated by estrogen, especially in females during pregnancy.

"Likely because this is something the human body is already accustomed to, evidence from preclinical animal studies suggested that side effects to this approach would likely be minimal when this moves into the clinic," said the study's first author Christopher Natale, Ph.D., Ridky's former graduate student.

Natale is currently the Vice President of Research at Linnaeus Therapeutics, a company he and Ridky co-founded to further investigate the translational potential of this work. A multi-site Phase I trial in patients with advanced cancer is currently ongoing.

COLUMBUS, Ohio - A new statement issued today by the American Heart Association emphasizes the importance of taking a multidisciplinary approach to the management of cardiovascular disease during pregnancy and outlines heart care before, during and after pregnancy.

Dr. Laxmi Mehta, a cardiologist at The Ohio State University Wexner Medical Center, chaired the statement, which described how cardio-obstetrics has become an important team in managing heart-related problems during pregnancy. The number of pregnancy-related deaths in the United States has more than doubled over the last two decades and the main cause is cardiovascular disease, according to the American Heart Association. Pre-existing conditions such as diabetes and high blood pressure have contributed to the increased rate of death as well as advanced maternal age, which is associated with pre-term birth, preeclampsia and chronic hypertension.

"Maternal mortality is on the rise, and the need is greater than ever for a cardio-obstetrics program like here at The Ohio State University Wexner Medical Center. These pregnancy heart teams comprehensively manage cardiovascular disease during pregnancy and ultimately help reduce pregnancy-related deaths," said Mehta, who is director of Preventative Cardiology and Women's Cardiovascular Health at the Wexner Medical Center.

A cardio-obstetrics team is often comprised of obstetricians, cardiologists, anesthesiologists, maternal fetal medicine specialists, geneticists, nurses and pharmacists who work together to develop a comprehensive approach for managing cardiovascular disease prior to, during pregnancy, delivery and postpartum. The authors said preconception counseling by the cardio-obstetrics team is essential for women with pre-existing cardiac conditions or a history of preeclampsia, which is characterized by high blood pressure starting after 20 weeks of pregnancy.

"Being pregnant can put a lot of stress on the body, especially the heart," Mehta said. "During the first trimester of a normal pregnancy, the heart rate increases and blood pressure decreases. In the second and third trimesters, the heart rate and blood pressure increase and don't decrease until after birth. For those with certain cardiovascular diseases, these up-and-down swings can be dangerous."

Mehta and the other authors outlined medical conditions in pregnancy and recommendations for medication and care. Hypertensive disorders are the most common and include preeclampsia, gestational hypertension, chronic hypertension and chronic hypertension with superimposed preeclampsia. The authors noted that women who develop preeclampsia have a 71 percent increased risk of cardiovascular death, are 2 ½ times more at risk of coronary artery disease and four times more at risk of heart failure during their lifetime.

Other medical conditions addressed in the statement included ischemic heart disease, arrhythmias, aortic disease, deep venous thrombosis, pulmonary embolism and valvular heart disease.

"A lot of women are unaware that having any of these issues during pregnancy puts them at a higher risk of developing heart disease in the future, and it may surface years down the road," Mehta said. "That's why it's so important for women with pregnancy-related heart disease to continue to see a cardiologist regularly after they've delivered their baby."

When it comes to labor and delivery, the authors recommended most women with cardiovascular disease have vaginal births instead of cesarean sections unless there are obstetric problems such as breech presentation, fetal heart rate abnormalities or failure to progress to labor. They noted that the cardio-obstetrics team formulates delivery plans in women with high risk conditions on a case-by-case basis.

"General understanding of cardiovascular disease during pregnancy should be a core knowledge area for all cardiovascular and primary care clinicians," Mehta said. "Involvement of the cardio-obstetrics team from pre-conception to postpartum care is critical because these experts working together can help identify ways to prevent maternal morbidity and mortality. Additionally, clinicians and women should be aware of elevated lifetime risks of cardiovascular disease in women who have adverse pregnancy outcomes like preeclampsia."

The American College of Cardiology together with other North American cardiovascular societies has issued a framework for ethically and safely reintroducing invasive cardiovascular procedures and diagnostic tests after the initial peak of the COVID-19 pandemic. The document was published today in the Journal of the American College of Cardiology.

The COVID-19 pandemic has forced appropriate, but significant, restrictions on routine medical care, including invasive procedures to treat heart disease and diagnostic tests to diagnose heart disease. Many hospitals and practices have attempted to defer and replace these critical procedures with intensified triage and management of patients on waiting lists; however, many patients with untreated cardiovascular disease are at an increased risk of adverse outcomes, and delays in the treatment of patients with confirmed cardiovascular disease can be detrimental. Also, reduced access to diagnostic testing can lead to a high burden of undiagnosed cardiovascular disease that will further delay time to treatment.

Cardiovascular disease is the leading cause of death in women and men worldwide and these patients need prioritization as health care systems return to normal capacity. In this document, North American cardiovascular societies outline how to reintroduce regular cardiovascular care in a progressive manner with appropriate safeguards.

The authors have outlined three areas that must be considered when reintroducing services, including:

Ethical considerations that include maximizing benefits by prioritizing procedures that will ensure the most lives or life years are saved over those that benefit fewer people to a lesser degree, ensuring fairness in how cases are treated, ensuing proportionality so that the risk of further postponing treatment is weighed again exacerbating the spread, and maintaining consistency in reintroduction across populations regardless of ability to pay and assuring health equity.

Collaboration between regional public health officials, health authorities and cardiovascular care providers to manage the dynamic balance between provision of essential cardiovascular care and responding to future fluctuations in COVID-19 infections and hospital admissions.

Protection of patients and health care workers through regions having the necessary critical care capacity, personal protective equipment (PPE), and trained staff available, and a transparent plan for testing and re-testing potential patients and health care workers for COVID-19. Strategies for social distancing between patients and health care workers should also be considered, including virtual pre-procedural clinics, virtual consenting for procedures and diagnostic tests, and minimizing the number of health care workers in physical contact with any given patient.

"Unprecedented times call for unprecedented collaboration, and a collaborative approach will be essential to mitigate the ongoing morbidity and mortality associated with untreated cardiovascular disease," said Athena Poppas, MD, FACC, ACC president and one of the authors on the document. "It is essential that we work together to ensure cardiovascular disease patients are safely cared for during this pandemic and that we don't allow for a new crisis of undiagnosed, untreated or worsening cardiovascular disease to occur in the aftermath of this pandemic."

BOSTON - (May 1, 2020) - Excess white fat causes obesity, which in turn can drive diabetes and many other metabolic diseases that are growing at epidemic rates around the world. But all white fat is not born equal. For instance, "intra-abdominal" fat, i.e. fat within the belly, is known to carry higher risks of disease than "subcutaneous" fat that sits under the skin and often accumulates in the hips and thighs. Researchers from Joslin Diabetes Center and Boston University now have discovered different types of white fat cells, even within a single site, that may play distinct roles in disease.

"A central question in our research on metabolic disease is whether white fat cells in different parts of the body, and even within a single part of the body, are different enough that some might predispose you to disease and some might not," says C. Ronald Kahn, MD, Joslin's Chief Academic Officer and Head of the Section on Integrative Physiology and Metabolism. "If so, determining the mechanisms for these differences could lead to development of novel therapies for diabetes, obesity and related conditions."

Earlier studies had identified several types of white fat cells in mice, but this is one of the first to discover multiple types in humans, says Kahn, who is co-senior author on a Nature Communications paper presenting the work and professor at Harvard Medical School.

Within fat tissue, fat cells evolve from "preadipocytes" or precursor cells to mature cells. As they do, their patterns of gene expression change. A technique called single-cell RNA sequencing examines these expression patterns on a cell-by-cell basis, offering an extremely detailed look at how the patterns vary between cells.

The collaboration between Joslin and Boston University began with two sets of single-cell RNA sequencing data on human subcutaneous white fat preadipocytes that progressed into mature stages in culture. Gathered from healthy humans, one data set was collected by scientists at the Broad Institute of Harvard and MIT and the other by the lab of Joslin's Yu-Hua Tseng, PhD.

Simon Kasif, PhD, Boston University professor of biomedical engineering and co-senior author on the paper, then led an integrated analysis of both data sets with a novel mathematical approach to understanding the patterns of gene expression in these cells.

The analysis identified two subtypes of human white subcutaneous fat that displayed quite distinct patterns of gene expression. Among the distinctions, one subtype showed patterns indicating much higher intake of glucose, a crucial resource in metabolism.

Additionally, the investigators found that "zinc nuclear finger" genes, a group of master regulator genes whose function in fat cells is not well understood, were expressed at much higher levels in one class of preadipocytes. This expression may help to control whether the cells become mature fat cells, the scientists suggested.

"We think this research is the tip of the iceberg--if we study more samples of human fat, we will find more subtypes," says Kahn. It would be very helpful, for instance, to examine samples of intra-abdominal fat and fat from people with various metabolic conditions. Broadening the research into white fat cell types would aid in connecting various patterns of obesity with the risks and mechanisms of metabolic disease, he says.

"Body fat is linked to many different conditions beyond diabetes," Kahn emphasizes. "This research could be important for understanding the risk factors for other metabolic diseases such as fatty liver disease and atherosclerosis, and even non-metabolic diseases that are increased by obesity, such as cancer and Alzheimer's disease."

"The study highlights the potential of bringing interdisciplinary expertise from four laboratories to integrate biology, artificial intelligence, systems biology and data obtained from clinical samples to catalyze discovery," says Kasif.

"Metabolic diseases are highly associated with environmental factors," Kasif adds. "This work supports the relatively understudied hypothesis that environmental factors may modify the trajectory of how cells develop and our understanding of how this process may influence biology and metabolic disease."

MADISON, Wis. -- Precision medicine has the potential to tailor treatments to a patient's unique genetic sequence. But achieving this precision -- or developing new drugs -- requires knowing which genes are involved in disease.

"Unfortunately, we don't really have a good understanding of how these genetic differences can derive differences in traits, whether that's cholesterol or obesity," says Brian Parks, a professor of nutritional sciences at the University of Wisconsin-Madison.

To overcome these limitations, Parks and his collaborators have developed a new method that can pluck previously unknown genes out of the dark. By combining the fine-grained detail available from animal studies with the statistical power of genetic studies involving hundreds of thousands of human genomes, researchers have discovered a new gene involved in regulating the body's cholesterol.

The work provides a new target for understanding the genetic risk of high cholesterol, which is linked to heart disease. Just as important, the study provides a new way to reveal how genetic variation underlies a number of human diseases, which is the first step toward treating them.

Parks and his team members at other universities recently published their findings in the journal Cell Metabolism. The newly identified gene, Sestrin1, regulates cholesterol levels by shutting off cholesterol production in the liver when food provides enough of the essential nutrient.

Key to their findings was the relative strengths of animal and human studies. Parks' team could use mouse livers to investigate genetic networks involved in cholesterol synthesis, providing data that is rarely available in humans. They identified 112 genes linked to known cholesterol genetic networks.

Then, the researchers looked to see which of those 112 genes overlapped with potential cholesterol-linked DNA sequences in humans. The human data came from enormous genetic studies that amass health data to try to find a link between genes and disease.

"We can do these very large studies in humans of 500,000 people, and we can identify regions of the genome that are associated with, say, differences in blood cholesterol," says Parks. "But that just gives us kind of a lamppost to shine a light. It doesn't tell us what underlying gene or pathway is potentially contributing to that association."

Of the 112 genes they started with, 54 had ties to human data. "And most of them are well-known to be involved in cholesterol or liquid metabolism. But we were interested in the ones that were unknown," says Parks.

Twenty-five of those genes had not been previously linked to cholesterol levels in humans, which made them potential new targets. Parks' team studied those 25 genes in mouse models and compared them with fresh batches of human genomic data. Sestrin1 stood out.

The gene had never before been associated with cholesterol, but the research team found that Sestrin1 helps regulate cholesterol levels in the blood. It promotes cholesterol synthesis until it is shut off by cholesterol from the diet. Mice missing the gene were unable to regulate cholesterol levels properly. They developed high cholesterol when consuming diets containing normal levels of cholesterol because their livers didn't respond properly.

The researchers say they had an advantage investigating cholesterol, which is primarily controlled by just one tissue, the liver. But their method combining mouse and human data has the potential to help uncover other, previously unknown genes -- a huge help for understanding and treating diseases.

"The possibility certainly exists to extend this technique to other traits like obesity," says Parks.

As the number of coronavirus cases continues to rise and the deaths mount, the American Society for Artificial Internal Organs (ASAIO) has drafted a set of recommendations for health care workers on the front lines, to help them make decisions on how to treat the most critical patients, those with severe lung or heart failure

"An urgent need exists to enhance our understanding of the roles of extracorporeal membrane oxygenation (ECMO) and other types of artificial lung and heart support in the management of severely ill patients with COVID-19 who develop acute respiratory, and less commonly cardiac, compromise untreatable by conventional therapy," reports lead author Dr. Keshava Rajagopal, professor of clinical sciences at the University of Houston College of Medicine, in both Circulation: Heart Failure and ASAIO Journal. Dr. Faisal Cheema, associate professor of clinical sciences, is a co-author on the paper.

ECMO circuits contain a pump and a gas exchanger and can be used to support the lungs and/or heart, depending upon the way in which the circuitry is connected to a patient.

Because the coronavirus pandemic emerged and spread so quickly, clinical unknowns exist of when to apply such drastic measures.

"It is not known when it is clinically appropriate to use the most advanced forms of lung and heart support for COVID-related respiratory and heart failure and so we discuss this in terms of non-COVID usage," said Rajagopal, who said these decisions are critical in a resource-scarce environment.

The more advanced the therapy, generally the less of it exists in supply. How to deploy the scarcest of resources under pandemic circumstances is not well defined. The new guidelines recommend that a critical consideration in deciding when to deploy ECMO and other types of artificial lung/heart support, and even lesser therapies such as mechanical ventilation, is to assess whether the patient has a good likelihood of recovery.

"In a pandemic we have to decide how to allocate limited resources, and the first two questions that need to be asked are: One, is the patient sick enough to warrant the therapy, and two, is the patient well enough to tolerate the risks of the therapy? Next, we have to determine if the supply of the resource sufficient at the given time," said Rajagopal, who compares what could happen with the most advanced therapies, supply wise, to what has already happened with ventilators in some hospitals.

The recommendations call for non-invasive therapies first, such as continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) for short durations. Once a patient fails these and requires invasive mechanical ventilation (MV), then other recommendations are:

Whenever feasible, all patients with severe hypoxemic respiratory failure with COVID-19 ARDS should undergo either manual or artificial prone-positioning, depending upon the resources available.

Lung-protective mechanical ventilation (MV) should be used in patients with COVID-19-related acute hypoxemic respiratory failure.

The decision to implement ECMO should follow a clear failure of invasive MV, paralytic agents and prone positioning.

Because little has been written about the protocol doctors must take when treating the serious or critical COVID-19 patients, the recommendations will be updated.

"We call this a living, working document because we are still getting information and we intend to republish a final version and second paper once we have more experience from around the world," said Rajagopal.

The immune responses of a female mouse before pregnancy can predict how likely her offspring are to have behavioral deficits if the immune system is activated during pregnancy, according to researchers from the Center for Neuroscience at the University of California, Davis. The findings, published April 23 in the journal Brain, Behavior, and Immunity, could help resolve what role serious infections during pregnancy play in the later development of conditions such as autism and schizophrenia in offspring.

Both genetics and a variety of environmental risk factors are thought to play a role in mental illness, said Professor Kim McAllister, director of the Center for Neuroscience and senior author on the paper. Most pregnancies are resilient, she said. Although the risk from maternal immune activation is low, it could provide a way in to the underlying problems that lead to schizophrenia or autism.

"We don't have a good handle on what causes these diseases," she said. "But, maternal infection is a risk factor that we know contributes. So, our research focuses on how to predict which pregnancies are at risk and discover new ways to intervene and prevent disease in offspring."

The first evidence for a role for maternal infection in mental and developmental disorders came from the influenza epidemic of 1918, McAllister said. Epidemiological studies 15 to 20 years later of children who were in gestation at the time showed an increase in these disorders. Other evidence comes from animal studies.

Mouse model of immune activation

Apart from influenza, a wide variety of viruses and bacteria have been implicated in maternal immune activation. So the effect is more likely due to the mother's reaction to infections than with the infectious organism itself.

To reproduce this in mice, McAllister's team doses pregnant mice with a molecule called polyinosinic:polycytidylic acid, or poly (I:C), which is double-stranded RNA, the genetic material for many viruses including influenza and coronaviruses. The immune system recognizes poly (I:C) as if it were a virus and triggers an immediate inflammatory response, especially releasing a molecule called interleukin-6, or IL-6.

The mice continue with pregnancy and when the offspring are about 2 months old, the researchers test them for behavioral abnormalities, such as repetitive behaviors or freezing in place.

One of the advantages of working with laboratory mice is that they are bred so that they are genetically very similar. That makes it easier to see the effect of particular genes or environmental risk factors.

But when graduate student Myka Estes tried to treat laboratory mice with poly (I:C), she found to her surprise that their responses varied widely, even though the mice were all of the same age and genetic background, housed in the same cages in the same conditions.

Professor Judy Van de Water, an immunologist at the UC Davis School of Medicine and part of Estes' thesis committee, suggested looking at baseline immune reactivity in the mice before they became pregnant.

When they did that, the team found that the IL-6 response of a particular mouse to poly (I:C) before it became pregnant could predict the likelihood of behavioral problems in offspring if the mouse were treated with poly (I:C) later during pregnancy.

"People assume that their mice are all the same, but there is clearly a wide range of baseline immunoreactivity," McAllister said. That baseline immunoreactivity turns out to predict resilience or susceptibility to immune activation during pregnancy.

"We can dose them with poly (I:C) and look at the IL-6 response and predict which ones will have affected offspring if we treat them during pregnancy," she said.

Basic mechanisms and biomarkers

That has a couple of important implications. Firstly, with a reliable model for resilience and susceptibility, researchers can start to work out what genes and proteins involved in brain development are affected by immune activation and how this could lead to neurodevelopmental disorders.

"The next steps are to figure out what it is that is different about those mice," McAllister said. "Now that we can predict which mice are at risk, we want to determine how specific patterns of immune signaling in the mom cause distinct outcomes in offspring. We are hoping to figure out how maternal infection can lead to no problem in many pregnancies and to a range of distinct diseases in offspring from other pregnancies."

Secondly, it could lead to biomarkers for identifying pregnancies at higher risk from infections and taking steps to protect mothers by vaccination or treatment. That will likely involve further work in mice followed up with experiments in nonhuman primates before moving into human studies.

Washington, DC - May 4, 2020 - Korean researchers have screened 48 FDA-approved drugs against SARS-CoV-2, and found that two, that are already FDA-approved for other illnesses, seem promising. The FDA approval for other uses would greatly reduce the time needed to gain FDA approval of use in COVID-19. The research is published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

The investigators tested the drugs in Vero cells, a cell line developed from kidney cells of the African Green Monkey, which are commonly used to grow viruses for vaccine production.

An anti-helminthic drug called niclosamide demonstrated "very potent" antiviral activity against SARS-CoV-2, according to coauthors Sangeun Jeon, Meehyun Ko, and their collaborators, of the Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam, Korea. "Not surprisingly, its broad-spectrum antiviral effect has been well documented in the literature, including antiviral properties against SARS- and MERS-CoV," they write.

A downside of niclosamide is low absorption, which undercuts the drug's power by reducing the dose that reaches the target tissue. However, "Further development or drug formulation could enable an effective delivery of this drug to the target tissue," according to the report.

Despite substantially lower antiviral potency, ciclesonide, an inhaled corticosteroid used to treat asthma and allergic rhinitis, also showed promise against SARS-CoV-2. Intriguingly, the investigators note that a study published earlier this year ( by Matsuyama et al.) a treatment report of 3 patients infected by SARS-CoV-2, demonstrated antiviral activity and revealed the drug's molecular target to be a viral protein called Nsp15.

"With its proven anti-inflammatory activity, ciclesonide may represent as a potent drug which can manifest [the] dual roles [of antiviral and anti-inflammatory] for the control of SARS-CoV-2 infection," the investigators conclude. The anti-inflammatory activity might play a critical role in dampening or preventing the cytokine storms, an immune inflammatory overreaction that can kill COVID-19 patients.

Many worry strenuous exercise could hurt their joints

10 years of vigorous activity did not pose risk

Strenuous activity for one to two hours weekly reduces risk of knee osteoarthritis by 30%

Osteoarthritis affects 32.5 million adults in U.S.

CHICAGO---People at high risk for knee osteoarthritis (OA) may be nervous and reluctant to participate in strenuous physical activities such as jogging, cycling, singles tennis and skiing. But a new Northwestern Medicine study that followed high-risk individuals for 10 years showed vigorous exercise did not increase their risk of developing OA and may even protect them from it.

"Our study findings convey a reassuring message that adults at high risk for knee OA may safely engage in long-term strenuous physical activity at a moderate level to improve their general health and well-being," said Alison Chang, associate professor of physical therapy and human movement sciences at Northwestern University Feinberg School of Medicine.

The study will be published in JAMA Network Open May 4.

Osteoarthritis is the most common joint disorder in the United States, affecting an estimated 32.5 million adults, according to the Centers for Disease Control. The knee is the most commonly affected joint. The lifetime risk of developing symptomatic, radiographic knee OA (as diagnosed on an x-ray) is approximately 38% to 45%. The estimated median age of diagnosis is 55 years.

In this observational study of 1,194 persons at high risk for but without radiographic evidence of knee OA who were followed for up to 10 years, long-term participation in strenuous physical activities was not associated with risk of developing radiographic knee OA. In fact, the vigorously exercising individuals in the study were 30% less likely to develop OA, although the number was not considered statistically significant.

The activities included jogging, swimming, cycling, singles tennis, aerobic dance and skiing. Persistent extensive sitting was not associated with either elevated or reduced risk.

Excessive body weight, history of joint injury or surgery, aging and chronic knee symptoms place an individual at elevated risk for developing knee OA. Although regular physical activity and exercise provide multiple health benefits, uncertainty about whether vigorous physical activity participation could cause pain and further tissue damage is a common concern. The researchers' analysis showed nearly 50% of the adults at high risk for this disease did not engage in any strenuous physical activity over eight years.

"People suffering from knee injuries or who had arthroscopic surgical repair of ACL or meniscus are often warned that they are well on the path to develop knee OA," Chang said. "They may be concerned that participating in vigorous activities or exercises could cause pain and further tissue damage. To mitigate this perceived risk, some have cut down or discontinue strenuous physical activities, although these activities are beneficial to physical and mental health."

How the study worked:

The study analyzed data from the Osteoarthritis Initiative, a longitudinal observational study of men and women (age range: 45 to 79 years) with or at an increased risk of developing knee OA, recruited from four communities in the U.S. At the study onset and subsequent visits for up to 10 years of follow-up, the participants received X-rays for both knees to determine knee OA disease status and reported their weekly strenuous physical activity participation and sitting patterns.

In 1,194 participants who had no knee OA confirmed by X-ray at the study onset, researchers identified four distinct long-term trajectory patterns of strenuous physical activity participation and three distinct trajectory patterns of extensive sitting over an 8-year period. They then examined if long-term engagement of strenuous physical activity or extensive sitting behavior were each associated with risk of developing knee OA.

"Adults at high risk for knee OA may safely engage in long-term strenuous physical activity at a moderate level," Chang said. "Health care providers may consider incorporating physical activity counselling as part of the standard care for high-risk individuals at an early stage when physical activity engagement is more attainable."