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The novel SARS-CoV-2 coronavirus that emerged in the city of Wuhan, China, last year and has since caused a large scale COVID-19 epidemic and spread to more than 70 other countries is the product of natural evolution, according to findings published today in the journal Nature Medicine.

The analysis of public genome sequence data from SARS-CoV-2 and related viruses found no evidence that the virus was made in a laboratory or otherwise engineered.

"By comparing the available genome sequence data for known coronavirus strains, we can firmly determine that SARS-CoV-2 originated through natural processes," said Kristian Andersen, PhD, an associate professor of immunology and microbiology at Scripps Research and corresponding author on the paper.

In addition to Andersen, authors on the paper, "The proximal origin of SARS-CoV-2," include Robert F. Garry, of Tulane University; Edward Holmes, of the University of Sydney; Andrew Rambaut, of University of Edinburgh; W. Ian Lipkin, of Columbia University.

Coronaviruses are a large family of viruses that can cause illnesses ranging widely in severity. The first known severe illness caused by a coronavirus emerged with the 2003 Severe Acute Respiratory Syndrome (SARS) epidemic in China. A second outbreak of severe illness began in 2012 in Saudi Arabia with the Middle East Respiratory Syndrome (MERS).

On December 31 of last year, Chinese authorities alerted the World Health Organization of an outbreak of a novel strain of coronavirus causing severe illness, which was subsequently named SARS-CoV-2. As of February 20, 2020, nearly 167,500 COVID-19 cases have been documented, although many more mild cases have likely gone undiagnosed. The virus has killed over 6,600 people.

Shortly after the epidemic began, Chinese scientists sequenced the genome of SARS-CoV-2 and made the data available to researchers worldwide. The resulting genomic sequence data has shown that Chinese authorities rapidly detected the epidemic and that the number of COVID-19 cases have been increasing because of human to human transmission after a single introduction into the human population. Andersen and collaborators at several other research institutions used this sequencing data to explore the origins and evolution of SARS-CoV-2 by focusing in on several tell-tale features of the virus.

The scientists analyzed the genetic template for spike proteins, armatures on the outside of the virus that it uses to grab and penetrate the outer walls of human and animal cells. More specifically, they focused on two important features of the spike protein: the receptor-binding domain (RBD), a kind of grappling hook that grips onto host cells, and the cleavage site, a molecular can opener that allows the virus to crack open and enter host cells.

Evidence for natural evolution

The scientists found that the RBD portion of the SARS-CoV-2 spike proteins had evolved to effectively target a molecular feature on the outside of human cells called ACE2, a receptor involved in regulating blood pressure. The SARS-CoV-2 spike protein was so effective at binding the human cells, in fact, that the scientists concluded it was the result of natural selection and not the product of genetic engineering.

This evidence for natural evolution was supported by data on SARS-CoV-2's backbone - its overall molecular structure. If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness. But the scientists found that the SARS-CoV-2 backbone differed substantially from those of already known coronaviruses and mostly resembled related viruses found in bats and pangolins.

"These two features of the virus, the mutations in the RBD portion of the spike protein and its distinct backbone, rules out laboratory manipulation as a potential origin for SARS-CoV-2" said Andersen.

Josie Golding, PhD, epidemics lead at UK-based Wellcome Trust, said the findings by Andersen and his colleagues are "crucially important to bring an evidence-based view to the rumors that have been circulating about the origins of the virus (SARS-CoV-2) causing COVID-19."

"They conclude that the virus is the product of natural evolution," Goulding adds, "ending any speculation about deliberate genetic engineering."

Possible origins of the virus

Based on their genomic sequencing analysis, Andersen and his collaborators concluded that the most likely origins for SARS-CoV-2 followed one of two possible scenarios.

In one scenario, the virus evolved to its current pathogenic state through natural selection in a non-human host and then jumped to humans. This is how previous coronavirus outbreaks have emerged, with humans contracting the virus after direct exposure to civets (SARS) and camels (MERS). The researchers proposed bats as the most likely reservoir for SARS-CoV-2 as it is very similar to a bat coronavirus. There are no documented cases of direct bat-human transmission, however, suggesting that an intermediate host was likely involved between bats and humans.

In this scenario, both of the distinctive features of SARS-CoV-2's spike protein--the RBD portion that binds to cells and the cleavage site that opens the virus up--would have evolved to their current state prior to entering humans. In this case, the current epidemic would probably have emerged rapidly as soon as humans were infected, as the virus would have already evolved the features that make it pathogenic and able to spread between people.

In the other proposed scenario, a non-pathogenic version of the virus jumped from an animal host into humans and then evolved to its current pathogenic state within the human population. For instance, some coronaviruses from pangolins, armadillo-like mammals found in Asia and Africa, have an RBD structure very similar to that of SARS-CoV-2. A coronavirus from a pangolin could possibly have been transmitted to a human, either directly or through an intermediary host such as civets or ferrets.

Then the other distinct spike protein characteristic of SARS-CoV-2, the cleavage site, could have evolved within a human host, possibly via limited undetected circulation in the human population prior to the beginning of the epidemic. The researchers found that the SARS-CoV-2 cleavage site, appears similar to the cleavage sites of strains of bird flu that has been shown to transmit easily between people. SARS-CoV-2 could have evolved such a virulent cleavage site in human cells and soon kicked off the current epidemic, as the coronavirus would possibly have become far more capable of spreading between people.

Study co-author Andrew Rambaut cautioned that it is difficult if not impossible to know at this point which of the scenarios is most likely. If the SARS-CoV-2 entered humans in its current pathogenic form from an animal source, it raises the probability of future outbreaks, as the illness-causing strain of the virus could still be circulating in the animal population and might once again jump into humans. The chances are lower of a non-pathogenic coronavirus entering the human population and then evolving properties similar to SARS-CoV-2.

Botulinum toxin (BoNT) is used for a range of applications from treating chronic pain to reducing the appearance of wrinkles, but when injected it can diffuse into the surrounding tissue and give rise to adverse effects. A new study publishing March 17 in the open-access journal PLOS Biology by Linxiang Yin and Min Dong of Boston Children's Hospital, USA and colleagues shows that a subtle modification of an FDA-approved form of BoNT enhances binding to the nerve cells and improves the drug's potency and safety.

Botulinum toxin (BoNT) is produced by the Clostridium botulinum bacterium in seven serotypes, BoNT/A through G. All work in a similar way: after attaching to nerves near their junction with muscles (the neuromuscular junction), a portion of the toxin crosses the nerve's membrane to prevent release of neurotransmitter and thereby paralyze the muscle. A commercial form of BoNT/A is approved for clinical treatment of various forms of muscle overactivity as well as cosmetic reduction of wrinkles, while a commercial form of BoNT/B is approved for a movement disorder called cervical dystonia.

BoNTs have two sites that recognise two separate receptors at the nerve terminal. Previous work has shown that several BoNTs including BoNT/B have an extended loop along the amino acid chain between the two receptor binding sites. Structural modeling suggested that if this loop contains hydrophobic (oily) amino acids it could interact with lipids in the nerve cell membrane, providing a third point of attachment and so increasing binding efficiency. These hydrophobic amino acids are present in the loop of several BoNTs, but not in BoNT/B.

Because potency is increased and adverse effects decreased by stronger binding, the authors investigated whether adding hydrophobic amino acids to this lipid-binding loop in BoNT/B might improve binding of the toxin to the nerve terminal. They showed that replacing just two amino acids in the loop with hydrophobic tryptophans did in fact enhance binding in vitro. They then produced a new BoNT/B containing this mutation plus a pair of mutations that had been previously shown to enhance binding to one of the two BoNT/B receptors, and demonstrated that this engineered toxin was more potent than the approved form of BoNT/B in a standard mouse paralysis assay. In addition, the new toxin caused less reduction in body weight, an effect consistent with a reduction in diffusion of the toxin away from the injection site.

"Our study shows that the changes introduced into BoNT/B can increase the therapeutic potential of the toxin and reduce adverse effects," Dong said. "Engineering the botulinum toxins in this way may provide a new avenue for improving safety and clinical benefit from these drugs."

70% have concerns that COVID-19 will hurt their personal economic situation -

Ongoing series of surveys of 1,300 patients is tracking changing concerns over two weeks as pandemic continues -

First webinar March 17 at 1:30pm ET with registered nurse and three people living with autoimmune disease -

Series of upcoming public webinars enable patients to share concerns and questions wks of 3/16 and 3/23 -

SEATTLE - March 17, 2020 - As the global pandemic continues and its impact increasingly disrupts daily life in the U.S., a new ongoing survey launched this week reveals specific concerns about the novel coronavirus among people living with chronic illnesses, who feel these conditions make them more susceptible to the virus (73%) and are beginning to turn to each other (58%) and their doctors (36%) for more information. Epidemiologists have identified people with serious chronic medical conditions as one of the two key demographic groups (along with older adults) that are at high risk for poor outcomes from COVID-19 .

Health Perspectives Group fielded the first of a series of ongoing surveys this week among 1,300 members of its Health Stories Project social sharing community who are living with or caring for chronic conditions, tracking their awareness of and concerns about the novel coronavirus pandemic and COVID-19, the illness caused by the recently identified novel coronavirus. Survey participants span age groups (18-92), genders, race/ethnicities, education level, location (urban, suburban, rural) and 17 chronic disease areas. The survey will be re-administered to the same respondents, who have agreed to participate, every two days over the next two weeks to track changes in their concerns, disease status and access to information in real time.

In addition to the survey, Health Perspectives Group will host a series of webinars in the coming weeks featuring a health professional and patients living with specific chronic conditions, starting with autoimmune diseases on Tuesday, March 17 at 1:30 pm ET, followed by respiratory, oncology and cardiovascular, to be scheduled. For more information, visit http://hpgroupllc.com/webinars or contact connect@hpgroupllc.com

Key Initial Findings

In the first week of significant impact of the pandemic in the U.S., people living with chronic health conditions are alert and concerned about both broad and personal impacts of novel coronavirus/COVID-19. Among respondents, 33% watch, read or listen to the news daily, 35% several times a day and 20% almost constantly, across a wide range of sources, including TV (75%), news websites (64%), news apps (53%) and social media (75%).

When considering general impact of the pandemic, 56% of respondents think there will be a widespread outbreak of COVID-19 this year (19% say sometime in the future and 12% are not sure), and 89% of respondents expressed concern that the outbreak will hurt the economy.

As information about and understanding of the virus evolves and knowledge about risks for their specific diseases is not yet widely available, patients are seeking information and support from each other: 44% of respondents have talked to other people with their condition to address their own concerns, and 44% helped calm other people with their condition.

One statistic that has the potential for significant impact: already at this early stage, 36% of patients have discussed this coronavirus with their healthcare providers. As burdens on doctors and the healthcare system continue to grow, this number is a call to action for patient groups and other organizations with public platforms to gather current facts and share them with patients in their disease areas quickly and effectively.

"As we face this unprecedented global medical event, we are committed to sharing the voices of patients living with chronic diseases through the ongoing survey of Health Stories Project members who have raised a hand to share their experiences and concerns, highlighting their needs that are not being addressed effectively," said Cheryl Lubbert, President and CEO of Health Perspectives Group, parent company of Health Stories Project. "As we repeat the survey over the next days and weeks, we will analyze and share the result across categories and diseases as quickly as possible to provide a real-time snapshot of how the COVID-19 situation is evolving, and hopefully resolving, for these patients."

Topics addressed in the ongoing survey include:

Impact of their current condition

Frequency of news monitoring and sources

Awareness and concern about novel coronavirus/COVID-19

Anticipated impact of COVID-19 on economy and personal health and economic situation

How novel coronavirus/COVID-19 is impacting work and daily life

Sources for disease-specific information

When viewed through the lens of different age groups and diseases, the findings from the first survey offer some interesting and unexpected contrasts.

Findings By Age Group

The age groups in the survey are classified as the Silent Generation (age 75-92), Baby Boomers (56-74), Gen X (40-55), Millennials (24-39) and Gen Z (18-23). When considering perceived impact on the economy and their own health, several age differences were apparent. Overall, 89% of respondents expressed that they were concerned (somewhat, very or extremely) that the outbreak will hurt the economy, split evenly with about 30% of respondents in each sub-category of concern, with one exception: Gen Z (18-23) respondents are the most optimistic, with 13% not very concerned, 36% somewhat concerned and only 14% extremely concerned that the outbreak will hurt the economy.

Gen Z (18-23) respondents had a more positive outlook on their own potential to contract COVID-19. While overall 73% of respondents feel their condition makes them more susceptible to the novel coronavirus, only 47% of Gen Z respondents do, with 53% responding that they do not feel they are more susceptible.

Findings By Disease

Survey respondents, on the whole, are taking precautions in their daily lives because of COVID-19. However, some people with specific conditions are being more proactive than others, while those with immune and respiratory conditions (logical risk for infection) and cardiovascular disease (which has been mentioned in early reports from other countries as a specific risk factor) are not reporting heightened preventive measures that might be expected: [see chart in image with this release]

One Particular Bright Spot

Finally, as we prepare for the next administration of this survey in a few days, public health officials and media commentators will be pleased to know that universally, across all categories, 83% of survey respondents said they were washing their hands more frequently in response to the COVID-19 pandemic. It will be encouraging to see this number rise even higher in future results.

Life expectancy in the USA is no longer rising. This stagnation has long been largely attributed to increasing numbers of drug deaths due to the opioid crisis. But Mikko Myrskylä and colleagues have now shown that deaths due to cardiovascular diseases are in fact having a much larger impact on life expectancy.

Over each decade of the past century, life expectancy in the USA rose by two years. This is no longer the case. Since 2010, life expectancy has not improved. Until now, this fact has mainly been attributed to the rising number of drug deaths due to the opioid crisis.

But Mikko Myrskylä, Director of the Max Planck Institute for Demographic Research in Rostock, together with Neil Mehta and Leah Abrams from University of Michigan have shown a stall in declining cardiovascular deaths is a more likely explanation for the end of stagnation of life expectancy. They have published their findings in the scientific journal PNAS.

Drug-related deaths have little influence on life expectancy

The remaining life expectancy of 25-year-old Americans would have risen by 1.1 years between 2010 and 2017 if deaths from cardiovascular diseases had declined as much over that period as they did between 2000 and 2009.

By contrast, the rising number of drug-related deaths had a much smaller influence on life expectancy. "If the number of drug-related deaths had remained constant after 2010, male life expectancy would have risen just 0.4 years, or by around five months," Mikko Myrskylä explained. Thus, over the long run, reducing the number of drug-related deaths will not be sufficient to ensure that life expectancy in the USA resumes its upward trajectory.

March 17, 2020 - Proton pump inhibitors - a widely used class of drugs used to treat acid reflux and related symptoms - may lead to an increased risk of fractures in children and adolescents, reports a study in the Journal of Pediatric Gastroenterology and Nutrition (JPGN). Official journal of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, JPGN is published by Wolters Kluwer.

"This study suggests an increased risk of fracture among otherwise healthy pediatric patients exposed to PPIs," according to the new research, led by Nathan Robert Fleishman, MD, Children's Mercy Kansas City in Kansas City, Mo. The researchers believe their findings have important implications for the care of children taking PPIs - especially long-term users.

As in Adults, PPIs May Increase Fracture Risk in Children

The study included data on children and adolescents, average age four years, receiving care at 51 US children's hospitals from 2011 to 2015. Data were drawn from the cooperative Pediatric Hospital Information System database. A total of 32,001 care encounters where the patient received a PPI were matched to the same number of encounters without PPI use. The study excluded patients with complex chronic conditions, or with conditions or medications predisposing to fracture risk.

The analysis showed a significantly higher fracture rate in children exposed to PPIs: 1.4 percent, compared to 1.2 percent in those not exposed to PPIs. The authors performed a further analysis to adjust for differences in patient characteristics, including sex, race, insurance status, and type and intensity of care encounter.

In this adjusted analysis, the odds of fracture remained significantly higher in children exposed to PPIs: adjusted odds ratio 1.2. In other words, all other risk factors being equal, the probability of fracture would be 20 percent higher in a child taking PPIs.

In both groups, the upper extremity (arm and hand) was the most common fracture location. However, children exposed to PPIs were more likely to have fractures of the lower extremity (leg and foot), ribs, or spine. In both groups, fractures were most common in one- to three-year and nine-to-13-year age groups. The findings suggested a "class effect" of PPIs: fracture risk was increased with all PPIs, not any particular drug or combination of drugs.

"While our findings are statistically significant, the relative risks are small," Dr. Fleishman comments. "However, our study design tended to underestimate the actual risk."

Proton pump inhibitors are widely used to treat acid reflux and other upper intestinal disorders in children as well as adults. Commonly used PPIs include lansoprazole, omeprazole, and esomeprazole - all of which are available over-the-counter, as well as by prescription.

Although PPIs have historically been considered "exceptionally safe," several reports have suggested that they may be implicated in a wide range of complications. In adults, PPIs have been linked to a small but significant increase in the risk of fractures, especially with long-term use. Only a few studies have looked at PPIs and fracture risk in children, with mixed results.

"Our study highlights the need to limit the use of PPIs to individuals who are clearly benefiting and for the least duration necessary," comments study coauthor Thomas Attard, MD. "Additionally, children who are on these medications long-term warrant ongoing follow up." The researchers hope the findings will stimulate further research and strategies to limit fracture risk in children who require PPIs for longer periods of time.

"Proton pump inhibitors are effective medications and have an important role in the treatment of specific diseases," Dr. Fleishman adds. "We should be aware of the potential side effects of these (and all) medications we prescribe. We owe it to our patients to ensure we are continually evaluating the risks and benefits of our treatments in the context of their disease course."

Researchers at the University of Cincinnati have found in a retrospective study that African-American men are less likely to use a more targeted biopsy option for prostate cancer, despite an increased incidence in this group of patients.

These findings are published in the March 9 issue of the journal Prostate Cancer and Prostatic Diseases (Nature). The study is led by Connor Hoge, a student at the UC College of Medicine, and Dr. Abhinav Sidana, director of urologic oncology and assistant professor in the Division of Urology at the UC College of Medicine. Sidana is also a UC Health urologist.

"Black men have a significantly higher incidence and are up to three times more likely to die of prostate cancer than white men," says Sidana, corresponding author on this study. "MRI-ultrasound biopsy has emerged as a promising option for the detection of prostate cancer. In this study, we wanted to identify differences in use of MRI-ultrasound biopsy between black and white men with possible prostate cancer."

Sidana says the standard biopsy for men with suspicion of having prostate cancer is a random needle collection of between 12 to 40 samples from the prostate. However, because of the random nature of the collection, this can lead to overdiagnosis of prostate cancer where treatment is not needed, underdiagnosis prostate cancer where treatment is needed and a higher rate of tests that read negative for cancer when it is truly malignant.

With fusion biopsy, a navigation system similar to a GPS tracking device allows physicians to target biopsies to the exact suspicious location. MRI and ultrasound images are aligned and overlaid on real-time ultrasound to identify targets that are then labeled high, medium or low suspicion for cancer. This allows doctors to pinpoint the biopsy, meaning less sticks with a needle and more accurate samples.

The study included 619 men, of which 182 were African-American and 437 were white; the patients were all treated at UC Medical Center. Forty-one (22.5%) African-American men underwent MRI-ultrasound biopsy compared with 225 (51.5%) of white men.

"After adjusting for other factors, including age, race, prostate-specific antigen levels (which can determine risk for prostate cancer in the blood), other physical screening tactics, family history and health insurance providers, the odds of African-American men having MRI-ultrasound biopsies were one-third the odds of white men having that type of biopsy," says Sidana. "Although MRI-ultrasound biopsies are shown to be a better way to detect early-stage prostate cancer, we're seeing this deficiency in a group of patients that would benefit the most from its use. We need to further investigate whether this difference is due to patient preference or if there are underlying socioeconomic, cultural or provider biases influencing this."

New Rochelle, NY, March 16, 2020--A new study of 1,365 racially/ethnically diverse, low-income pregnant women found that 4% reported e-cigarette use. White non-Hispanic women were more likely to use e-cigarettes compared to women who used conventional cigarettes or reported no tobacco product use, according to an article published in Journal of Women's Health, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. Click here to read the full-text article on the Journal of Women's Health website through April 16, 2020.

The study entitled "Electronic Cigarette Use During Preconception and/or Pregnancy: Prevalence, Characteristics, and Concurrent Mental Health Conditions" also found that nearly one third of women who reported e-cigarette use had symptoms of depression in pregnancy, which was 4 times that of women who reported no tobacco product use and 2 times that of women who used conventional cigarettes. The long-term health effects of e-cigarettes are not known. However, most e-cigarettes contain nicotine, which is known to be a harmful reproductive and developmental agent. The coauthors of this study were L. G. Rollins, PhD and colleagues from The Miriam Hospital, Alpert Medical School of Brown University, School of Public Health of Brown University, and the Centers for Disease Control and Prevention.

Susan G. Kornstein, MD, Editor-in-Chief of Journal of Women's Health and Executive Director of the Virginia Commonwealth University Institute for Women's Health, Richmond, VA, states: "E-cigarette use has not been shown to be safe during preconception and/or pregnancy, and screening for any type of tobacco product use is recommended. Not only can screening lead to cessation efforts, but Rollins et al. show that women who report e-cigarette use during pregnancy also have a greater likelihood of depressive symptoms, severe mental health conditions, and substance abuse."

What The Study Did: This observational study looked at how common nonmedical prescription opioid use was among transgender girls and young women and risk factors associated with it.

Authors: Arjee J. Restar, M.P.H., of the Brown University School of Public Health in Providence, Rhode Island, is the corresponding author.

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

(10.1001/jamanetworkopen.2020.1015)

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

Abdominal arterial (or aortic) aneurysm in older men is associated with levels of certain subtypes of white blood cells, a study from the University of Gothenburg, Sweden, shows. The study results belong to an expanding research field that is expected improve both knowledge of the disease and treatment options.

Enlargment of the abdominal aorta, also known as abdominal aortic aneurysm, is found in 1-2 percent of all 65-year-old men in Sweden. Its incidence in women is a great deal lower. The condition means that local enlargement of the abdominal part of the body´s main artery occurs, in association with weakening of the vascular walls.

Most of those who have this disease are symptom-free, but if the artery successively enlarges the risk of rupture increases. Giving up smoking has a positive effect on the course of the disease, and every year about a thousand people in Sweden with this diagnosis are treated with preventive vascular surgery.

If rupture of the aorta occurs, it usually proves fatal in 70-80% of the patients. However, cases have become fewer with the decline in smoking and the introduction of a national screening program over the years 2006-2015. Today, this program includes all 65-year-old men in Sweden: eight out of ten opt to be investigated and, moreover, the program has created new scope for research.

The current study, published in the Journal of Internal Medicine, is part of the relatively early research ensuing from the screening program. It comprises data on 16,256 men screened in Gothenburg from 2013 to 2017. The number of men with abdominal aortic aneurysm included was 151, and these men were compared with 224 screened, matched controls.

The senior author is Asa Tivesten, senior physician and professor of medicine at Sahlgrenska Academy, University of Gothenburg.

"We've examined levels of various subtypes of white blood cells (leukocytes), and been able to see that some are elevated in men in whom the disease was detected at the screening, compared with healthy controls. This may tell us something about which mechanisms are involved in the development of the disease, and all this kind of knowledge can be valuable," she says.

"The results," she continues, "strengthen the hypothesis that inflammation is an important mechanism for the development of aneurysms. And that may come to be relevant to future drug development. Today, surgery is the only possible treatment, but if we're able to treat the disease with drugs in the future, at an earlier stage, this will have been a major step forward."

The first author of the study is Marcus Langenskiold, senior consultant surgeon and associate professor in vascular surgery at the University of Gothenburg's Sahlgrenska Academy.

"What's interesting is that we've found factors associated with incidence of the disease, even after adjusting the figures by eliminating smoking. This opens up a research field where we might see what underlies the growth of some aneurysms and not others. Right now, we have no medicines to influence this growth, but the study creates new research opportunities," Langenskiold says.

"The advantage is that we've now got screened patients, matched controls and a forward-looking perspective. A lot of research reports in the field, not least in the area of leukocytes, are based on data on patients admitted to hospital emergency departments, and that may make the data misleading."

Fear is a major factor behind people's reluctance to take part in clinical research, such as trials to test new medicines and treatments, a global review has found.

In the UK, up to two thirds of trials currently fail to recruit their target number of participants for vital medical research.

The review, led by researchers at the University of York and Hull York Medical School, found that fear about testing new treatments and possible side effects was the most common reason given by patients for not wanting to participate.

The researchers looked at the results of more than 400 studies from around the world on the reasons behind recruitment to health and medical studies.

Concerns about privacy and confidentiality have also increased over the past decade, the study suggests.

Among black and minority ethnic (BAME) patients, distrust in research and medical professionals was also a common reason given for not wanting to participate.

The authors of the study are calling for the development of new schemes to increase participation in research, which address patient anxieties and motivations.

Lead author of the study, Dr Peter Knapp, from the Department of Health Sciences at the University of York and the Hull York Medical School, said: "Clinical trials are an essential part of developing new medicines and improving healthcare, but recruiting patients to take part is one of the biggest challenges researchers face.

"Our review highlights how people are held back from taking part in research by their fears surrounding losing control of the treatments they receive and worries about possible side effects.

"Lack of trust was also identified as a common barrier for minority ethic patients around the world - perhaps a legacy of major historical violations of ethical standards in cases like the Tuskegee syphilis experiment."

The study found that on the other hand trust in doctors and clinical staff; a desire to help others, and the potential for improvements in their own health, were key factors that motivated patients to get on board with research.

Common methods that are currently in place in the NHS to increase patient participation in research are designed to prompt memory and raise awareness via schemes including phone reminders and personalised letters addressed to patients. The research highlights how these methods may have missed the mark as neither of these factors were identified in the study as a barrier to participation.

Dr Knapp added: "Interestingly, we found quite a few gaps between the main reasons people gave for their reluctance to take part and the interventions currently in place in healthcare systems like the NHS to try to remove barriers to participation.

"There is a need for more research to identify effective recruitment strategies that draw on psychological theory and the facilitators and barriers identified in this overview.

"Feelings of fearfulness are clearly a key issue and so it would make sense to look at interventions focused on directly addressing patient concerns.

"A desire to help develop better healthcare for others also came up as a strong reason for taking part in research and trials, and so this - people's sense of altruism - is another possibility that could be explored as a way of appealing to people."

Exercising can be a chore. We know it's good for us, and we may do it, but it's not always fun.

When training gets tough, finding something or someone that helps us get over that motivational hump can be just what we need. Researchers at the Norwegian University of Science and Technology (NTNU) have now tested how social media can help.

"We wanted to encourage and support people in feeling good about their training," says Professor Frode Stenseng at NTNU's Department of Education and Lifelong Learning.

The results of a recent experiment published in Frontiers in Psychology show a clear effect of targeted motivation on Instagram.

Over 500 study participants were recruited through Facebook and other online channels. Participants were at different training levels and had varying degrees of fire in their belly, but all of them exercised.

"A lot of emotions can come up when you exercise, no matter what level you're at," says Stenseng.

Participants were asked how motivated they were to exercise and how much they enjoyed their training. They were randomly split into two groups.

One group was able to follow an Instagram account called #dinmotivation. The researchers posted motivational posts on this account every three days over four weeks.

"We tried to make participants aware of their own motivation to exercise, and to increase their awareness of why they were training," says Stenseng.

Participants were then asked again about their exercise motivation and enjoyment.

People in both groups were equally prepared to exercise after the initial four weeks. They continued to train equally. But how much they enjoyed their training was different.

"Participants who followed the account postings developed more positive feelings related to their training. The other participants didn't," says Stenseng.

The results were clear. The people who had followed the Instagram postings reported enjoying their exercise much more than the ones who hadn't.

Following the postings involved spending no more than a few minutes per month on Instagram.

There's no lack of influencers with perfect bodies who are happy tell you about the joys of exercise on various social media. But whether they can help you to the same degree is uncertain at best.

"Today's influencers are undoubtedly having a great impact, and this was part of the reason for conducting our study," says first author and clinical psychologist Silje Berg.

Social media offer a multitude of tips and advice without necessarily having any scientific basis for them. A lot of the research to date has shown how this can adversely affect the message receivers.

"Our study is in many ways a counterpart to this. We wanted to show a method using social media that yields a significant positive effect by relying on scientific psychological theories," says Berg.

The posts on Instagram were based on self-determination and passion theory. That is, they were designed to give people a sense of belonging, mastery and autonomy. Autonomy should give a person the feeling that what they're doing is in line with their own needs and desires.

"We want to show how the influence of social media can be positive and used to promote public health - rather than the opposite. It can also inform how we should be critical of the source regarding content that appears in our feed. Awareness is key for achieving the positive effect we want," she says.

"Watching influencers is probably more like watching TV," says Stenseng.

After all, it's fun to watch talented athletes on TV, without thinking that you will ever be as good as them, or that the show will help you get up off the couch.

Likewise, influencers who write about exercise are often top-level athletes, partly because it's their job, so it's doubtful that you will ever reach their level. But it can be exciting to follow them anyway - even if it doesn't necessarily increase your own exercising enjoyment.

The researchers conclude that social media can be a good and inexpensive approach to reaching people with different messages about exercise and health - if it's done right.

"We meet people where they are," says Stenseng.

Using social media in a thoughtful way can improve the training pleasure of the individual, and at the same time contribute to public health.

"Several platforms are having a big impact. It's interesting how some exercise apps promise exercise enjoyment and motivation without having any clear theories for how they want to achieve that. Now our study has shown that theoretical content can have a positive effect, so we should encourage more people in this market to become knowledge-based," says Berg.

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Dual therapy reduces risk for bleeding better than triple therapy for patients with atrial fibrillation undergoing PCI

Abstract: http://annals.org/aim/article/doi/10.7326/M19-3763
Editorial: http://annals.org/aim/article/doi/10.7326/M20-0572
URL goes live when the embargo lifts

Use of dual therapy with a direct oral anticoagulant (DOAC) plus P2Y12 inhibitor was associated with reduced risk for major bleeding compared with triple therapy with a vitamin K antagonist (VKA) plus aspirin and P2Y12 inhibitor for patients with nonvalvular atrial fibrillation after percutaneous coronary intervention (PCI). Findings from a systematic review and meta-analysis are published in Annals of Internal Medicine.

Patients with ischemic heart disease and atrial fibrillation undergoing PCI create a clinical conundrum. It is not clear which antithrombotic regimen is most appropriate for preventing major adverse cardiovascular events in such patients. Evidence has favored DOAC over VKA for these patients for their atrial fibrillation management, but when antiplatelet therapy is also needed following PCI, recent trials have studied an alternative approach - dual therapy consisting of a DOAC and a P2Y12 inhibitor versus triple therapy comprising a VKA and DAPT (dual antiplatelet therapy). Theoretically, the cardiovascular benefits gained by using triple therapy could be offset by higher risk for bleeding, whereas withdrawal of aspirin might lead to higher rates of stent thrombosis and ischemic events with dual therapy.

Researchers from West Virginia University and Johns Hopkins University reviewed 4 trials encompassing nearly 8,000 patients to examine the effects of dual versus triple therapy on bleeding and ischemic outcomes in adults with atrial fibrillation after PCI. At the median follow-up of 1 year, high-certainty evidence showed that dual therapy was associated with reduced risk for major bleeding compared with triple therapy. Low-certainty evidence showed inconclusive effects of dual versus triple therapy on risks for all-cause mortality, cardiovascular mortality, myocardial infarction, stent thrombosis, and stroke. Results including sensitivity analyses, however, were compatible with a possible increased risk for ischemic end points with use of dual versus triple therapy.

Media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with the lead author, Safi U. Khan, MD, please contact Cassie Thomas at cassie.thomas@hsc.wvu.edu.

2. Conflicts of interest should be considered when evaluating health-related claims of CBD studies
The majority of cannabidiol studies with cannabidiol-related industry funding, conflicts of interest, or author employment have positive conclusions

Abstract: http://annals.org/aim/article/doi/10.7326/M19-3650
URL goes live when the embargo lifts

Conflicts of interest should be taken into account when evaluating studies investigating the health effects of cannabidiol (CBD), a chemical compound in cannabis. Researchers found that studies with cannabidiol-related industry funding, disclosed conflicts of interests, or author employment had conclusions that were supportive of cannabidiol. Findings from a brief research report are published in Annals of Internal Medicine.

Currently, only one CBD-derived drug has received approval from the U.S. Food and Drug Administration (FDA), and that drug is approved to treat a rare form of epilepsy. Regardless, companies continue to market and sell CBD products claiming that they prevent, cure, or treat various conditions. Given the growing number of companies invested in CBD's commercial success, along with previous evidence demonstrating associations between authors' conflicts of interest (COIs) and pro-industry conclusions, it is necessary to evaluate what research is being done on CBD and the industry's potential role in disseminating evidence to patients and physicians through the published literature.

Researchers from Yale School of Public health identified 417 articles published between 2014 and 2019 that discussed the characteristics, use, or therapeutic effect of CBD. Of these, 99 were human studies and 318 were animal studies, basic science studies, nonsystematic reviews, editorials, or commentaries. Among all 417 articles, approximately one fifth disclosed any CBD-related industry funding, and half of them received support from the same company. Of the 99 human studies, more than 60 percent of them had a CBD-related COIs (i.e. industry funding, COI disclosure, or author employment). Conclusions supportive of CBD were found in 110 studies with any CBD-related funding, COI disclosure, or author employment (110/149; 73.8%) compared to 164 studies without such conflicts (164/268; 61.2%). The authors suggest that given the potential for industry bias, sponsorship, and author affiliations, conflicts should be taken into account when evaluating the legitimacy of health-related claims from CBD studies.

Media contacts: For an embargoed PDF please contact Lauren Evans at laevans@acponline.org. To speak with the lead author, Joshua D. Wallach, MS, please contact him directly at joshua.wallach@yale.edu or 203-785-5551.

Also new in this issue:

Early Detection of Sporadic Pancreatic Ductal Adenocarcinoma: Problems, Promise, and Prospects
Suresh T. Chari, MD; Ayush Sharma, MBBS; Anirban Maitra, MBBS

Ideas and Opinions

Abstract: http://annals.org/aim/article/doi/10.7326/M19-2336

Annals Understanding Clinical Research: Studies Using Randomized Trial Data to Compare Nonrandomized Exposures
Catharine B. Stack, PhD; Anne R. Meibohm, PhD; Joshua M. Liao, MD, MSc; and Eliseo Guallar, MD, DrPH

Understanding Clinical Research

Abstract: http://annals.org/aim/article/doi/10.7326/M20-0071

ANN ARBOR, Mich. - While symptoms of appendicitis may be common, a new study suggests that accurately diagnosing the condition in the emergency department may be more challenging.

The study, published in JAMA Network Open, highlights that appendicitis is one of the most common surgical emergencies in the United States, but previous data show an appendicitis diagnosis is missed in 3.8% to 15% of children and in 5.9% to 23.5% of adults during an emergency department visit.

"In this study, we examined patients that initially presented to an emergency department with symptoms of appendicitis, but were not diagnosed at that first presentation," says the study's lead investigator, Prashant Mahajan, M.D., MPH, a professor and vice-chair of emergency medicine at Michigan Medicine and division chief of pediatric emergency medicine at C.S. Mott Children's Hospital.

Using insurance claims data, Mahajan and his team found that 6% of adults and 4.4% of children, who initially presented to the emergency department with symptoms associated with appendicitis, weren't diagnosed with appendicitis at the initial visit, but rather, at a repeat health care visit.

"The repeat health care visit could be either again at the emergency department or another health care facility, and the majority of these diagnoses were made within seven days of the initial emergency department visit," says Mahajan, also a member of the University of Michigan Institute for Healthcare Policy and Innovation.

Factors associated with a missed diagnosis

Mahajan and his team investigated factors that could explain why a diagnosis of appendicitis was missed during the patient's first visit to the emergency department.

He explains that symptoms of appendicitis are common, including abdominal pain, constipation, nausea and/or vomiting, fever and diarrhea.

"Many instances of potentially missed appendicitis in children and adults were initially labeled as constipation," Mahajan says. "Suggesting that in some instances, cases with appendicitis were either misdiagnosed as constipation or the label of constipation may have led to a particular type of cognitive bias called premature closure, which may have predisposed the provider to a missed diagnosis."

The research team also found a missed diagnosis was more common in women and patients with pre-existing medical conditions. In addition, diagnostic tests played a role in who was or was not diagnosed.

"One other finding that was particularly interesting is that patients who received only abdominal X-rays were more likely to be in the potentially missed appendicitis group," Mahajan says.

He notes that this finding suggests the need for health care providers to have better guidance on appropriate use of imaging.

"There is a potential to reduce unnecessary abdominal X-rays for the evaluation of abdominal pain, and use computed tomography (CT) scans for a more select group of patients either in the emergency department or on a follow-up visit," Mahajan says.

But, he notes that just because the study findings suggest that patients who were accurately diagnosed with appendicitis at the initial emergency department visit had more CT scans, the scans shouldn't always be automatically performed.

"We're not saying that CT scans should be used on all cases of abdominal pain," Mahajan says. "Instead, based on the study finding that most cases were diagnosed at the repeat visit, we hope this finding will give guidance to emergency department and other health care providers on when to follow up with patients, as well as when to request advanced imaging."

Follow-up care for appendicitis

Mahajan says the study highlights the need for health care providers to follow up with patients.

"Our data suggests that patients with abdominal pain who visit the emergency department may need some form of close follow-up health care to enhance the diagnosis of appendicitis," Mahajan says.

In addition, he says this study can shed further light on the frequency of diagnostic errors.

"This study provides health care providers with guidance regarding follow-up care in order to reduce the burden of diagnostic errors, which is estimated to occur in 12 million people every year in the U.S. and results in billions of dollars of unnecessary health care expenses," Mahajan says.

"Since the majority of diagnostic errors are preventable, our findings add to the current state-of-science to help improve diagnostic quality."

A team of researchers from Russia and Greece has shown a way to determine the origins and nature of quasar light by its polarization. The new approach is analogous to the way cinema glasses produce a 3D image by feeding each eye with the light of a particular polarization: either horizontal or vertical. The authors of the recent study in the Monthly Notices of the Royal Astronomical Society managed to distinguish between the light coming from different parts of quasars -- their disks and jets -- by discerning its distinct polarizations.

Active galactic nuclei, also known as quasars, are massive black holes with matter orbiting around them. They emit two oppositely directed jets of plasma traveling out into space at close to the speed of light.

Any massive black hole has matter orbiting around it, slowly falling toward it and emitting light. This matter forms what is known as an accretion disk. Due to a mechanism that is not yet fully understood, part of the matter approaching the black hole makes an escape. It is accelerated to tremendous velocities and expelled along the black hole's axis of rotation in the form of two symmetric jets of hot plasma. When a quasar is observed, the radiation picked up by a telescope comes from the jets, the accretion disk, and also from the stars, dust, and gas in the host galaxy.

To study galactic nuclei, researchers use a range of telescopes. Prior research had shown that the parts of a quasar emit two different kinds of light, technically referred to as distinctly polarized light.

Most of the telescopes operate in the optical range and see a galactic nucleus as a tiny faraway dot. They cannot tell which part of the quasar the light comes from and where the jet points if it happens to be the light source. All an optical telescope can do is measure the polarization of light, which has been shown to contain clues about the origins of that radiation.

Radio telescopes offer a much better resolution and produce an image that reveals the direction of the jet. However, these telescopes pick up no radiation from the most interesting central region, which includes the accretion disk.

The astrophysicists therefore had to combine the strengths of both types of telescopes for a detailed view of quasars.

Yuri Kovalev, who heads the MIPT Laboratory of Fundamental and Applied Research of Relativistic Objects of the Universe, commented: "The fact that jet radiation was polarized was known. We combined the data obtained by radio and optical telescopes, and showed that the polarization is directed along the jet. The conclusion from this is that hot plasma must be moving in a magnetic field that is coiled like a spring."

But there's more to it.

"It turned out that by measuring the polarization of the light picked up by the telescope, we can tell which part of radiation came from the jet and determine its direction," another co-author of the study, MIPT's Alexander Plavin said. "This is analogous to how 3D glasses enable each eye to see a different picture. There is no other way to obtain such information about the disk and jet with an optical telescope."

The findings are important for modeling black hole behavior, studying accretion disks, and understanding the mechanism that accelerate particles to nearly the speed of light in active galactic nuclei.

March 13, 2020 - A UK study of patients participating in low-dose CT lung cancer screening highlights the importance of spirometry (breathing tests) in the assessment of possible chronic obstructive pulmonary disease (COPD), and demonstrates that over-reliance on radiological changes alone may result in detection of clinically insignificant disease. The new study is published online in the Annals of the American Thoracic Society.

In "Prevalence, Symptom Burden and Under-Diagnosis of Chronic Obstructive Pulmonary Disease in a Lung Cancer Screening Cohort," Professor Samuel Janes of University College London's Lungs for Living Research Centre led a study that explored associations between symptoms, the presence of other diseases (comorbidities), spirometry and emphysema in patients enrolled in the Lung Screen Uptake Trial (LSUT). LSUT tested whether specifically targeted invitation strategies could enhance the participation of high-risk, low-income individuals in low-dose CT screening for lung cancer. Mamta Ruparel, MRCP, of the Lungs for Living Research Centre, helped lead the COPD study.

"More than half of those attending a 'lung health check' as part of a pre-screening assessment were found to have physiological parameters of airflow obstruction consistent with a diagnosis of COPD, while two-thirds did not report a prior diagnosis," Prof. Janes explained. "This study highlights that, while the finding of emphysema was fairly common in this population of current or past heavy smokers who were at risk of lung cancer, the physiological changes of airway obstruction found through spirometry was the strongest signal of the presence of respiratory symptoms and thus potentially clinically relevant COPD."

The study only looked at COPD and did not test the effectiveness of low-dose CT screening for detecting early lung cancer, which has already been proven.

The COPD researchers asked participants about current or recent respiratory symptoms. Those who reported a history of current cough or shortness of breath within the previous 12 months were regarded as having respiratory symptoms. Participants were also asked about a history of COPD, pneumonia, asthma and other potential comorbidities such as coronary heart disease, high blood pressure and diabetes. Participants were labelled as having "undiagnosed COPD" if they met with the standard spirometric definition of COPD and did not report a prior diagnosis of COPD, chronic bronchitis or emphysema.

All participants were given spirometry testing, without being given a bronchodilator in advance. Airflow limitation was classified according to accepted standards. Nine-hundred eighty six participants were divided into three groups, based on spirometry results and their reported history of COPD: "no COPD," "undiagnosed COPD," and "known COPD." Health and demographic variables were statistically analyzed. Participants' CT scans were read by radiologists specializing in lung disease. COPD was subjectively classified by the radiologists as "none," "mild," "moderate" or "severe" based on visual inspection of their CT images.

Thirty-two percent of those with "undiagnosed COPD" had no emphysema on their CT scans. Five-hundred sixty of 986 individuals (57 percent) included in the analysis had pre-bronchodilator spirometry consistent with COPD. Sixty-seven percent did not have a prior history of COPD and were considered "undiagnosed." Emphysema prevalence in those with known COPD was 73 percent, while those considered "undiagnosed" had a prevalence of 68 percent. Inhaler use and symptoms were more common in the "known" than "unknown" COPD group, while comorbidities were common in all groups. Statistically adjusted odds of respiratory symptoms were more significant for airflow obstruction than emphysema.

"Thirty-two percent of participants with airflow obstruction who did not report a prior diagnosis of COPD had no emphysema on their CT scan, while, conversely, individuals with emphysema did not always have airflow obstruction," said Dr. Ruparel. "Based on our findings, reliance on CT alone to diagnose COPD risks missing individuals who may actually have this condition, while over-diagnosing others. Since individuals at risk for lung cancer are also at risk for COPD, we recommend including spirometry in low-dose CT lung cancer screening programs, in order to assist in making accurate diagnoses."