Body

January 12, 2021 - A change in evidence-based guidelines for vasectomy may have led to a reduction in the number of follow-up tests to confirm the procedure was successful, reports a study in Urology Practice®, an Official Journal of the American Urological Association (AUA). The journal is published in the Lippincott portfolio by Wolters Kluwer.

Originally published in 2012, and then updated in 2015, the AUA clinical guideline could significantly reduce the number of men undergoing multiple postvasectomy semen analyses (PVSAs) to confirm it's safe to stop using other methods of birth control, according to new research by Tony Chen, MD, of University of Washington, Seattle, and colleagues. Dr. Chen comments: "Our study of nearly 90,000 patients strongly suggests that men underwent fewer repeat PVSAs after the guideline update, potentially avoiding many unnecessary tests and reducing costs."

One-third reduction in repeat testing after vasectomy
Vasectomy is a safe and highly effective method of permanent contraception in men, performed about 500,000 times per year in the United States. Follow-up PVSA tests, done two to four months after the procedure, are recommended to confirm that vasectomy was successful. Previous standard of practice called for two consecutive PVSAs showing no measurable sperm count (azoospermia).

However, there were concerns this previous practice may have been inconvenient for patients while leading to increased costs. Meanwhile, new evidence suggested that less-stringent criteria might be just as effective in confirming the success of vasectomy. The 2012 AUA guidelines called for just one PVSA showing no or only rare, nonmoving (nonmotile) sperm.

Dr. Chen and colleagues used a national insurance claims database to analyze more than 87,000 men who underwent vasectomy and had at least one claim for follow-up PVSA between 2007 and 2015. Data from before and after the 2012 AUA guideline update were used to see if the new recommendation coincided with a reduced number of PVSAs performed.

The percentage of men undergoing repeat PVSAs decreased after the guideline update: from 39 percent in 2007-12 to 31 percent in 2013-15. After adjustment for other factors, the percentage of vasectomy patients undergoing repeat PVSA decreased by about one-third (odds ratio 0.68).

There was also a small, but significant reduction in the percentage of men undergoing three or more PVSAs (odds ratio 0.82). Men who had only one PVSA had longer average times to the first follow-up test. That was consistent with an AUA recommendation to wait within a range of 8 to 16 weeks before the first PVSA.

Dr. Chen and colleagues note some important limitations of their study. Many urologists "bundle" the vasectomy procedure and follow-up testing, meaning there's no new insurance claim when PVSA is performed. Nearly 80 percent of vasectomy patients in the database had no separate claims for PVSA.

"Although we can't prove that the reduction in repeat PVSAs resulted directly from the new guidelines, the results are strongly suggestive that they had an impact," Dr. Chen adds. "If the one-third reduction we found is correct and applicable to the male population at large, that will mean a significant reduction in costs and inconvenience related to follow-up testing for the many thousands of men who undergo vasectomy each year." The researchers call for further studies "to improve adherence to clinical guidelines and optimize value for this commonly performed procedure."

LA JOLLA, CALIF. - Jan 12, 2021 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified the sensor in human lungs that detects SARS-CoV-2 and signals that it's time to mount an antiviral response. The study, published today in Cell Reports, provides insights into the molecular basis of severe disease and may enable new strategies for the treatment and prevention of COVID-19.

"Our research has shown that MDA-5 is the immune cop that's tasked to keep an eye out for SARS-CoV-2 and call for back-up," says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study. "MDA-5 recognizes replicating viruses in lung cells and activates interferon, the body's own frontline defender against viral invasion. Without a proper interferon response, viral infections can lead to deadly, out-of-control inflammatory reactions."

The new study surveyed 16 viral RNA binding proteins in human lung epithelial cells and identified MDA-5 as the predominant sensor responsible for activating interferon. MDA-5 detects double-stranded viral RNA--a form that the SARS-CoV-2 virus takes when it replicates to spread the infection. Prior to this research, it was known that activating interferon is key to a coordinated immune response to the virus, but the sentinel switch that controls the process was unknown.

"Understanding the biology of a virus and how it is detected is paramount to controlling infection and disease spread," says Chanda. "SARS-CoV-2 appears to disable the innate immune arm of our surveillance system, which, in the case of SARS-CoV-2 is controlled by MDA-5, and prevents the activation of interferon. It's the interferon response that drives the subsequent activation of many genes that exert antiviral activities--and data suggests that we need this activity to control early stages of viral infection and avoid the worst outcomes of COVID-19.

"Whether our bodies can defeat the virus's offensive tactics and activate interferon greatly influences the severity of disease. Past studies have shown that interferon responses are higher in patients with mild-to-moderate cases compared to reduced levels in critically ill patients," adds Chanda.

According to the World Health Organization, as of January 2021 there have been nearly 87 million confirmed cases of COVID-19, including nearly 1.9 million deaths. Although remdesivir and two antibody treatments have received emergency use authorization by the FDA, cases continue to rise. Newly approved vaccines are rapidly being deployed worldwide to end the crisis, however a handful of people are experiencing severe allergic reactions to the shots.

"There is still a tremendous need to develop effective therapies for COVID-19 and to prepare for future outbreaks," says Chanda. "It's possible that patients who become critically ill are deficient in the interferon signaling pathway. This research opens new avenues toward therapies that enhance the MDA-5 signaling to boost interferon levels early in infection to prevent severe disease.

"It also creates opportunities to develop COVID-19 vaccines that include an adjuvant(s) to enhance MDA-5 signaling. These would be formulations that use less 'vaccine' to minimize toxicity and side effects," adds Chanda.

Philadelphia, January 12, 2021 - A special issue of the Journal of the American College of Radiology (JACR), published by Elsevier, challenges conventional wisdom across the imaging community. This collection of articles, the "Provocative Issue," presents extreme opinions on pressing issues confronting radiologists with the deliberate aim of sparking positive dialog and debate that will lead to innovative solutions to improve patient care and imaging-related outcomes.

The issue is guest-edited by:

Caroline Chung, MD, MSc, Director of Advanced Imaging - Strategic Initiative and Director of Imaging Technology and Innovation, Department of Radiation Oncology and Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;

Christoph I. Lee, MD, MS, Director, Northwest Screening and Cancer Outcomes Research Enterprise, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA; and

Reed A. Omary, MD, MS, Chairman, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center and School of Medicine, Nashville, TN, USA.

"We expect this special issue will provoke strong reactions from our readers, ranging from shock, offense, and even disgust," explain the co-guest editors. "The articles were deliberately selected to challenge the conventional wisdom across the imaging community."

"We live in a divisive time of polarization on social, political, and scientific fronts. Yet, when oppositive or counter-intuitive points of view are brought forward, meaningful discussions can lead to new perspectives and novel solutions," write the co-guest editors. "This special issue will challenge us to consider bold ideas that go against the grain. Our goal is to spark debate so that radiology can continue to evolve within our complex Darwinian healthcare ecosystem, leading to greater benefits for society."

Articles in this special issue encompass the five content pillars of the JACR: health services research and policy; clinical practice management; data science; training and education; and leadership. Some of the provocative questions posed are the following:

Are prospective employer-initiated whole-body cancer screening programs a benefit and incentive for employees?

Matching imaging services to clinical context - can less be more?

Rethinking the approach to artificial intelligence (AI) for medical image analysis - is there a case for precision diagnosis?

Should we rethink patient consent in the era of AI and big data?

Can clinician-scientists survive in the modern era?

Is there a case for vertically integrating emergency radiology into emergency medicine?

Should there be duty hour limits for radiologists?

Are we over-supporting junior faculty and neglecting mid- and late-career faculty planning?

Of particular note are two featured articles that debate the paradox of scarcity and discuss potential solutions. The use of physician extenders, also known as nonphysician practitioners (NPPs), in medicine has increased over time within a multitude of specialties including radiology. Radiologists are expensive to train and then spend too much time on low-complexity tasks and too little on high-complexity tasks, notes Saurabh Jha, MBBS, MS, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA, who makes the point for training physician extenders to take on the less complex cases.

"Radiologists should train and supervise physician extenders to read portable chest radiographs, which should eventually be relinquished to them, so that we can focus on tasks exacting more skill and more befitting of our rigorous medical training," argues Dr. Jha. "Perhaps physician extenders reading serial radiographs can free radiologists to advise clinical teams on those serial radiographs."

In a counterpoint article, Daniel A. Ortiz, MD, Summit Radiology Services, PC, Cartersville, GA, USA, and colleagues observe that although labor costs have been reduced and radiologists can focus more on complex imaging studies and interventional procedures, there are unintended consequences of NPPs in practice that could diminish physicians' role as healthcare providers. They therefore encourage radiologists to consider an alternative to NPPs in diagnostic radiology: the incorporation of rapidly evolving AI algorithms into daily practice.

"Narrow AI algorithms can easily be integrated into existing workflow and amalgamated into a platform for use by radiologists," the authors argue. "Many of the gains touted by proponents for the use of NPPs, such as efficiency, will likely be soon realized through AI to the effect of preserving the radiologist's role, supplemented by AI. The ultimate goal for our community should not be relegating work to others but rather to work the complexities of developing a future in which we empower ourselves to remain at the helm of the imaging care to our patients' benefit."

The co-guest editors comment that the ever-increasing workload and the threat of radiologist workforce burnout will force us to consider how to keep up with imaging demands. Physician extenders and AI solutions are only two possibilities for practices to consider.

A final article provides an entertaining voyage into space and how the experience around radiation exposure within medicine can be applied to radiation exposure considerations in suborbital space tourism.

"By exploring the provocative, we hope this special issue will serve as a catalyst to advance the field and expand the confines of radiology," conclude the co-guest editors.

LOS ANGELES (Jan. 11, 2021) -- Cell-derived exosomes are effective in treating disease when mixed with the dominant protein in breast milk and given orally, a new Smidt Heart Institute study of laboratory mice shows. The findings, published in the peer-reviewed Journal of Extracellular Vesicles, could help develop new oral medications for treating patients with muscular dystrophy and heart failure.

The study builds on more than a decade of research led by Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and Cedars-Sinai professor of Cardiology. The research has focused on human cardiosphere-derived cells (CDCs) and a type of extracellular vesicle, called an exosome, that is secreted by those cells and travels throughout the body. Exosomes contain various biomolecules.

"When we started our first human trial in 2009, we were injecting the cells into the hearts of patients, and we thought the cells themselves were the therapeutic answer," Marbán said. "Now, we know it's really the exosomes that do the heavy lifting, and our recent work shows that they could be just as effective when administered orally."

Since that first study concluded in 2010, Marbán has led several studies that have each produced new insights and new methods of delivering the cells to patients and an expansion of the type of patients the cells could potentially help.

The first studies led by Marbán involved patients with heart disease and clogged arteries. After a parent of a muscular dystrophy patient asked Marbán if CDCs might help muscular dystrophy patients who experience progressive muscle weakness - including weakness of the heart muscle - and loss of muscle mass, Marbán began additional research projects aimed at developing treatments for muscular dystrophy patients.

"The work by Dr. Marban and his team highlight the ingenuity our investigators bring to addressing human disease," said Jeffrey A. Golden, MD, Cedars-Sinai's Vice Dean for Research and Graduate Education. "By building on his efforts to develop novel therapeutics for cardiovascular disease, he has found an exciting and novel path to treating another challenging clinical disorder, muscular dystrophy, and in so doing provided the groundwork to expand this strategy to other disorders."

Muscular dystrophy is a group of diseases caused by abnormal genes (mutations) that interfere with the production of proteins needed to form and maintain healthy muscle - including the heart muscle.

In the most recent study, exosomes secreted by CDCs were mixed with casein, the major protein found in the milk of most mammals. The casein-coated exosomes were then fed to laboratory mice that had muscular dystrophy.

Casein is the basis of cheese and often is an ingredient in food products. Decades of medical research have shown that babies who are breastfed might have reduced risk for certain allergic diseases, asthma, obesity and Type 2 diabetes. Casein-rich breast milk, which contains many natural exosomes, also may help improve an infant's cognitive development.

In this study, laboratory mice with muscular dystrophy were organized into four groups. One group of lab mice was fed CDC-derived exosomes mixed with casein, a second group received the exosomes without casein, a third group received casein only, and a fourth group received food with no added exosomes or casein. Those four groups were compared against a control group of lab mice that did not have muscular dystrophy.

Results showed that the mice with muscular dystrophy who were fed the CDC-derived exosomes experienced improved heart function as well as improved mobility and exercise capacity and that giving the exosomes orally distributed them throughout the body. The effects were enhanced by mixing the exosomes with casein.

"Especially for the patient population we are now targeting, patients with muscular dystrophy, the results are promising," Marbán said. "If we can prolong the amount of time before muscular dystrophy patients have to use a wheelchair, that would be a huge quality-of-life improvement."

New Rochelle, NY, January 12, 2021--The Centers for Disease Control and Prevention (CDC) is committed to removing unnecessary medical barriers to contraception use by people with certain characteristics or medical conditions. The CDC is celebrating the 10th anniversary of the release of its U.S. Medical Eligibility Criteria for Contraceptive Use (MEC), with an exclusive article published in the peer-reviewed Journal of Women's Health. Click here to read the article now.

The CDC has updated the MEC recommendations over the past decade based on new evidence. It has collaborated with national partners to disseminate and implement the guidelines and has conducted surveys of health care providers to assess changes in attitudes and practices around contraception safety and provision.

"While the recommendations include necessary restrictions based on evidence, most contraceptive methods can be safely used by most people, even those with medical conditions," state Kathryn Curtis, PhD, and coauthors from the CDC. "Therefore, providing access to the full range of FDA-approved contraceptive methods through patient-centered counseling and shared decision-making can improve quality of care and allow people to find the contraceptive method that best meets their needs."

"The CDC remains diligent about updating its recommendations and applying the latest data to areas that may currently lack a high-quality evidence base. The article by Curtis et al. provides a look at future considerations and efforts underway by the CDC to facilitate dissemination and implementation of the MEC recommendations," says Journal of Women's Health Editor-in-Chief Susan G. Kornstein, MD, Executive Director of the Virginia Commonwealth University Institute for Women's Health, Richmond, VA.

North Carolina did not expand Medicaid eligibility under the Affordable Care Act, which continued to put many low-income women at risk for losing health care coverage post partum. The state did comply with ACA standards for simplifying Medicaid enrollment, automating the process and removing a stringent and often cumbersome financial assessment process. Analysis from researchers at Duke University found that these reforms enabled more low-income women to qualify for full Medicaid and reduced the number of women who instead qualified for more limited benefits under the state's Medicaid for Pregnant Women program. Researchers examined Medicaid claims and vital statistics in North Carolina from 2011 to 2017 and determined that, after changing the full Medicaid enrollment process in 2013 to adhere to the ACA standards, enrollment in full Medicaid during pregnancy doubled and Medicaid for Pregnant Women fell. Full Medicaid does not expire after 60 days and allows women access to crucial preventative health services that include primary care and contraception.

Despite seeing gains in insurance coverage for preventive health services under the Affordable Care Act, the US has seen a declining rate of primary care visits over the past fifteen years. Are fewer individuals seeing primary care physicians? The authors of this study compared two factors that contribute to that decline to determine whether it was the number of primary care patients or the frequency of their clinical visits that contributed most to the overall decline. Over a fifteen year period from 2002 to 2017, both the number of unique patients seeing PCPs and the number of visits per patient declined. At the start of their analysis in 2002, most Americans saw a primary care physician about 4.3 times in a two-year span. By the end of the study in 2016, frequency of contact dropped to about 3.7 visits. Additionally, the total number of unique patients who had contact with a primary care physician decreased by 2.5% over 15 years and declined across all age groups at varying rates. Applying the rates to adjusted population estimates, the authors conclude that less frequent visits by the average American makes up a larger proportion of the primary care decline compared to the number of primary care patients overall.

Deaths from ischemic heart disease and hypertensive diseases in the United States increased during the COVID-19 pandemic over the prior year, while globally, COVID-19 was associated with significant disruptions in cardiovascular disease testing. These findings are from two papers publishing in the Journal of the American College of Cardiology that examined the indirect effects of the pandemic on cardiovascular disease patients and their care.

The impact of the COVID-19 pandemic has been substantial, but there are concerns about the indirect impact of the pandemic as well, particularly for heart disease patients. Many reports have suggested that large mortality increases during the pandemic cannot be explained by COVID-19 alone. During the height of stay-at-home orders in the U.S., hospitals reported a decline in the number of heart attack and stroke patients being diagnosed and treated at the hospital. The assumption was that some patients feared contracting COVID-19 at a hospital and were choosing to delay care or not seek care at all for emergencies, including heart attacks. The American College of Cardiology issued a statement and infographic on the safety of hospitals during the COVID-19 pandemic and urged people to seek immediate care if needed.

Cardiovascular Deaths During the COVID-19 Pandemic in the United States

In this study, researchers examined whether population-level deaths due to cardiovascular causes (ischemic heart disease, heart failure, hypertensive diseases, cerebrovascular disease and other disease of circulatory system) changed in the U.S. during the early phase of the pandemic, relative to the same period in the year prior, and if these changes were more pronounced in states that experienced the initial surge of COVID-19 cases.

Using data from the National Center for Health Statistics, researchers looked at death rates from cardiovascular causes in the U.S. from March 18, 2020 - June 2, 2020 (the pandemic) and January 1, 2020 - March 17, 2020 (before the pandemic) and compared them to the same periods in 2019. They found that deaths from ischemic heart disease and hypertensive diseases increased after the onset of the pandemic in 2020, compared with changes over the same period in 2019. In contrast, deaths caused by heart failure, cerebrovascular disease or other diseases of the circulatory system did not change nationally. New York City experienced the largest relative increase in deaths due to ischemic heart disease (139%) and hypertensive diseases (164%) during the pandemic. The remainder of New York state, New Jersey, Michigan and Illinois also experienced significant increases in deaths due to these conditions, while Massachusetts and Louisiana did not see a change in cardiovascular deaths.

"Our findings suggest that the pandemic may have had an indirect toll on patients with cardiovascular disease, potentially due to the avoidance of hospitals out of fear of exposure to the virus, increased health care system strain and the deferral of semi-elective procedures and care," said Rishi K. Wadhera, MD, MPP, MPhil, lead author of the study, a cardiologist at Beth Israel Deaconess Medical Center and an assistant professor at Harvard Medical School. "U.S. public health officials and policymakers should improve public health messaging to encourage patients with acute conditions to seek medical care."

International Impact of COVID-19 on the Diagnosis of Heart Disease

The COVID-19 pandemic caused health care delivery disruptions across the globe in 2020, including delays in cardiovascular disease diagnosis and timely treatment. Heart disease is the No. 1 killer worldwide, and outcomes are dependent on early and effective diagnosis to determine the best possible treatment. In this study researchers sought to determine the full magnitude of reductions in diagnostic heart disease procedures in 2020 and how that might impact long-term cardiovascular disease outcomes.

Surveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures in 108 countries. According to researchers, procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Specifically, transthoracic echocardiography decreased by 59%, transesophageal echocardiography by 76% and stress tests by 78%. Coronary angiography (invasive or computed tomography) decreased 55%. Researchers also classified countries into four economic levels (low, lower-middle, upper-middle and high) and found that location in a low/lower-middle income country was associated with an additional 22% reduction in cardiac procedures and less availability of personal protective equipment and telehealth.

"These findings raise serious concerns for long-term adverse cardiovascular health outcomes resulting from decreased diagnosis," said Andrew J. Einstein, MD, PhD, lead author of the study, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, and a cardiologist at New York-Presbyterian/Columbia University Irving Medical Center. "Efforts to improve timely patient access to cardiovascular diagnosis in this and future pandemics, particularly in low- and middle-income countries, are warranted."

Scientists have used a "galaxy-sized" space observatory to find possible hints of a unique signal from gravitational waves, or the powerful ripples that course through the universe and warp the fabric of space and time itself.

The new findings, which appeared recently in The Astrophysical Journal Letters, hail from a U.S. and Canadian project called the North American Nanohertz Observatory for Gravitational Waves (NANOGrav).

For over 13 years, NANOGrav researchers have pored over the light streaming from dozens of pulsars spread throughout the Milky Way Galaxy to try to detect a "gravitational wave background." That's what scientists call the steady flux of gravitational radiation that, according to theory, washes over Earth on a constant basis. The team hasn't yet pinpointed that target, but it's getting closer than ever before, said Joseph Simon, an astrophysicist at the University of Colorado Boulder and lead author of the new paper.

"We've found a strong signal in our dataset," said Simon, a postdoctoral researcher in the Department of Astrophysical and Planetary Sciences. "But we can't say yet that this is the gravitational wave background."

In 2017, scientists on an experiment called the Laser Interferometer Gravitational-Wave Observatory (LIGO) won the Nobel Prize in Physics for the first-ever direct detection of gravitational waves. Those waves were created when two black holes slammed into each other roughly 130 million lightyears from Earth, generating a cosmic shock that spread to our own solar system.

That event was the equivalent of a cymbal crash--a violent and short-lived blast. The gravitational waves that Simon and his colleagues are looking for, in contrast, are more like the steady hum of conversation at a crowded cocktail party.

Detecting that background noise would be a major scientific achievement, opening a new window to the workings of the universe, he added. These waves, for example, could give scientists new tools for studying how the supermassive black holes at the centers of many galaxies merge over time.

"These enticing first hints of a gravitational wave background suggest that supermassive black holes likely do merge and that we are bobbing in a sea of gravitational waves rippling from supermassive black hole mergers in galaxies across the universe," said Julie Comerford, an associate professor of astrophysical and planetary science at CU Boulder and NANOGrav team member.

Simon will present his team's results at a virtual press conference on Monday at the 237th meeting of the American Astronomical Society.

Galactic lighthouses

Through their work on NANOGrav, Simon and Comerford are part of a high stakes, albeit collaborative, international race to find the gravitational wave background. Their project joins two others out of Europe and Australia to make up a network called the International Pulsar Timing Array.

Simon said that, at least according to theory, merging galaxies and other cosmological events produce a steady churn of gravitational waves. They're humungous--a single wave, Simon said, can take years or even longer to pass Earth by. For that reason, no other existing experiments can detect them directly.

"Other observatories search for gravitational waves that are on the order of seconds," Simon said. "We're looking for waves that are on the order of years or decades."

He and his colleagues had to get creative. The NANOGrav team uses telescopes on the ground not to look for gravitational waves but to observe pulsars. These collapsed stars are the lighthouses of the galaxy. They spin at incredibly fast speeds, sending streams of radiation hurtling toward Earth in a blinking pattern that remains mostly unchanged over the eons.

Simon explained that gravitational waves alter the steady pattern of light coming from pulsars, tugging or squeezing the relative distances that these rays travel through space. Scientists, in other words, might be able to spot the gravitational wave background simply by monitoring pulsars for correlated changes in the timing of when they arrive at Earth.

"These pulsars are spinning about as fast as your kitchen blender," he said. "And we're looking at deviations in their timing of just a few hundred nanoseconds."

Something there

To find that subtle signal, the NANOGrav team strives to observe as many pulsars as possible for as long as possible. To date, the group has observed 45 pulsars for at least three years and, in some cases, for well over a decade.

The hard work seems to be paying off. In their latest study, Simon and his colleagues report that they've detected a distinct signal in their data: Some common process seems to be affecting the light coming from many of the pulsars.

"We walked through each of the pulsars one by one. I think we were all expecting to find a few that were the screwy ones throwing off our data," Simon said. "But then we got through them all, and we said, 'Oh my God, there's actually something here.'"

The researchers still can't say for sure what's causing that signal. They'll need to add more pulsars to their dataset and observe them for longer periods to determine if it's actually the gravitational wave background at work.

"Being able to detect the gravitational wave background will be a huge step but that's really only step one," he said. "Step two is pinpointing what causes those waves and discovering what they can tell us about the universe."

What The Study Did: This randomized clinical trial compares the effects of two antibiotic strategies (oral moxifloxacin versus intravenous ertapenem followed by oral levofloxacin) on hospital discharge without surgery and recurrent appendicitis over one year among adults presenting to the emergency department with uncomplicated acute appendicitis.

Authors: Paulina Salminen, M.D., Ph.D., of Turku University Hospital in Turku, Finland, is the corresponding author.

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

(doi:10.1001/jama.2020.23525)

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

PULLMAN, Wash. - Biomarkers in human sperm have been identified that can indicate a propensity to father children with autism spectrum disorder. These biomarkers are epigenetic, meaning they involve changes to molecular factors that regulate genome activity such as gene expression independent of DNA sequence, and can be passed down to future generations.

In a study published in the journal Clinical Epigenetics on Jan. 7, researchers identified a set of genomic features, called DNA methylation regions, in sperm samples from men who were known to have autistic children. Then in a set of blind tests, the researchers were able to use the presence of these features to determine whether other men had fathered autistic children with 90% accuracy.

"We can now potentially use this to assess whether a man is going to pass autism on to his children," said Michael Skinner, professor of biological sciences at Washington State University and corresponding author on the study. "It is also a major step toward identifying what factors might promote autism."

Incidence of autism spectrum disorder has increased dramatically over time from 1 in 5,000 people in 1975 to 1 in 68 in 2014. While improved diagnosis and awareness can account for some of that change, many researchers believe the recent increase over the last two decades may be due to environmental and molecular factors. Previous studies have also shown that children can inherit the disorder from their parents, and that fathers are more often linked to autism transmission than mothers.

In the current study, researchers from WSU, Valencia Clinical Research Center and Valencia University in Spain, looked at sperm epigenetics, the molecular processes that affect gene expression, in two groups of men: 13 who had fathered sons with autism, and 13 who had children without the disorder. They looked specifically at DNA methylation, a chemical modification that happens when a methyl group attaches to a DNA strand and can turn genes on or off.

The researchers identified 805 different DNA methylation regions that can potentially act as an epigenetic biomarker for susceptibility to father offspring with autism. They tested their findings by attempting to identify fathers who did or did not have autistic children just from their sperm samples. In blind tests of 18 men, they correctly identified all the fathers, except for two false negatives, an accuracy rate of about 90%.

More work and expanded trials need to be done to develop the study's findings into a potential medical tool, and Skinner and his colleagues are working on a more extensive study involving more than 100 men.

With further research, this biomarker could also be used to trace how the epigenetic changes occurred in the first place, said Skinner.

"We found out years ago that environmental factors can alter the germline, the sperm or the egg, epigenetics," said Skinner. "With this tool we could do larger population-based studies to see what kinds of environmental factors may induce these types with epigenetic changes."

New research shows people who pursue meaningful activities - things they enjoy doing - during lockdown feel more satisfied than those who simply keep themselves busy.

The study, published in PLOS ONE, shows you're better off doing what you love and adapting it to suit social distancing, like swapping your regular morning walk with friends for a zoom exercise session.

Simply increasing your level of activity by doing mindless busywork will leave you unsettled and unsatisfied.

Co-lead researcher Dr Lauren Saling from RMIT University in Melbourne, Australia said while novelty lockdown activities - like baking or painting - have their place, trying to continue what you enjoyed before lockdown can be more rewarding.

"Busyness might be distracting but it won't necessarily be fulfilling," she said.

"Rather, think about what activities you miss most and try and find a way of doing them."

Survey participants rated their level of wellbeing as it was during social distancing and retrospectively one month beforehand.

They also indicated how much time they spent engaged in various activities and nominated how important each activity was for them.

Although participants reported feeling more positive emotions while doing novelty 'meaningless' activities like binge watching TV, they also felt more negative emotions - they felt unhappy just as much as they felt happy.

But when substituting activities enjoyed before lockdown - like dining with friends - for a virtual alternative, their positive and negative emotions were more subdued.

Saling said busyness riles you up, prompting you to change your behaviour, but meaningful activity - doing what you enjoy - calms you down.

"Extreme emotions are not necessarily a good thing," she said.

"Emotions are a mechanism to make you change your behaviour.

"But when you're doing what you love, it makes sense that you feel more balanced - simply keeping busy isn't satisfying."

Saling said the study challenged assumptions that we are either happy or sad and that we can stave off sadness by keeping busy.

Rather, those who kept busy with mindless tasks felt more frustrated and even when they were happy felt less fulfilled.

"The study showed positive and negative affect worked together, not as opposites," Saling said.

"Respondents who simply stayed busy during lockdown reported an increase in both positive and negative emotions.

"This heightened emotionality will tend to shift you away from activity in general and towards meaningful activity."

The study also found the biggest change in positive emotions before and during lockdown was experienced by people aged under 40.

Saling said this was likely because it was harder for that age group to successfully substitute meaningful activities into a lockdown context.

The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association, Acta Pharmaceutica Sinica B (APSB) is a monthly journal, in English, which publishes significant original research articles, rapid communications and high quality reviews of recent advances in all areas of pharmaceutical sciences -- including pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis and pharmacokinetics.

Featured papers in this issue are:

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5 by authors Yang Liu, Xiaojia Liu, Na Zhang, Mingxiao Yin, Jingwen Dong, Qingxuan Zeng, Genxiang Mao, Danqing Song, Lu Liu and Hongbin Deng. Berberine diminishes the expression of programmed cell death ligand-1 and promotes antitumor immunity via inhibiting the deubiquitination activity of COP9 signalosome 5 (CSN5) in non-small cell lung cancer.

Inhibitory effects of baicalein against herpes simplex virus type 1 by authors Zhuo Luo, Xiu-Ping Kuang, Qing-Qing Zhou, Chang-Yu Yan, Wen Li, Hai-Biao Gong, Hiroshi Kurihara, Wei-Xi Li, Yi-Fang Li and Rong-Rong He. Baicalein exerts potent ability against HSV-1 infection and dual mechanisms were disclosed. The authors research indicates that baicalein is highly effective in combating HSV-1 infection. Dual mechanisms were involved in its antivirus effect, namely the inactivation of free viral particles to neutralize the infectivity and the suppression of NF-kB activation, which is distinct from that of acyclovir. Hence, this work offers experimental basis for baicalein as a potential drug in treating HSV-1 infection and related diseases.

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension by authors Yuncong Yang, Sirui Zhang, Qian Zhou, Chen Zhang, Yuqi Gao, Hao Wang, Zhe Li, Deyan Wu, Yinuo Wu, Yi-You Huang, Lei Guo and Hai-Bin Luo. A potent and highly selective PDE10A inhibitor, 14·3HCl (IC50 = 2.8 nmol/L and >3500-fold selectivity) with a remarkable bioavailability of 50% was obtained to verify the feasibility for the anti-PAH treatment. The crystal structure of PDE10A-14 complex illustrated the binding pattern, providing a guideline for rational design of highly selective PDE10A inhibitors.

Other articles published in the issue include:

Reviews

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives
Yizhen Yin, Fener Chen

Small molecules targeting the innate immune cGAS?STING?TBK1 signaling pathway
Chunyong Ding, Zilan Song, Ancheng Shen, Tingting Chen, Ao Zhang

Original Articles

Targeting castration-resistant prostate cancer with a novel RORg antagonist elaiophylin
Jianwei Zheng, Junfeng Wang, Qian Wang, Hongye Zou, Hong Wang, Zhenhua Zhang, Jianghe Chen, Qianqian Wang, Panxia Wang, Yueshan Zhao, Jing Lu, Xiaolei Zhang, Songtao Xiang, Haibin Wang, Jinping Lei, Hong-Wu Chen, Peiqing Liu, Yonghong Liu, Fanghai Han, Junjian Wang

GSH-responsive SN38 dimer-loaded shape-transformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy
Congcong Lin, Fan Tong, Rui Liu, Rou Xie, Ting Lei, Yuxiu Chen, Zhihang Yang, Huile Gao, Xiangrong Yu

CORM-2-entrapped ultradeformable liposomes ameliorate acute skin inflammation in an ear edema model via effective CO delivery
Gwan-Yeong Lee, Alam Zeb, Eun-Hye Kim, Beomseon Suh, Young-Jun Shin, Donghyun Kim, Kyoung-Won Kim, Yeong-Hwan Choe, Ho-Ik Choi, Cheol-Ho Lee, Omer Salman Qureshi, In-Bo Han, Sun-Young Chang, Ok-Nam Bae, Jin-Ki Kim

Selectively enhancing radiosensitivity of cancer cells via in situ enzyme-instructed peptide self-assembly
Yang Gao, Jie Gao, Ganen Mu, Yumin Zhang, Fan Huang, Wenxue Zhang, Chunhua Ren, Cuihong Yang, Jianfeng Liu

Bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption
Yanjuan Huang, Zhanghong Xiao, Zilin Guan, Zishan Zeng, Yifeng Shen, Xiaoyu Xu, Chunshun Zhao

A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility
Yixian Zhou, Boyi Niu, Biyuan Wu, Sulan Luo, Jintao Fu, Yiting Zhao, Guilan Quan, Xin Pan, Chuanbin Wu

IiWRKY34 positively regulates yield, lignan biosynthesis and stress tolerance in Isatis indigotica
Ying Xiao, Jingxian Feng, Qing Li, Yangyun Zhou, Qitao Bu, Junhui Zhou, Hexin Tan, Yingbo Yang, Lei Zhang, Wansheng Chen

"The findings provide an increased understanding of how the virus gets through the stomach and intestinal system. Continued research can provide answers to whether this property can also be used to create vaccines that ride 'free rides' and thus be given in edible form instead of as syringes," says Lars-Anders Carlson, researcher at Umeå University.

The virus that the researchers have studied is a so-called enteric adenovirus. It has recently been clarified that enteric adenoviruses are one of the most important factors behind diarrhea among infants, and they are estimated to kill more than 50,000 children under the age of five each year, mainly in developing countries.

Most adenoviruses are respiratory, that is, they cause respiratory disease, while the lesser-known enteric variants of adenovirus instead cause gastrointestinal disease. The enteric adenoviruses therefore need to be equipped to pass through the acidic environment of the stomach without being broken down, so that they can then infect the intestines.

With the help of the advanced cryo-electron microscope available in Umeå, the researchers have now managed to take such detailed images of an enteric adenovirus that it has been possible to put a three-dimensional puzzle that shows what the virus looks like right down to the atomic level. The virus is one of the most complex biological structures studied at this level. The shell that protects the virus' genome when it is spread between humans consists of two thousand protein molecules with a total of six million atoms.

The researchers were able to see that the enteric adenovirus manages to keep its structure basically unchanged at the low pH value found in the stomach. They could also see other differences compared to respiratory adenoviruses in how a particular protein is altered in the shell of the virus as well as new clues to how the virus packs its genome inside the shell. All in all, it provides an increased understanding of how the virus manages to move on to create disease and death.

"The hope is that you will be able to turn the ability that this unpleasant virus has to get to something that can instead be used as a tool to fight disease, perhaps even COVID-19. This is a step in the right direction, but it is still a long way off," says Lars-Anders Carlson.

Several of the new vaccines being tested against COVID-19 are based on genetically modified adenovirus. Today, these adenovirus-based vaccines must be injected to work in the body. If a vaccine could instead be based on enteric adenovirus, the vaccine might be given in edible form. This would, of course, facilitate large-scale vaccination.

NEW YORK, NY (Jan. 11, 2021)--A new study has found that up to 20% of glioblastomas--an aggressive brain cancer--are fueled by overactive mitochondria and may be treatable with drugs currently in clinical trials.

Mitochondria are responsible for creating the energy that fuels all cells. Though they are usually less efficient at producing energy in cancer, tumor cells in this newly identified type of glioblastoma rely on the extra energy provided by overactive mitochondria to survive.

The study, by cancer scientists at Columbia University's Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, was published online Jan. 11 in Nature Cancer.

The study also found that drugs that inhibit mitochondria--including a currently available drug and an experimental compound that are being tested in clinical trials--had a powerful anti-tumor effect on human brain cancer cells with overactive mitochondria. (Follow-up, unpublished work found that the same drugs are also active against mitochondrial tumors in glioblastomas growing in mice).

Such drugs are being tested in patients who have a rare gene fusion--previously discovered by the same researchers--that also sends mitochondria into overdrive.

"We can now expand these clinical trials to a much larger group of patients, because we can identify patients with mitochondria-driven tumors, regardless of the underlying genetics," says Antonio Iavarone, MD, professor of neurology, who led the study with Anna Lasorella, MD, professor of pediatrics. Both are members of Columbia's Institute for Cancer Genetics.

Study Finds Four Types of Brain Cancer

The study found that all brain cancers fall into one of four groups, including the mitochondrial subtype.

By classifying brain cancers based on their core biological features, and not just genetic alterations or cell biomarkers, the researchers have gained new insights into what drives each subtype and the prognosis for patients.

"Existing classifications for brain cancer are not informative. They don't predict outcomes; they don't tell us which treatments will work best," Lasorella says.

The importance of an accurate classification system is best illustrated by the example of breast cancer. Breast cancers have very well-defined subtypes that led to the development of therapies that target the key hallmarks, such as estrogen receptors or HER2, that sustain specific subtypes.

"We feel that one of the reasons therapeutic progress in brain cancer has been so slow is because we don't have a good way to classify these tumors," Iavarone says.

Glioblastoma is the most common--and most lethal--primary brain tumor in adults. Median survival for individuals with glioblastoma is only 15 months.

The new study showed that glioblastoma can be classified in four biological groups. Two of them recapitulate functions active in the normal brain, either stem cells or neurons, respectively. The two other groups include mitochondrial tumors and a group of tumors with multiple metabolic activities ("plurimetabolic") that are highly resistant to current therapies.

Patients with the mitochondrial tumors had a slightly better prognosis--and lived for a few more months--than patients with the other three types.

"We are excited about the mitochondrial group, because we have drugs for that group in clinical trials already," Lasorella says, "but the classification now gives us ideas about how to target these other three and we are starting to investigate these more intensely."

"We're going beyond one mutation, one drug concept," she says. "Sometimes it's possible to get a response that way. But it's time to target tumors based on the commonalities of their core biology, which can be caused by multiple different genetic combinations."

Single-Cell Analyses Opens New View of Brain Cancer

The new findings were only possible by utilizing recent advances in single-cell analyses, which allowed the scientists to understand--cell by cell--the biological activity of thousands of cells from a single tumor.

Overall, the scientists characterized the biological properties of 17,367 individual cells from 36 different tumors.

In addition to analyzing each cell's genetic mutations and levels of gene activity, the researchers looked at other modifications made to the cells' genomes and the proteins and noncoding RNAs made by each cell.

Using the data, the researchers devised a computational approach to identify core biological processes, or pathways, in the cells rather than the more common approach of identifying gene signatures. "In this way, we can classify each individual tumor cell based on the real biology that sustains them," Iavarone says.

Most tumors, the researchers found, were dominated by cells from one of the four subtypes, with a smattering of cells from the other three.

Applying Same Techniques to Other Cancers

Lasorella and Iavarone are now applying the same techniques to multiple different aggressive cancers.

This "pan-cancer" approach, they say, should identify commonalities among different types of cancer regardless of the tumor's origin. If such common pathways exist, drugs that treat mitochondrial brain cancer may also be able to treat mitochondrial types of lung cancer, for example.

"When we classify based on the cell's core biological activities, which all cells rely on to survive and thrive, we may find that cancers share more in common than was previously apparent by just looking at their genes," Lasorella says.