Body

PITTSBURGH, April 9, 2020 - A novel clinical trial developed by researchers at the University of Pittsburgh School of Medicine launched today at UPMC to address one of the most important debates during the COVID-19 pandemic: How should doctors decide between quickly adopting new therapies, such as the anti-malarial drug hydroxychloroquine, and waiting until they are tested in longer clinical trials?

"The solution is to find an optimal tradeoff between doing something now, such as prescribing a drug off-label, or waiting until traditional clinical trials are complete," said Derek Angus, M.D., M.P.H., professor and chair, Department of Critical Care Medicine at Pitt and UPMC. "We've developed a way to do that with an adaptive clinical trial model that relies on a type of artificial intelligence known as reinforcement learning to identify the best, evidence-backed therapy for COVID-19 much faster than using the traditional scientific approach."

Before COVID-19 emerged, Angus and a wide range of international collaborators had developed a platform, called REMAP-Community Acquired Pneumonia (REMAP-CAP), designed to find optimal treatments for severe pneumonia both in non-pandemic and pandemic settings. When COVID-19 began circulating, REMAP-CAP was rapidly adapted, as per its intent, to incorporate additional treatment regimens specifically targeting the SARS-CoV-2 virus. The international team describes the REMAP-CAP platform in a manuscript published today in the Annals of the American Thoracic Society (AnnalsATS).

REMAP (randomized, embedded, multi-factorial, adaptive platform) allows researchers to rapidly test multiple treatment approaches simultaneously at a lower cost and with fewer patients than traditional clinical trials. The REMAP design, first described by Angus in 2015 in the Journal of the American Medical Association (JAMA), is a flexible version of what are called "adaptive platform trials." "Adaptive platform trials are rapidly being endorsed by the U.S. Food and Drug Administration, the Bill & Melinda Gates Foundation and others as a long-needed revolution in clinical trials," said Angus, who holds the Mitchell P. Fink Endowed Chair at Pitt.

He compares the REMAP approach to a chef offering a prix fixe menu with appetizer, main course and dessert. The chef may try various combinations, serving sizes and options, sometimes leaving out the appetizer or dessert, and adjusting on the fly as plates come back scraped clean or barely touched, until hitting on the combination that sells best.

The UPMC-REMAP-COVID19 trial, built on the backbone of the REMAP-CAP platform, will be particularly powerful because it is being integrated with the electronic health record system at UPMC, noted Angus. "In a pandemic, doctors will not have the time to debate the pros and cons of every possible clinical trial. By building this one-stop solution at the point-of-care, we are rolling out an approach that can assure that every patient admitted with COVID-19, if they choose to, can be enrolled in the program."

"We must throw out old ways of thinking and fuse clinical care and clinical research into one extremely efficient system," said Angus, who authored a recent viewpoint in JAMA advocating for the "learning while doing" approach. "This is an unprecedented pandemic and we need an unprecedented response."

UPMC-REMAP-COVID19 will open across UPMC's 40-hospital system and begin with multiple treatments tested simultaneously in different combinations -- including hydroxychloroquine, steroids and medications called immunomodulators that alter the responsiveness of the immune system. If new drugs need to be tested, they are simply rolled into the platform as study amendments, rather than tested in separate free-standing trials. All participants will receive the current standard of care, and most also will receive one, two or three of the experimental treatment options. This means that, at launch, only 12.5% of participants will be strictly assigned to the placebo arm of the trial and, within weeks, researchers expect that about 99% of patients will be receiving one or more active therapies specifically targeting COVID-19.

Furthermore, because the UPMC-REMAP-COVID19 platform is connected to the worldwide REMAP-CAP, the trial learns from the entire international experience. REMAP-CAP is enrolling patients with COVID-19 in North America, Europe, Australia and New Zealand, and expanding rapidly.

"The trial design uses a machine-learning model that incorporates data from patients enrolled across the world to continuously learn which therapies and combinations of therapies are performing best," explained AnnalsATS co-author Scott Berry, Ph.D., president and senior statistical scientist of Berry Consultants, who worked with Angus and his colleagues to build the statistical model. "Last week, the Chief Medical Officer of the United Kingdom's National Health Service urged every hospital in the country to participate in this trial. As more institutions join, the model learns faster."

If one of the treatments shows early signs of performing better than the others, patients are automatically enrolled more often into that treatment option. Physicians can be assured that they are always betting on the winning horse in the moment, and poorly performing options are quickly discontinued.

"This allows us to always rapidly identify which treatment works best, while keeping the number of patients needed to achieve statistical significance low," said Angus. "It also means we get the best treatment to the most patients right out of the gate."

In a perspective published in the New England Journal of Medicine, researchers from the Benson-Henry Institute (BHI) for Mind Body Medicine at Massachusetts General Hospital (MGH) and from UC Davis Health call for broader use of mind-body practices.

In a time when meditation, yoga and mindfulness increase in popularity for general well-being, the piece emphasizes the necessity of fully integrating these stress-reduction practices into patient treatment plans and medical research.

Stress exacerbates anxiety and depression and plays a role in conditions such as cardiovascular disease, autoimmune disorders, irritable bowel syndrome, headaches and chronic pain, according to lead author Michelle Dossett of UC Davis Health.

"By reducing the body's stress response, mind-body practices can be a powerful adjunct in medicine by helping to decrease patients' symptoms and improving their quality of life," said Dossett, who was a physician and researcher with BHI when the perspective was written.

Dossett also noted that mind-body practices can be helpful in reducing stress related to the COVID-19 epidemic.

Despite its recent rise in popularity among the general public, mind-body medicine isn't new. Researchers at BHI have been integrating the field of mind-body medicine into MGH's clinical care, research and training programs since 2006. Early research on the advantages of such techniques dates back 40+ years, when the institute's founder and perspective senior author, Herbert Benson, became one of the first Western physicians to bring spirituality and healing into medicine and is most famously known for his work with the Relaxation Response.

"The Relaxation Response," Benson has stated, "is an inborn, anti-stress capacity that transcends the differences that separate mind from body, science from spirituality and one culture from another."

At BHI, mind-body medicine is widely recognized as the third leg of a three-legged stool: the first leg is surgery, the second is pharmaceuticals and the third is self-care, in which patients learn techniques to improve their own health through mind-body medicine, nutrition and exercise.

"Western medicine has produced revolutionary health benefits through advances in pharmacotherapies and procedures," the researchers wrote in the perspective. "It now faces enormous challenges in battling stress-related noncommunicable diseases. ...Chronic pain, often perpetuated by psychosocial stress, has become an epidemic that our pharmaceutical arsenal is poorly equipped to handle and medical costs continue to soar. Mind-body therapies can be a helpful adjunct in managing chronic pain and other stress-related noncommunicable diseases by fostering resilience through self-care."

The article also addresses skeptical patients' preconceived notions of mind-body medicine as well as the anticipated barriers of service coverage and clinician education on the appropriate use of these tools. These challenges further reinforce the need for continued research and investment into the development and implementation of personalized practices to maximize their public health potential.

What The Study Did: Emergency department data were used to describe the number, type, severity and factors associated with firework-related eye injuries that occurred in the United States from 1999 to 2017.

Authors: Natasha Nayak Kolomeyer, M.D., of Thomas Jefferson University in Philadelphia, 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/jamaophthalmol.2020.0832)

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

LEXINGTON, Ky. (April 9, 2020) -- Linda J. Van Eldik, director of the Sanders-Brown Center on Aging at the University of Kentucky, co-authored a paper reporting the first human clinical study of a drug candidate that suppresses injury and disease-induced inflammation of the brain.

The paper was accepted in February by Clinical Pharmacology in Drug Development and the article published online this week. Clinical Pharmacology in Drug Development is an international, peer-reviewed, online publication focused on publishing high-quality clinical studies, especially those presenting first-time in-human study results.

The article explains how acute brain injuries resulting from trauma or cerebrovascular injury, such as traumatic brain injury (TBI) and intracerebral hemorrhage (ICH), are major medical problems that cause substantial mortality and neurologic damage. The authors state in the article, "Although there have been significant advances in the medical management of patients with acute brain injuries, there is a clear and urgent need for interventions that improve neurologic recovery and outcomes."

To address that need, a small-molecule drug candidate now known as MW189 was developed. MW189 blocks abnormal inflammation in the brain that is known to contribute to injury- and disease-induced neurologic impairments in a number of acute and chronic brain disorders. This study examining MW189 in healthy adult volunteers was performed by a collaborative team from UK, Duke University, and Northwestern University. The work by Van Eldik and the rest of the team is substantial as it is the first time MW189 had been tested in humans. The study was open to healthy men and women between the ages of 18 and 50 years.

The article reports that MW189 was safe and well-tolerated by volunteers, with no clinically significant concerns after either a single dose or multiple administrations of MW189. "This is an important result," said Van Eldik, "because in order to get future FDA approval of any drug for patients, the drug candidate first has to be tested and shown to be safe in healthy volunteers." Van Eldik goes on to say "overall, these studies support further development of MW189 for treatment of patients with acute brain injuries such as TBI or hemorrhagic stroke."

Immunotherapies using immune checkpoint inhibitors (ICI) have dramatically improved cancer survival in the last decade, resulting in the Nobel Prize for Medicine in 2018.

Unfortunately, a significant number of cancer patients are refractory to ICI or relapse these treatments by developing resistance mechanisms. Metastatic UM is one of the most refractory cancers treated with immunotherapies and why these cancer patients do not respond to these treatments are still unknown.

The study conducted by researchers from the University of Liverpool and Turku, using state-of-the-art technologies to phenotype human UM tumors, sheds some light on the mechanisms behind resistance to immunotherapies.

"One of the most common genetic alterations that initiates the development of uveal melanoma occurs in a tumor suppressor gene called BAP1. This gene is found absent or mutated in almost 50% of all UM patients and is associated with high-risk of metastasis development, in which immunotherapy will not work", says the lead author of the study, Dr Carlos R. Figueiredo from the University of Turku, Finland.

The researchers found that UM cells lacking the BAP1 protein activate specific mechanisms that are responsible for shutting down T lymphocytes, the most important immune cells that fight and kill cancer cells.

Most importantly, the researchers discovered which molecules are potentially responsible for this process in UM. Strikingly, some of these molecules can be promptly targeted using existing drugs that are approved for the management of other diseases.

Therefore, these results build a foundation for a new era of combinatory treatments using immune checkpoint inhibitors against metastatic uveal melanoma. However, the researchers highlight that further clinical studies are needed to establish the efficacy of these combinatory treatments.

PLYMOUTH MEETING, PA [April 9, 2020] -- The National Comprehensive Cancer Network® (NCCN®)--an alliance of leading cancer centers--is continuing to share new resources for optimal cancer management amid new and changing challenges related to the Coronavirus Disease 2019 (COVID-19). The nonprofit organization's Best Practices Committee has published a new article online-ahead-of-print in JNCCN--Journal of the National Comprehensive Cancer Network detailing their recommendations for keeping cancer patients, caregivers and staff as safe as possible.

"The unprecedented challenges we are all facing from the COVID-19 pandemic heighten NCCN's commitment to sharing evidence-based consensus from leading medical experts as rapidly as possible, free-of-charge, to everyone around the world," said Robert W. Carlson, MD, Chief Executive Officer, NCCN. "We are doing everything we can to review and share reliable information that will help keep oncology patients, providers, and staff safe under the new reality of increased risk."

"We can continue to provide our patients with effective and compassionate care, without sacrificing the health and safety of our teams, colleagues, and families, by carefully evaluating any emerging research and modifying our treatment approaches accordingly," said lead author Pelin Cinar, MD, MS, UCSF Helen Diller Family Comprehensive Cancer Center. "People with cancer and their loved ones already go through so much, and now they face new fears around catching COVID-19 or delaying necessary treatment. By sharing these recommendations, we want to reassure the oncology community that there are some aspects of care that we can and will control in order to improve outcomes for people with cancer."

The JNCCN article contains the most current information at the time of publication, but notes that recommendations regarding public safety and practice may change rapidly; individuals can also keep up with the most up-to-date information via the CDC website.

The NCCN Best Practices Committee recommendations can be summarized as follows:

Patient Safety

Prescreen and screen for COVID-19 symptoms and exposure history via telephone calls or digital platforms

Develop screening clinics to allow for patients with symptoms to be evaluated and tested in a dedicated unit with dedicated staff

Convert in-person visits to telemedicine visits when possible

Limited or no visitor policy

Limit surgeries and procedures to only essential, urgent, or emergent cases

Consideration of alternative dosing schedule to allow for fewer in-person visits to the cancer center and/or the infusion center

Switch from infusional therapy to oral oncolytics if equivalent formulation is available

Transition outpatient care to care-at-home whenever possible (e.g. pump disconnection, administration of growth factors, hormone therapy)

Increase interval between scans or use biochemical markers in lieu of scans

Provide resources for wellness and stress management for patients

Healthcare Worker Safety

Assure availability and use of appropriate personal protective equipment (PPE) per guidelines

Create a centralized resource or website to communicate recommendations to the healthcare workers around PPE and workflows

Implement daily screening tools and/or temperature checks

Telecommute when possible, with limited onsite staff participating in rotations on a daily basis

Establish clear stay-at-home and return-to-work guidelines

Provide resources for wellness and stress management for healthcare workers

The full article can be found at: https://jnccn.org/page/May%20Special%20Feature%20on%20COVID-19%20/new-special-feature-on-covid19.

In addition to Dr. Cinar, the article includes authors from Abramson Cancer Center at the University of Pennsylvania, Duke Cancer Institute, Fred & Pamela Buffett Cancer Center, Mayo Clinic Cancer Center, Moffitt Cancer Center, Ohio State Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Seattle Cancer Care Alliance (including Fred Hutchinson Research Center and University of Washington), University of Colorado Cancer Center, and Yale Cancer Center/Smilow Cancer Hospital.

Meanwhile, NCCN continues to add to, and update, the growing list of free resources available at NCCN.org/covid-19. Recently-published items include:

General

Asymptomatic Testing Strategy (UAB Medicine)

Cancer Patients Factsheet (Huntsman Cancer Institute)

Communicating Changes in Delivery of Care (University of Michigan Rogel Cancer Center)

N95 Respirator Decontamination and Re-Use Process (University of Nebraska Medical Center)

Patient Scheduling Recommendations (Huntsman Cancer Institute)

Providing Oncology Treatments in the Outpatient Setting

PPE Conservation Plan (University of Colorado Cancer Center)

Self Screen Signs All Translations (UCSF)

Universal Masking Guidelines (Huntsman Cancer Institute)

Utah Crisis of Standards 2010 Influenza Pandemic Algorithm

Visitor Policy Letter (Huntsman Cancer Institute)

Treatment of Cancer by Site

Breast Cancer

Colorectal Cancer

Melanoma

Non-Melanoma Skin Cancer

Prostate Cancer

T-Cell and Primary Cutaneous Lymphomas

Screening and Early Detection

Prostate Cancer

Supportive Care

Hematopoietic Growth Factors

Self-Care and Stress Management (Providers)

Self-Care and Stress Management (Patients/Caregivers)

NCCN remains committed to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives under any circumstances. The organization has continued posting new updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)--which contain optimal recommendations for normal resource levels in the United States--while also sharing new shorter term guidance for adjusting cancer care during the COVID-19 pandemic. NCCN's Global Program also provides guidelines to account for differing regional resource levels and non-English languages, while the NCCN Foundation® provides funding for versions in non-medical language for patients and caregivers. The NCCN Guidelines® are always available free-of-charge for non-commercial use at NCCN.org (free registration required) or via the Virtual Library of NCCN Guidelines® App.

TAMPA, Fla. - Prostate cancer is the most common malignancy among men in the United States. It is also the second most common cause of cancer-related deaths. Despite improved treatments for prostate cancer, many patients with advanced disease eventually develop drug resistance. Researchers in the Center of Excellence for Evolutionary Therapy at Moffitt Cancer Center believe that adaptive treatments based on evolutionary principles may be an effective approach to prostate cancer treatment by preventing the development of drug resistance and prolonging patient survival. In an article published today in Nature Communications, the research team provides a closer look at a model and data showing that individual patient alterations in the prostate-specific antigen (PSA) biomarker early in treatment can predict outcomes to later treatment cycles of adaptive therapy. These models could eventually be used to devise patient specific treatments according to changing tumor growth and biomarker patterns.

Patients with prostate cancer are commonly treated with radiation therapy or surgery followed by androgen deprivation therapy (ADT) at the highest tolerated dose to kill as many cancer cells as possible. While initial responses to this approach are often effective, eventually patients develop drug resistance and their tumors recur.

"Continuous treatment, by maximally selecting for resistant phenotypes and eliminating other competing populations, may actually accelerate the emergence of resistant populations - a well-studied evolutionary phenomenon termed competitive release," said study author Heiko Enderling, Ph.D., associate member of Moffitt's Department of Integrated Mathematical Oncology.

Enderling and his team, in collaboration with scientists from Duke University, University of North Carolina and Arizona State University, believe that instead of using a continuous maximum tolerated dose, a better approach would be to use adaptive therapy with intermittent dosing. This treatment strategy is based on changing patterns of biomarker levels in individual patients; treatment may increase or decrease or even be temporarily halted according to patient-specific markers and tumor dynamics.

"Fully harnessing the potential of intermittent prostate cancer therapy requires identifying ADT resistance mechanisms, predicting individual responses and determining potentially highly patient-specific, clinically actionable triggers for pausing and resuming intermittent-ADT cycles," said study lead author Renee Brady, Ph.D., a post-doctoral fellow in the Department of Integrated Mathematical Oncology at Moffitt. She added this seemingly daunting challenge could be overcome by advances in mathematical modeling.

Previous mathematical models are based on a variety of different resistance mechanisms and include numerous variables; however, they do not completely predict patient responses and outcomes to intermittent ADT. The Moffitt team built its model on a different theory; they hypothesized that prostate cancer stem cells contribute to tumor differences between patients and treatment failure. They devised a model that simulated and predicted the dynamics of three factors during intermittent ADT: prostate cancer cells, differentiated cancer cells and the biomarker PSA. The researchers validated their model to show that stem cells are highly associated with intermittent ADT resistance. Patients who are resistant are more likely to have stem cells with higher rates of self-renewal, subsequently leading to higher levels of prostate cancer stem cells and changing levels of the biomarker PSA during each treatment cycle.

The researchers combined their model with clinical data from a study of intermittent-ADT therapy and demonstrated that it predicted the development of patient resistance with 89% accuracy. Furthermore, they demonstrated that by using this model, they could predict which patients would benefit from alternative treatments.

These results demonstrate the feasibility of using mathematical models to guide adaptive therapy clinical trials and provide more personalized treatment options to improve patient outcomes. "This ability to learn from early treatment cycles and predict subsequent responses adds an essential degree of personalization and flexibility to a cancer treatment protocol," said Enderling.

MINNEAPOLIS - People who live in urban areas with higher levels of air pollution may score lower on thinking and memory tests and may also lose cognitive skills faster over time, or it is possible they also may not, according to a study published in the April 8, 2020, online issue of Neurology®, the medical journal of the American Academy of Neurology. Researchers examined the association of air pollution levels and cognitive impairment and decline in participants in two large epidemiological studies. They found an association between the air pollution and cognitive decline in one study group but not in the other.

"As people live longer lives and the aging population grows, age-related cognitive decline is a growing public health concern with profound social, economic and health effects, so finding ways to reduce the risk is important," said study author Erin R Kulick, Ph.D., M.P.H., of Brown University School of Public Health in Providence, R.I., and a member of the American Academy of Neurology. "Air pollution can affect large populations of people because it has known cardiovascular risks, and previous research has found that it may also contribute to cognitive decline. However, the results of our research were mixed."

The study involved people living in the Northern Manhattan area of New York City who were enrolled in two larger long-term studies: 5,330 people with an average age of 75 enrolled in the Washington Heights-Inwood Community Aging Project; and 1,093 people with an average age of 70 enrolled in the Northern Manhattan Study. Both groups were ethnically and racially diverse with black, white and Hispanic participants.

All participants were given medical exams at the beginning of the study as well as cognitive tests to measure memory, language skills and executive function, which involves thinking skills like organizing, planning and completing tasks.

The group from the Washington-Heights-Inwood study of 5,330 participants was followed an average of seven years with six rounds of follow-up testing every 18 months to two years. The Northern Manhattan study group of 1,093 participants was followed for five years with one follow-up round of testing.

Researchers used the residential addresses of each participant to determine their exposures to three air pollutants. Those pollutants were nitrogen dioxide and two groups of particulate matter, particles of liquids or solids suspended in air that were less than 2.5 microns in diameter called fine particulate matter and particles that were less than 10 microns in diameter called respirable particulate matter. Average levels of air pollutants were similar for both groups of participants. In each group, participants were divided into four groups based on their air pollution exposure.

Researchers found that participants in the Washington-Heights Inwood study were exposed to a yearly average of 32 parts per billion of nitrogen dioxide, 13 micrograms per cubic meter (μg/m3) of fine particulate matter and 21 μg/m3 of respirable particulate matter The U.S. Environmental Protection Agency (EPA) considers up to 53 parts per billion to be a safe level of yearly average exposure to nitrogen dioxide, up to 12 μg/m3 for fine particulate matter and up to 50 μg/m3 for respirable particulate matter.

"While the levels were in the range considered safe by the EPA, it's possible that these results reflect higher levels from an earlier point in time. It also raises the question of whether the federal levels are low enough to protect people's health," said Kulick.

The researchers found that in the Washington Heights-Inwood group, people with greater exposure to higher levels of air pollution had lower scores on the tests at the beginning of the study and more rapid rates of decline.

Exposure to nitrogen dioxide was linked to an accelerated rate of cognitive decline comparable to one year of aging. Results were similar for fine and respirable particulate matter.

In the Northern Manhattan group, researchers did not find an association between cognitive function and air pollution. Kulick says the difference in results may be because the second group was much smaller and only had one round of follow-up compared to six rounds for the first group.

"A strength of our study was that we were able to analyze the rates of cognitive decline over time so it adds important findings to the growing body of scientific evidence about air pollution and its effects on the brain health of older adults," Kulick said. "More research is needed to better understand our study's mixed results. The good news for public health is that air pollution can be reduced, and has been in some cities, through laws and regulation. But there are still millions of people living in areas of the United States where major air quality improvements are needed."

A limitation of the study was that while it included levels of air pollution near a person's residence, it did not account for levels of pollution at the workplace or elsewhere. Also, many participants grew up in other countries and may have had different exposures to air pollution at younger ages.

COLUMBUS, Ohio - Medical marijuana users who say they have high levels of pain are more likely than those with low pain to say they use cannabis three or more times a day, a new study finds.

However, daily marijuana users with severe pain also reported their health had become worse in the past year.

The results don't necessarily mean that marijuana is not effective in treating at least some kinds of pain, according to the researchers. But it suggests more research is needed before marijuana is accepted as an effective treatment for severe pain.

"It's not clear if marijuana is helping or not," said Bridget Freisthler, co-author of the study and professor of social work at The Ohio State University.

"The benefits aren't as clear-cut as some people assume."

The study was published recently in the International Journal of Drug Policy.

One issue is the complex relationship between pain, marijuana use and self-reported health, said Alexis Cooke, lead author of the study and postdoctoral scholar in psychiatry at the University of California, San Francisco.

"Having high chronic pain is related to poorer health, so it may be that people who are using marijuana more often already had worse health to begin with," Cooke said.

"There are still a lot of questions to answer."

The study involved a survey of 295 medical marijuana dispensary patients in Los Angeles. The surveys were conducted in 2013, when California allowed marijuana use only for medical purposes.

All participants were asked how often they used marijuana; rated how their current health compared to one year ago (on a five-point scale from "much better" to "much worse"); and were asked two questions about their pain levels. Based on their answers, the researchers rated participants' pain as low, moderate or high.

Among those surveyed, 31 percent reported high pain, 24 percent moderate pain, and 44 percent were in the low-pain category.

Daily marijuana use was reported by 45 percent of the sample, and 48 percent said they used three or more times per day.

The percentage of participants who used marijuana every day did not differ by pain categories. But about 60 percent of those who reported high pain used the drug three or more times a day, compared to 51 percent of those with moderate pain and 39 percent of those in the low-pain group.

Findings showed no association between daily marijuana use and change in health status among those with low levels of pain. But daily marijuana use was linked to worsening health status among those reporting high levels of pain.

However, strangely, there was no association between how often participants used marijuana per day and changes in health status. There's no easy explanation for this, Freisthler said.

"It shows how little we know about marijuana as medicine, how people are using it, the dosages they are receiving and its long-term effects," she said.

People use marijuana for a variety of different types of pain, including cancer, joint pain, HIV and nerve pain. Researchers don't know if marijuana has different effects on different causes of pain, Cooke said.

"Chronic pain is also associated with depression and anxiety. Marijuana may help with these problems for some people, even if it doesn't help with the pain," she said.

In addition, marijuana use seems to help people who have lost their appetite due to pain or nausea caused by cancer drugs.

"It may not be the pain that patients are trying to address," Cooke said.

The results do suggest we need to know more about the link between marijuana and pain relief, Freisthler said.

"Particularly since the opioid crisis, some people have been touting marijuana as a good substitute for opioids for people in pain," she said.

"But our study suggests we don't know that marijuana is helping to address pain needs."

Philadelphia, March 31, 2020 - DNA sequencing is becoming a more commonplace method for detecting diseases and improving precision medicine. Because DNA sequencing does not detect all possible disease-causing mutations, RNA sequencing is often used to address this important gap. However, RNA sequencing is typically performed on clinically-accessible tissues from blood and skin and likely does not represent a complete view of the rest of the body.

Hoping to refine the usefulness of RNA sequencing, a team of researchers from Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania reviewed a database of RNA sequencing results in non-clinically-accessible tissues from organs like the brain and heart. This helped them identify differences between tissues that were well expressed to help identify when clinically-accessible tissues like blood and skin samples are most useful and when they are not. To aid future sequencing and aid diagnosis, the study team also developed an online resource outlining how these differences affect specific tissues and genes of interest. The findings were published online today by the journal Genetics in Medicine.

Researchers continue to improve the ability of sequencing tests to detect genetic mutations that drive disease. Exome sequencing captures about 31% of inherited genetic disorders, and genome sequencing improves this rate somewhere between 10% and 15%, meaning that the majority of patients who receive this screening will not receive a proper molecular diagnosis. One of the primary difficulties is the number of non-coding variants these tests capture. These variants are capable of causing disease, but they are difficult to predict and therefore often ignored by existing diagnostic techniques.

One way these variants can cause problems is their ability to alter RNA splicing, or the process by which non-coding parts of genes are removed so that only the coding portions are available to create necessary proteins. Therefore, variants that affect RNA splicing can alter the function of essential proteins, which can lead to disease. RNA sequencing can help detect these variants and add to the knowledge gleaned from exome and genome sequencing. However, RNA sequencing is complicated because the gene must be expressed in the tissue of interest, and often those tissues are not accessible.

"We know that we are unable to test tissues in the brain, heart and certain other organs for diagnostic purposes, but we also know that using RNA sequencing on these tissues could reveal important genetic information we might not otherwise be able to capture," said Elizabeth Bhoj, MD PhD, an attending physician with the Division of Human Genetics at CHOP, an assistant professor of pediatrics at the Perelman School of Medicine, and senior co-author of the study. "By studying both clinically- and non-clinically-available tissues, we hoped this study would reveal the true extent of what we may be missing with current RNA sequencing methods."

The study team quantified RNA splicing in 801 RNA-sequenced samples from 56 different adult and fetal tissues. Genes and splicing events were identified by the team in each non-clinically-available tissue, which then allowed the researchers to determine when RNA sequencing in each clinically-available tissue actually inadequately represents them. The team then developed its own online resource, MAJIQ-CAT, so that others could explore their analysis for specific genes and tissues.

The researchers found that 40.2% of non-clinically-available tissues have RNA splicing that is inadequately represented in at least one clinically-available tissue, and 6.3% of genes have splicing inadequately represented by all clinically-available tissues. While a majority (52.1%) of these genes have low expression in clinically-available tissues, the study team showed that 5.8% are inadequately represented despite being well-expressed, thereby representing a significant portion of genes of interest not being properly captured by traditional RNA sequencing methods.

"By using MAJIQ-CAT, researchers can determine which accessible tissues, if any, best represent RNA splicing in genes and tissues of interest," Bhoj said. "While this does not address the entire gap left by current exome and genome sequencing methods, we believe we can capture more genes and determine how they affect human health."

The research team drew from their diverse scientific backgrounds for this study to improve clinical diagnosis. Bhoj and her lab provided expertise in genetics and clinical diagnostics with the computational expertise of the lab of Yoseph Barash, PhD, an associate professor in the Department of Genetics at Penn. The work was led by Joseph Aicher, an MD/PhD student in the Genomics and Computational Biology program at Penn who was co-mentored by Bhoj and Barash.

What The Study Did: Data for 950,000 black, white, Asian and Hispanic patients in the U.S. diagnosed with prostate, ovarian, breast, stomach, pancreatic, lung, liver, esophageal, or colorectal cancers were analyzed to examine differences by race and ethnicity in stage at diagnosis, use of therapy, overall survival and cancer-specific survival.

Authors: Haiyong Wang, Ph.D., of the Shandong First Medical University and Shandong Academy of Medical Sciences in Shandong, China, 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/jamanetworkopen.2020.2950)

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

Clinicians in many countries are using what's known as the Growth Assessment Protocol (GAP) to monitor fetal growth in pregnant women. Some reports state that the programme may be linked with reduced rates of stillbirth, but rigorous studies have not been conducted. A study published in Ultrasound in Obstetrics & Gynecology calls these claims into question.

By studying more than 11 million singleton pregnancies in UK regions with similar healthcare systems, the study's investigators demonstrated that the stillbirth rate in Scotland declined faster than in England and Wales between 2010 and 2015, despite a significantly lower uptake of the GAP program in Scotland. The findings suggest that the reduction in stillbirth rate in England and Wales cannot be attributed solely to implementation of the GAP program.

"The greater decline in the stillbirth rate in Scotland, despite the low uptake of the programme, suggests that other beneficial public health measures common to both systems are responsible," the authors wrote.

As COVID-19 ravages the globe, researchers are working tirelessly to develop new diagnostics, vaccines and therapeutics. The question on the minds of scientists in many diverse fields is how they can help. Now, some researchers are publishing their thoughts on this topic in the form of editorials, perspectives and viewpoints in various ACS journals.

In an editorial in Industrial & Engineering Chemistry Research, Christopher Nicholas compares the current situation to the influenza pandemic of 1918, which killed 30 million people. Now, the world is in a much better position to prevent deadly diseases, Nicholas says, in part because of widespread water chlorination and chlorine-based disinfectants. Yet, a remaining challenge is developing robust, quick sensors with very low detection limits for viruses such as SARS-CoV-2, J. Justin Gooding and Sue Min Liu write in an editorial in ACS Sensors. To determine the correct course of action for healthcare workers and patients, diagnostic results are needed within minutes or even seconds, they say. In a viewpoint in ACS Chemical Neuroscience, Abdul Mannan Baig and colleagues present evidence that SARS-CoV-2 could target the central nervous system, possibly contributing to the virus' ability to cause sickness and death. A subsequent letter to the editor by Karlo Tojan expanded on possible methods for neurological involvement and short- and long-term clinical implications. And in a perspective in ACS Nano, Xiaoyuan Chen and co-workers describe promising new strategies that use cell-membrane mimics as decoys to trap viruses and other pathogens.

Meanwhile, viewpoints in Environmental Science & Technology offer ideas for how environmental scientists can help. According to Krista Wigginton and Alexandria Boehm, scientists need to gain a better understanding of how environmental conditions, such as sunlight, heat and humidity, can inactivate viruses. More research also needs to be done to ensure that wastewater treatment facilities protect against SARS-CoV-2 and other viruses excreted in urine or feces. Sewage could also be monitored to detect outbreaks before clinical cases are identified, the researchers say. Along these lines, Kang Mao, Hua Zhang and Zhugen Yang propose that portable, paper-based devices could be used to detect SARS-CoV-2 in community wastewater at an early stage, so that interventions can be taken quickly. In another perspective, Guibin Jiang and colleagues argue that there is a great need for research on how environmental factors, such as airborne dust, pollution, and aerosols from contaminated sewage, affect the transmission of SARS-CoV-2.

Relevant viewpoints and editorials are available at the hyperlinks above.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS' mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and its people. The Society is a global leader in providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a specialist in scientific information solutions (including SciFinder® and STN®), its CAS division powers global research, discovery and innovation. ACS' main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive news releases from the American Chemical Society, contact newsroom@acs.org.

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As the coronavirus pandemic claims lives and overwhelms health care systems throughout the world, scientists are closely watching several late-stage trials of the antiviral drug remdesivir. Developed to treat Ebola, remdesivir is now being tested against COVID-19. However, many infectious disease experts caution that the trials are unlikely to yield clear-cut results, according to an article in Chemical & Engineering News (C&EN), the weekly newsmagazine of the American Chemical Society. 

Gilead Sciences discovered remdesivir during the 2014 Ebola outbreak in West Africa. Although the drug was not effective in treating late-stage Ebola, it was shown to be fairly safe, Senior Correspondent Lisa Jarvis writes. Remdesivir blocks an enzyme called RNA polymerase that the Ebola virus -- and other RNA viruses, including SARS-CoV-2 -- uses to replicate. Scientists have already shown in lab experiments and animal studies that the drug can help treat and prevent infections of the coronaviruses that cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). Despite hints that remdesivir could also kill SARS-CoV-2, results from current clinical trials will likely be difficult to interpret, experts say.

Of the five Phase III studies testing remdesivir against COVID-19, two began in China in early February, one in the U.S. in February and two more in the U.S. in March. Because four of the five studies enrolled patients with moderate-to-severe diseases, which are more difficult to treat than milder cases, a failure of the drug in these trials doesn't necessarily mean it wouldn't work for patients treated earlier in the course of infection. Although the U.S. Food and Drug Administration typically takes 6-12 months to approve new drugs, the process will likely be expedited if results from these clinical trials look promising, according to experts.

OTTAWA - A new modelling paper, using data from Ontario, indicates that dynamic physical distancing and other measures could help maintain health system capacity and prevent intensive care units (ICUs) from becoming overwhelmed because of COVID-19, while allowing periodic psychological and economic breaks from restrictions. The paper is published in CMAJ (Canadian Medical Association Journal) https://www.cmaj.ca/content/cmaj/early/2020/04/08/cmaj.200476.full.pdf.

"Physical distancing and other public health measures can reduce COVID-19 spread, but once these measures are lifted, we're at risk of an uptick in cases," says Dr. Ashleigh Tuite, assistant professor of epidemiology at the Dalla Lana School of Public Health, University of Toronto. "Dynamic response measures that can be turned up and down in response to where we are on the epidemic curve provide a way to curb transmission while also providing periodic breaks and a chance to return to a more normal life."

The authors modelled several strategies to flatten the epidemic curve, focusing on scarce ICU resources, which can quickly become overwhelmed, over a 2-year period. These include the following scenarios:

Base case -- with limited testing, isolation and quarantine and an estimated 56% of the population becoming infected, projections estimated 107,000 hospital admissions and 55,000 cases in the ICU at the peak of the epidemic.

Fixed duration interventions -- using physical distancing and case finding over 12 and 18 months substantially reduced the number of people infected, with varying results depending on how aggressive the implemented physical distancing measures were.

Dynamic interventions -- turning off and on interventions to respond to the current state of the epidemic was projected to be effective at reducing the proportion of the population affected at the end of 2 years. This could involve dynamic physical distancing, which would intermittently ease some restrictions to provide periodic psychological and economic relief. For example, when implemented dynamically over 13 months, the median overall attack rate was reduced to 2%.

"There are likely going to be a series of ups and downs with dynamic interventions as transmission waxes and wanes," says Dr. Tuite. "With our model, we show that we can modulate response measures so that we don't overwhelm our health care system, while also attempting to lessen the societal and economic disruption of these measures."

"Repeated outbreaks of COVID-19 will most likely occur because of reintroduction of infection from other countries until a vaccine is developed or we develop herd immunity in which much of the population has developed antibodies to the virus," says co-author Dr. David Fisman, professor of epidemiology at the Dalla Lana School of Public Health.