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Medications currently used to treat multiple sclerosis (MS) can merely reduce relapses during the initial relapsing-remitting phase. Many patients, however, develop progressive MS at a later stage, with disability becoming progressively worse. This type cannot be sufficiently treated at yet. Possible causes why an effective therapy for progressive MS is still lacking have been compiled by an international research team in a review article in the journal Nature Reviews Drug Discovery from 9 August 2019.

For the purpose of the study, Bochum-based medical practitioners Professor Simon Faissner and Professor Ralf Gold from the Department of Neurology at St. Josef-Hospital, University Hospital at Ruhr-Universität Bochum, collaborated with Professor V. Wee Yong from the University of Calgary and Professor Jason Plemel from the University of Alberta in Edmonton. In their article, they discuss the mechanisms underlying progressive MS as well as data regarding potential therapy approaches collated in lab experiments and clinical trials. In the process, the authors link the discussion of therapy targets with results from pharmacological studies conducted with cell culture and animal models, as well as current clinical studies.

One disease, numerous mechanisms

"A bottom line of our analysis is that the reason why it is so difficult to treat progressive MS is the fact that progression is caused by various mechanisms," says Simon Faissner. "In order to provide more efficient treatment, we will probably need precise therapy approaches targeting various pathomechanisms." According to the authors, another problem is the fact that the full range of underlying mechanisms is not represented in any of the existing animal models. "Therefore, identifying potential therapeutic agents for a clinical study poses a considerable challenge," says Faissner.

Moreover, clinical studies to date have frequently followed different objectives, which means that the definition of what constitutes therapeutic success varied from study to study. The authors state that consistent criteria should ideally be implemented in order to render the studies comparable and to verify reliable treatment effects.

Financial obstacles

There are also financial aspects that impede the development of new drugs. There is evidence that drugs approved for another indication may also prove effective against multiple sclerosis. "But as patents for such medication have expired, pharmaceutical companies can't further develop them," explains Simon Faissner. "The implementation of studies to test the efficacy of those drugs for MS often fails due to a lack of funds."

Better therapy possible

Nevertheless, the authors conclude that the treatment of patients suffering from progressive MS will improve, as researchers gain a better and more detailed understanding of the underlying disease mechanisms. "These findings will enable us to introduce a more targeted therapy that will prevent patients from suffering more severe impairments as the disease progresses," predicts Faissner.

About multiple sclerosis

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, which manifests as relapsing-remitting MS in approximately 85 per cent of the patients. In the western world, it is the main cause of neurological disabilities in young people. The early stage of the disease is characterised by relapses with neurological symptoms such as optic neuritis, impairment of the motor function, and sensitivity impairments; today, more than twelve approved drugs exist that can be used to treat this type fairly effectively.

Despite effective therapy, the so-called secondary-chronic progressive MS emerges in the majority of patients after approximately 15 to 20 years, characterised by a scarcity of relapses and by progressive accumulation of disability. 10 to 15 per cent of the patients present with a primary progressive disease course at initial diagnosis. Today, new drugs for the progressive types of MS are available, such as Ocrelizumab and Siponimod. However, the therapy effects are as yet limited.

The U.S. Centers for Disease Control and Prevention report on the use of antibiotics in health care settings across the United States in 2018 tell us that while progress has been made to promote appropriate use of infection-fighting drugs, strengthened and continued efforts and greater resources are needed to protect some of the most valuable medicines we have and prevent the accelerating development of illness-causing bacteria that are resistant to treatment.

With evidence that about 30 percent of all antibiotic courses annually are prescribed unnecessarily, the report, Antibiotic Use in the United States: Progress and Opportunities, describes strides in antibiotic stewardship and surveillance in recent years, but also persisting challenges in ensuring that the leadership, expertise and education necessary to stewardship programs meets ongoing needs. In addition, highlighting the value of existing and growing numbers of antibiotic stewardship programs, the report underscores the need for policies requiring the programs at all health facilities.

The report also highlights critical leadership on the part of CDC in supporting the development of stewardship programs. Increased funding will be essential to the expansion of the agency's efforts, particularly at smaller facilities with fewer resources including rural hospitals and critical access hospitals.

As an organization of more than 11,000 infectious diseases specialists, the Infectious Disease Society of America knows the pivotal role of antibiotic stewardship in ensuring the continued effectiveness of existing medicines, and developed the Antimicrobial Stewardship Centers of Excellence Program to identify institutions that demonstrate commitment to combating antimicrobial resistance by aligning with evidence-based guidelines.

We urge the passage of the DISARM -- Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms - Act, legislation that will require hospitals to establish stewardship programs, raise reimbursement for new antibiotics and require hospitals to report antibiotic use and resistance data to CDC.

While strengthened stewardship is vital to stemming the threat of resistant infections, we recognize that a comprehensive response to antimicrobial resistance is essential. In addition to stewardship programs at all health settings and a "One Health" approach to limiting the impacts to humans and animals of excessive antibiotic exposure, this response must include policies, the allocation of the resources necessary to ensure infection prevention and surveillance, the development of new vaccines, diagnostics, and antibiotics, and investments in the necessary infectious diseases physician workforce.

WASHINGTON, D.C., August 13, 2019 -- Monitoring and tracking biological threats or epidemics require the ability to carry out medical and laboratory tests in the field during a disaster or other austere situations. Expensive laboratory equipment is often unavailable in these settings, so inexpensive point-of-care technology is needed.

Ordinary paper is often used in these situations, since it's cheap, portable and widely available. However, paper poses some problems that hinder its usefulness. In this week's issue of Biointerphases, from AIP Publishing, investigators from the University of Maine report a technique that greatly improves the performance of paper-based point-of-care technologies.

"Paper is a biodegradable resource that can help us address more future challenges than we think," co-author Caitlin Howell said.

In their research, the authors coated low-cost paper with a thin silicone polymer layer infused with a nontoxic silicone liquid and then folded the coated paper into precise geometries, creating vastly improved in-the-field devices for concentrating and testing biological samples. Although folded paper has been used in the past to create low-cost, portable field-testing equipment, it almost always relies on surface tension to move liquid through paper fibers.

Because these fibers vary widely in diameter and length, delivery of inconsistent volumes of fluid to the detector can occur, and losses of up to 50% of the fluid sample into the paper's pores are common. Also, paper pores are small, preventing the flow of large particles, such as blood cells and microbes, which significantly affects the accuracy of tests.

To address these issues, the coated paper creates a slippery overlayer that prevents biological materials, such as bacteria, from permanently sticking to the paper and allows droplets to slide off without leaving traces of fluid behind. It can be folded to create small cups to hold liquid samples.

The coated paper performed much more efficiently and reliably than dry, uncoated paper, regardless of the type of paper used, in terms of both the way the droplets evaporated and the way they easily slid off the paper.

Another test involved samples of live bacteria, E. coli and Staphylococcus aureus, placed into the paper cups and heated to concentrate and culture the samples. Coated paper performed much better than plain paper for E. coli, with nearly triple the number of bacteria in the coated-paper cups as compared to dry cups. Results for S. aureus were not quite as good, however, so further research will be needed.

Philadelphia, August 20, 2019 - Sepsis, a complex systemic response to infection leading to organ failure, is generally studied at the level of individual organs; this research has hinted at altered metabolic changes. A new study in the American Journal of Pathology, published by Elsevier, takes a two-pronged approach and investigates for the first time the metabolic changes across affected organs in a large animal model of sepsis and identifies both potential common and organ-specific metabolic alterations contributing to the disease process.

Lead investigator Monte S. Willis, MD, PhD, MBA, Co-Director of the Indiana Center for Musculoskeletal Health; Vice-Chair of Research, Department of Pathology and Laboratory Medicine; and Professor, Krannert Institute of Cardiology, at the Indiana University School of Medicine, Indianapolis, IN, USA, describes sepsis as "an inter-organ network issue."

"Part of the issue with improving sepsis outcomes is due to our limited understanding of the pathological process," explains Dr. Willis. "While the metabolic crosstalk of organs is taught conceptually, we tend to think of diseases in an organ-specific manner. We need to go beyond treatments that just target symptoms. Our studies illustrate that a broader system view of disease is needed and that metabolic intermediates may be responsible regulators of sepsis and other diseases."

In this study, pigs were infected with Pseudomonas aeruginosa (P. aeruginosa), a common bacterium found in soil, water, and plants. Individuals can become ill from eating P. aeruginosa-contaminated food or touching infected moist areas or improperly cleaned medical equipment. Eighteen hours after infection, investigators analyzed tissue samples from the pigs' intestine, skeletal muscle, liver, and lungs to determine how specific metabolic pathways were affected across organs.

Researchers identified both common metabolic alterations and organ-specific changes in a wider range of metabolic processes than previously reported. Organ-specific deficits in metabolism were also identified, with potential therapeutic implications.

"The observed organ-specific metabolic alterations provide clues to previously unexplored mechanisms of disease, while common metabolic alterations illustrate a broader array of changes than previously reported in individual organ studies. These studies provide insight into the potential for cross-communication among tissues in system disease and how specific organ damage may require therapeutic interventions targeting metabolism," notes first author Amro Ilaiwy, MD, of the Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.

Dr. Willis and his co-investigators emphasize the need to understand disease processes as a network of communicating organs instead of focusing on an isolated organ. Given a basic acceptance of metabolic crosstalk in diseases such as diabetes, there is a basis for expanding these concepts into other complex diseases in other disciplines, such as skeletal muscle and the heart.

An estimated 1.7 million US adults develop sepsis annually, resulting in almost 270,000 deaths. Sepsis produces complex hemodynamic and cellular changes including tissue damage and organ failure, leading to inadequate oxygen delivery to cells. Treatments generally target symptoms such as low blood pressure or the bacteria responsible for infection, but do not address the underlying pathophysiology that occurs in affected organs. Understanding the underlying pathophysiology occurring in affected organs has been a challenge. Some scientists believe that progress may have been somewhat stymied by approaches that either focus too narrowly on individual organs or aim too broadly at detecting widespread metabolic changes.

Bottom Line: An analysis of Framingham Heart Study data examined the association of the time between quitting smoking and new cases of cardiovascular disease (CVD). This analysis included nearly 8,800 individuals, including 2,371 heavy smokers who smoked 20 or more pack-years, which is equal to smoking one pack of cigarettes daily for 20 years. Over an average follow-up of 26 years, 2,435 first CVD events (heart attack, stroke, heart failure or cardiovascular death) occurred in the entire group, with 1,095 among heavy smokers. The authors report quitting smoking was associated with lower risk of CVD within five years for former heavy smokers compared with current smokers but their risk remained higher for 10 to 15 years after cessation compared with people who never smoked. Limitations of the study include its smaller sample size compared to some previous studies, and participants in the study were primarily white individuals of European ancestry, potentially limiting the generalizability of the findings to others.

Authors: Meredith S. Duncan, M.A., Vanderbilt University Medical Center, Nashville, Tennessee, and coauthors

(doi:10.1001/jama.2019.10298)

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

The prevalence of depression, cannabis use, and alcohol abuse increased among former smokers from 2005 to 2016 in the U.S., according to a new study published in the American Journal of Preventive Medicine. Therefore, increases in these risk factors for relapse among former smokers could threaten progress in reducing the prevalence of cigarette use. This is the first national U.S. study to focus on the prevalence and time trends of depression, marijuana use, and problematic alcohol use among former smokers.

"It's good news that as tobacco control efforts have been successful at reducing smoking, the proportion of former smokers among the U.S. population is increasing. However, as our study demonstrates, more of them are now suffering from depression and engaging in problematic substance use," said lead investigator Renee D. Goodwin, PhD, Institute for Implementation Science in Population Health, CUNY, and the Department of Epidemiology at Columbia University Mailman School of Public Health.

Conducted in 2018-9, the study investigated the prevalence of depression, cannabis, use and alcohol misuse among former smokers ages 18 and older in the U.S. from 2005 to 2016. Data were drawn from the National Survey on Drug Use and Health, an annual, nationally representative cross-sectional study. More than 67,000 individuals, aged 18 and over, participated in the study.

During the study period, the incidence of major depression increased from 4.88 percent to 6.04 percent, cannabis use during the previous year rose from 5.35 percent to 10.09 percent, and alcohol binge drinking during the previous month went up from 17.22 percent to 22.33 percent among former smokers.

The results show that the profile of former smokers has changed over the study period. An increasing percentage of the U.S. population who were ever smokers no longer smoke (50 percent in 2016, compared to 44.4 percent in 2002). Former smokers are slightly more likely to be male than female, married, and of non-Hispanic white ethnicity. In 2016 compared to 2002, former smokers were more likely to be older than 65, never married, have some college education and incomes over $75,000 a year. More than half of them had also quit smoking for three years or more. Factors that may have affected the results are the increasing legalization, decreasing perception of risk associated with use, and reduced stigma of cannabis, which may sometimes be used by smokers trying to quit tobacco. However, the investigators note that when former smokers use it, they increase their likelihood of returning to tobacco.

"Because previous research has demonstrated that these factors put former smokers at greater risk of relapsing with tobacco (and relapse is a risk that lingers for decades), our study should signal an alarm for public health leaders and health care providers. The findings represent a looming threat to the progress that has been made in reducing the prevalence of cigarette use," cautioned Goodwin, who is also professor of Biostatistics at the Graduate School of Public Health and Health Policy, CUNY.

Goodwin noted that the findings should have bearing on ongoing tobacco control policy decisions, "Since it has been shown that depression and substance use may compromise abstinence, anyone designing community-based public information campaigns and engaged in clinical interactions with former smokers should be made aware that modifiable predictors of relapse are increasing among former smokers. As such, screening for these issues and referral to treatment should be high priorities. These are important steps for assuring growing and sustained abstinence among the U.S. population, a trend with significant health and societal benefits."

Philadelphia, August 20, 2019 - Brain abnormalities in people at familial risk of schizophrenia and bipolar disorder emerge in unique patterns, despite the symptom and genetic overlap of the disorders, according to a study in Biological Psychiatry, published by Elsevier. Similarities between schizophrenia and bipolar disorder have led to the diagnoses being increasingly combined in studies of psychosis, but the findings highlight that risk for the disorders has distinct effects on the brain.

Schizophrenia and bipolar disorder tend to run in families, as relatives share genetic risk factors and exposure to life events that can increase risk of the disease, referred to as environmental risk factors. "We were interested in the relationship between this increased risk for schizophrenia or bipolar disorder and brain development," said first author Sonja M.C. de Zwarte, MSc, University Medical Center Utrecht, The Netherlands.

Relatives of bipolar disorder patients had larger intracranial volumes--a measure that includes total brain tissue and cerebrospinal fluid--and relatives of schizophrenia patients had smaller brain volumes when compared with people without family history of these disorders.

"The size of intracranial volume is considered a marker for early brain development. Thus, our findings suggest that the familial risk for these disorders is influencing brain development already early in life, and in a different manner," said Ms. de Zwarte.

The differences in brain development between the disorders will be an important consideration for future brain imaging studies of psychiatric disorders. "Recent focus on dimensional cross-diagnostic features of psychiatric disorders has deemphasized important complementary categorical distinctions. This imaging genomics study reminds us of the potential importance of these categorical distinctions," said John Krystal, MD, Editor of Biological Psychiatry.

The researchers also found differences in brain anomalies when the participants were separated by their relationship with the patients, though no clear pattern developed based on relative type. First-degree relatives share about 50 percent of their genes, so the variation between the types of first-degree relatives suggests that environmental risk factors also contribute to the brain anomalies in family members.

The international collaborative study by researchers of the ENIGMA consortium was the largest examination of first-degree relatives of patients with schizophrenia or bipolar disorder, including over 6,000 brain imaging datasets in a meta-analysis. The study emphasizes the usefulness of studying family members of people with psychiatric disorders to better understand how risk of the illnesses affects the brain, an approach that avoids the disease or medication effects that complicate studies of patients.

Chromatin organizes the approximately two meters of DNA present in the nucleus of every human cell so that, dependent on the cell type and state, certain genes can be activated, others repressed. The fundamental organizing unit of chromatin is the nucleosome, consisting of 146 base pairs of DNA wrapped around a histone octamer. Whenever a cell needs to adapt - for example, to respond to developmental or environmental signals or to DNA damage -, it needs to alter the accessibility of its DNA. Doing exactly this is the function of chromatin remodelers, enzymes that use the energy of ATP to move or evict nucleosomes. Chromatin remodeling complexes come in multiple flavors in human cells; a particularly interesting complex is the BAF complex. In fact, it is not only one complex, but many different ones. Up to 15 complex positions can be occupied by proteins encoded from 29 different genes, the combinatorics adding up to more than 10,000 theoretically possible different complexes.

What makes the BAF complex so relevant for human disease are the mutations that are found in the BAF complex genes in approximately every fifth human cancer. Currently, we have only a limited understanding how these mutations contribute to cancer development. Even more problematic, we do not have therapies to specifically cure BAF mutant cancers. Finding such therapies is challenging, because typically the genetic aberrations are so called loss of function mutations. These result in cancer cells lacking a specific BAF subunit protein, and it is hard to develop a drug against something that is not there.

To find ways to nevertheless target BAF mutant cells, Sandra Schick, postdoctoral fellow in the laboratory of Stefan Kubicek of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, first needed to generate a relevant cellular model. She therefore established a panel of 22 isogenic cell lines that differed only in each lacking a single different BAF subunit. In these cells, she first characterized the consequences of loss of a single subunit on complex composition, chromatin accessibility and transcription. "We identified preferential BAF complex configurations, which can be altered when single subunits are lost" said Schick. "Furthermore, there is an intense cross-talk between these subunits, so that, depending on the lost gene, other BAF subunits are incorporated with higher or lower frequency". These data indicate that although the original mutation results in the loss of one BAF subunit, the cancer promoting properties might be conferred by aberrant functions of the remaining BAF complexes. And such aberrant functions might again be druggable.

To test whether it is indeed the case that BAF mutant cancers become addicted to the function of the remaining complexes, the team went on to systematically deplete a second member of the BAF complexes in these cells that had already lost one subunit. From this large dataset they focused on three novel intra-complex synthetic lethalities, SMARCA4-ARID2, SMARCA4-ACTB, and SMARCC1-SMARCC2. The extensive systematic data on interaction proteomics, chromatin accessibility and transcription changes helped explain the molecular mechanism for these synthetic interactions. "But even more important to us was to prove that these novel targets hold up in relevant cancer cell lines beyond our cellular model system" explains Stefan Kubicek. And this is exactly what the researchers could prove, in a panel of 22 different cancer cell lines. "The SMARCC1-SMARCC2 pair was particularly strong and conserved, and we could show that cell lines with low SMARCC1 levels are extremely sensitive to loss of SMARCC2."

Spending on cannabis, cocaine, heroin and methamphetamine by Americans reached nearly $150 billion in 2016, with a large proportion of spending coming from the small share of people who use drugs on a daily or near-daily basis, according to a new RAND Corporation report.

Researchers estimate that from 2006 to 2016, the total amount of money spent by Americans on these four drugs fluctuated between $120 billion and $145 billion each year. By contrast, a different analysis finds that spending on alcohol in the U.S. was estimated to be $158 billion in 2017.

Total spending on cannabis, from both illegal and state-licensed sources, increased by approximately 50 percent from 2006 to 2016, from $34 billion to $52 billion. The market for cannabis is roughly the size of the cocaine and methamphetamine markets combined, and the size of the retail heroin market is now closer to the size of the marijuana market than it is to the other drugs, according to the analysis.

"To better understand changes in drug use outcomes and the effects of policies, policymakers need to know what is happening in markets for these substances," said Greg Midgette, the study's lead author, an assistant professor at University of Maryland and an adjunct policy researcher at RAND, a nonprofit research organization. "But it is challenging to generate these estimates, and given that critical data sources have been eliminated, it will likely be harder to generate these figures in the future."

In addition to estimating expenditures on cannabis, cocaine, heroin and methamphetamine, researchers from RAND used a variety of sources of information about drug use and drug prices to also estimate the number of people who use these substances and how much they consume.

The report shows that after falling precipitously from 2006 to 2010, consumption of cocaine continued to fall slowly through 2015, then increased in 2016. Results suggest there were 2.4 million individuals who used cocaine on four more or days in the past month in 2015 and 2016. Results also suggest that consumption grew in 2016 among a stable number of users as the price per pure gram declined.

Consumption of heroin increased approximately 10 percent per year between 2010 and 2016, according to the analysis. Whereas most heroin consumed in the United States comes from poppies grown in Mexico, the introduction of synthetic opioids like fentanyl into heroin markets has increased the risk of using heroin and complicated market analyses.

There was a steady increase in the amount of heroin seized within the United States and at the southwest border from 2007 through 2016. Changes in the composition of heroin users, potentially involving increased use among individuals without criminal histories, have increased the uncertainty underlying these estimates.

From 2010 to 2016, the number of individuals who used cannabis in the past month increased nearly 30 percent, from 25 million to 32 million. Changes in the potency of marijuana and the proliferation of nonflower products such as oils and waxes have made weight-based consumption estimates obsolete and forced a change in how researchers calculate expenditures.

Researchers say their estimates about methamphetamine use are subject to the greatest uncertainty because national data sets do a particularly poor job of capturing its use.

The federal government discontinued a critical data collection effort in 2003, the Arrestee Drug Abuse Monitoring, or ADAM, right before methamphetamine use was believed to be at its first peak during 2004 to 2006.

ADAM not only collected detailed information about drug market transactions from arrestees, it also included a voluntary urine screen that could only be used for research purposes. A limited version of ADAM was brought back in 2007 and then eliminated after 2013, right when methamphetamine consumption was believed to be picking back up.

"While there is considerable uncertainty surrounding national methamphetamine estimates, multiple indicators suggest methamphetamine use has exceeded its previous peak around 2005," said Beau Kilmer, co-author of the report and director of the RAND Drug Policy Research Center. "While there is much more we can do reduce opioid use disorders and poisonings involving synthetic opioids, we cannot ignore the growing problems associated with methamphetamine use."

The RAND researchers note that one important step to better address use of methamphetamine and understand all drug markets would be to fund again some version of the ADAM program that covers urban and rural areas.

ANN ARBOR, Mich. - Four in 10 parents say they are very or somewhat likely to move their child to a different provider if their doctor sees families who refuse all childhood vaccines, according to a new national poll.

Most American children receive recommended vaccines protecting them from dangerous illnesses like measles and whooping cough.

But doctors sometimes care for children whose parents refuse vaccines against providers' recommendations. And that is not news many parents of vaccinated children want to hear, suggests the C.S. Mott Children's Hospital National Poll on Children's Health at the University of Michigan.

Three in 10 parents polled say that their child's primary care office should ask parents who refuse all vaccines to find another health provider.

"Pediatricians strive to keep children healthy through regular well-child care and this includes encouraging families to follow recommended vaccine schedules. When a family refuses all childhood vaccines, it puts providers in a challenging position," says Mott Poll co-director Sarah Clark, MPH.

"A completely unvaccinated child is unprotected against harmful and contagious diseases, such as measles, pertussis and chicken pox. Children who skip vaccines also pose a risk of transmitting diseases to other patients. This can be especially risky exposure for vulnerable populations, including infants too young to receive vaccines, elderly patients, patients with weakened immune systems or pregnant women."

The report is based on responses from 2,032 parents of at least one child 18 or under.

The poll also found that many parents are unaware of policies in their child's primary care office regarding unvaccinated children.

Thirty-nine percent of parents say their provider has a policy requiring children to get all recommended vaccines and 8% say children are required to get some vaccines. Another 15% of parents say their child's primary care provider's office has no policy about vaccination while 38% don't know if one exists.

Only 6% of parents say their child's primary care office does not allow unvaccinated children to use the same waiting area as other patients, while 2% say the office allows unvaccinated children to use the waiting area if they wear a mask. Twenty-four percent of parents say their child's primary care office allows unvaccinated children to use the same waiting area as other patients with no restrictions.

Parents are also divided in their views on what those policies should be and whether parents should be notified that there are children in the practice whose parents have refused all vaccines.

Seventeen percent say a completely unvaccinated child should not be allowed use the waiting room, and 27% say unvaccinated children should wear masks in the waiting room to protect the most vulnerable patients. The remaining 28% of parents say the primary care office should allow the unvaccinated child to continue getting care with no restrictions.

About 4 in 10 parents (43%) say they would want to know if there were other children at their child's primary care office whose parents had refused all vaccines while 33% say they would not want to know. If there were other children in the office whose parents had refused all vaccines, 12% of parents say they are very likely and 29% somewhat likely to move their own child to a different health care provider.

Typically, Clark says, child health providers will have multiple discussions with parents to explain the importance of childhood vaccinations, and to answer any questions the parents have about possible side effects.

"Providers usually do their best to address any concerns parents may have related to hesitancy about vaccines," Clark says. "In addition to explaining how vaccines protect the health of the child, providers also may share information about why an unvaccinated child exposes other children and patients to dangerous health risks too."

The majority of U.S. children receive all vaccines recommended by the Centers for Disease Control and Prevention (CDC). Vaccines often are given in conjunction with well-child visits with the primary care provider.

Barriers in scheduling appointments or parents' awareness about recommended vaccines may cause children to experience delays in vaccination or to miss some vaccines. A less common situation - but increasing in recent years - is parent refusal of all vaccines for their child.

Clark says the recent measles outbreak highlights the need for both parents and health care providers to consider policies around unvaccinated children. The highly contagious measles virus can live for several hours in an area where an infected person coughed or sneezed. However, people can spread the disease even before symptoms appear.

When parents bring a child with suspected measles to the waiting room of a doctor's office or emergency room, Clark says, they may expose many other patients to the disease.

"Parents may assume that when they take their child to the doctor, they are in a setting that will not expose their child to diseases. Parents may not have considered that there could another child in the waiting room whose parents have refused all vaccines," Clark says. "When prompted to think about it, most parents want the doctor's office to have some policy to limit the risk from unvaccinated children."

"Primary care providers need to think carefully about whether to institute policies to prevent their patients from being exposed to vaccine-preventable diseases, and then communicate those policies to all patients in their practice," she adds.

"Any parent - and particularly parents of infants or immunocompromised children - should ask their child's primary care provider about policies surrounding unvaccinated children."

DALLAS, Aug. 19, 2019 -- People suffering from insomnia may have an increased risk of coronary artery disease, heart failure and stroke, according to new research in the American Heart Association's journal Circulation.

Previous observational studies have found an association between insomnia, which affects up to 30% of the general population, and an increased risk of developing heart disease and stroke. These observational studies were unable to determine whether insomnia is a cause, or if it is just associated with them, explained Susanna Larsson, Ph.D., lead study author and associate professor of cardiovascular and nutritional epidemiology at Karolinska Institutet in Stockholm, Sweden.

In this first-of-its-kind study on insomnia, Larsson and a colleague applied Mendelian randomization, a technique that uses genetic variants known to be connected with a potential risk factor, such as insomnia, to reduce bias in the results. The 1.3 million participants with or without heart disease and stroke were drawn from four major public studies and groups.

Researchers found genetic variants for insomnia were associated with significantly higher odds of coronary artery disease, heart failure and ischemic stroke - particularly large artery stroke, but not atrial fibrillation.

"It's important to identify the underlying reason for insomnia and treat it," Larsson said. "Sleep is a behavior that can be changed by new habits and stress management."

A limitation to this study is that the results represent a genetic variant link to insomnia rather than insomnia itself. According to Larsson, it was not possible to determine whether or not the individuals with cardiovascular disease had insomnia.

Imagine there were a drug that you could take soon after a heart attack that could reduce damage by protecting healthy heart muscle tissue.

"Cardiologists say that when a heart attack occurs, time is muscle," said Robert Gourdie, director of the Fralin Biomedical Research Institute at VTC Center for Heart and Reparative Medicine Research.

Without oxygen supplied by blood flow, heart cells die -- fast. But while a heart attack may only reduce blood and oxygen to an isolated section of heart cells -- causing what's called hypoxic ischemic injury -- those dying cells send signals to their neighbors.

"The problem is that the area of dying tissue is not quarantined. Damaged heart cells start to send out signals to otherwise healthy cells, and the injury becomes much bigger," said Gourdie, who is also the Commonwealth Research Commercialization Fund Eminent Scholar in Heart Regenerative Medicine Research and a professor in the Department of Biomedical Engineering and Mechanics in the Virginia Tech College of Engineering.

Scientists sometimes call this spread of injury signals to nearby healthy tissues a "bystander effect."

But what if there were a way to keep the injury localized to the group of cells that are directly affected by the hypoxic ischemic injury, while allowing the nearby heart muscle cells to remain intact?

A study published today (Monday, Aug. 19) in the Journal of the American Heart Association reveals that a new molecule developed by a team of researchers led by Gourdie could help preserve heart tissue during -- and even after -- a heart attack.

Nearly a decade ago Gourdie, in collaboration with a postdoctoral fellow in his lab, Gautam Ghatnekar, stumbled across a promising discovery. Gourdie's team discovered a compound that targets the activity of channels in cell membranes responsible for controlling key aspects of the bystander effect.

But the compound, called alphaCT1, also had other unexpected and beneficial effects, particularly in relation to skin wound healing.

"We found that it helped reduce inflammation, helped heal chronic wounds such as diabetic foot ulcers," said Gourdie.

Recognizing the compound's potential, Ghatnekar and Gourdie founded a company, FirstString Research Inc., to commercialize alphaCT1, which is now in phase III clinical trials for treating wounds.

Meanwhile, Gourdie has been trying to understand how the drug works on a molecular level, which led to the study just published in the Journal of the American Heart Association.

"This paper asks the question: how does this peptide drug actually work?" said Gourdie.

The group designed molecules with slight chemical differences from the parent molecule, which led to an unexpected discovery. One of the alphaCT1 variants -- called alphaCT11 -- showed more potency than the parent molecule.

"AlphaCT11 seems to be even more effective than the original peptide in protecting hearts from ischemic injury similar to those occurring during a heart attack," said Gourdie.

The study reveals that alphaCT11 gives a robust injury-reducing effect, even when given 20 minutes after the loss of blood flow that causes ischemic injury. When put to the same test, the parent peptide did not appear to provide a heart-protective effect when administered after ischemic injury.

"AlphaCT11 could provide the basis for a new way to treat heart attacks and prevent the spread of damage that occurs immediately after a heart attack," said Gourdie.

The researchers perfused isolated laboratory mouse hearts, keeping the organ alive and beating for a number of hours. Ongoing studies, through collaboration with Virginia Commonwealth University's Antonio Abbate and Stefano Toldo, will examine how alphaCT11 performs in live mice.

Gourdie is also developing new methods for delivering alphaCT11 using naturally-derived tiny lipid droplets called exosomes. These newer experiments could provide a stepping stone toward clinical trials in patients who have suffered a heart attack.

In 2017, some 10 million people suffered from tuberculosis and 1.6 million died of the disease. One reason why infection with Mycobacterium tuberculosis is so difficult to treat is that the bacteria can hide inside immune cells. University of Groningen scientists, together with a team from the Division of Rheumatology, immunology and Allergy led by professor D. Branch Moody at Harvard Medical School and several other colleagues, have now discovered a key mechanism in the bacteria which prevents the immune cells from killing them: the bacteria produce a unique type of antacid which gives the immune cells indigestion. The results were published in Nature Chemical Biology on 19 August 2019.

Invading bacteria are gobbled up by immune cells called macrophages. They encapsulate the intruders inside a phagosome, a vesicle which then fuses with another vesicle full of enzymes, the lysosome. After this fusion, the enzymes break the bacteria down. But not in the case of Mycobacterium tuberculosis: 'They can survive for years inside a macrophage, where antibiotics can barely reach them', explains University of Groningen chemist Jeffrey Buter, first author of the paper. He has worked for years on tuberculosis in Groningen under the supervision of Professor Adri Minnaard, as well as at Harvard Medical School, supervised by Professor David Branch Moody. Both supervisors are joint lead authors of the new paper.

Virulence

In a previous study published in 2014, the team identified lipids present in M. tuberculosis but not in M. bovis, a bacterium which is much less virulent. The lipids specific to M. tuberculosis could play a role in virulence. Indeed, an important candidate was found and identified as 1-tuberculosinyladenosine (1-TbAd), an adenosine modified by the attachment of a lipid in the 1-position. 'Such a modification is extremely rare in nature', says Buter, 'yet M. tuberculosis produces and releases a relatively large amount of this compound'.

Two enzymes critical to the production of 1-TbAd were identified, but the mechanism by which this molecule helped the tuberculosis bacterium to survive remained a mystery. 'Then, we found research performed by another group in 2004, in which it was shown that the fusion of the phagosome and lysosome was blocked due to these enzymes. As the phagosome needs to be acidic for fusion, this led us to the hypothesis that 1-TbAd played a role in preventing acidification of the phagosome'.

Antacid

'1-TbAd is a weak acid and in equilibrium with its basic counterpart', continues Buter. 'In the acidic environment of the phagosome, this base will reduce acidity'. This finding suggested that the molecule works as an antacid and prevents the phagosome from reaching the level of acidity required to fuse with the lysosome.

The group performed a series of experiments to rule out the possibility that the adenosine compound acted through a receptor. The findings confirmed that 1-TbAd does indeed work by reducing the acidity directly. Buter synthesized different variants of the molecule to determine which parts of the molecule were vital for its function. 'The lipid part is needed to cross the membranes and get into the phagosomes and lysosomes', says Buter.

Malaria

Microscopy studies performed in the lab of Nicole van der Wel at the Amsterdam UMC reveal that exposing macrophages to 1-TbAd makes their lysosomes swell up to five times their normal size. Tests with macrophages infected with M. tuberculosis show that the phagosomes only swell significantly in the presence of the enzyme Rv3378c needed to produce 1-TbAd. 'There are several mechanisms preventing the macrophages from killing M. tuberculosis, but we discovered what appears to be a key mechanism for bacterial survival'.

Interestingly, the mechanism by which 1-TbAd works is the same as how chloroquine kills the malaria parasite. 'This drug blocks the functioning of parasite's lysosomes'. It suggests that 1-TbAd could be used as an anti-malarial drug. 'But also, targeting the production of 1-TbAd could kill M. tuberculosis inside the macrophages. The enzyme Rv3378c would be an interesting target for drug discovery, as the enzyme is unique to the tuberculosis bacterium'.

PHILADELPHIA - Pancreatic cancer is one of the deadliest cancers, with patients surviving on average less than a year once the disease has spread. There is an urgent need to evaluate more therapeutic targets. The chemotherapeutic agent abemaciclib is effective in treating breast cancer, but there is limited preclinical evaluation of this targeted therapy in treating pancreatic cancer. New research from Sidney Kimmel Cancer Center - Jefferson Health (SKCC) provides evidence supporting the use of abemaciclib for pancreatic cancer, and suggests new targets that could improve the efficacy of the drug and break a common problem of drug resistance in this disease. The study was published in Molecular Cancer Research on August 5.

"We don't know how abemaciclib would work in pancreatic cancer and how its effects might be improved by combining it with other drugs," says senior study author Jonathan Brody, PhD, professor and director of research in the department of surgery at Thomas Jefferson University, co-leader of the Gastrointestinal Cancer Program at SKCC.

To study how the drug works, the researchers assessed the effects of abemaciclib in cell lines derived from pancreatic ductal adenocarcinoma. They found that the drug caused cell death and stopped cell growth. These effects translated into decreased tumor growth in mice that received the drug compared to those that received control saline injections. Abemaciclib targets enzymes that regulate cell division. However, these enzymes only work if they are paired with another group of enzymes.

"We proposed that targeting both groups of enzymes by pairing abemaciclib with another drug might yield synergistic anti-cancer effects," explains Christopher Schultz, PhD candidate at Thomas Jefferson University, who along with Dr. Teena Dhir, a surgical resident at Einstein Medical Center, were the co-lead authors of the study. In fact, current standard of care for pancreatic care often uses several chemotherapeutics in combination with each other. The team screened for possible therapeutic candidates to use in tandem with abemaciclib and found that inhibitors of two proteins called HuR and YAP1, showed synergistic inhibition of cancer growth. They confirmed this by treating cells with either abemaciclib alone or abemaciclib plus other potential anti-cancer agents, an HuR or YAP1 inhibitor, and found that the combination treatment was 2-4 times more effective at inhibiting cell viability.

A significant problem in treating cancer is drug resistance, meaning cancer cells become less sensitive to chemotherapeutics after long-term exposure. The researchers treated cell lines with abemaciclib for 10-12 months, mimicking chronic therapy, at which point the cells were four times more resistant to abemaciclib. When the cells were then exposed to common therapeutic agents like gemcitabine, they did not respond to the therapy. However, the abemaciclib-resistant cells were still sensitive to HuR or YAP1 inhibitors.

These findings provide further characterization of abemaciclib, and informs future clinical trials to evaluate this drug in patients. Moreover, the study is the first to show synergy between abemaciclib and HuR/Yap1 inhibitors in vitro. Further research of this combination therapy in vivo is underway.

"There are HuR and YAP1 inhibitors that have been shown to work in vivo, but they're not clinically available yet," says Dr. Brody, "We are working on developing a HuR inhibitor that will hopefully be used for clinical trials at Jefferson."

"The outstanding work from Dr. Brody and team underscores the Sidney Kimmel Cancer Center's commitment toward advancing scientific discoveries that can be translated into the clinical setting, offering a better treatment option for patients with pancreatic cancer, which is much-needed for this often deadly disease.," said Wm. Kevin Kelly, DO, Director of Solid Tumor Oncology and Associate Director of Clinical Research at SKCC. "These findings may help design new combination of targeted therapies for pancreatic cancer, which will help overcome drug resistance in these tumor."

Physical fitness is a strong mortality predictor and exercise training is now considered a cornerstone in the non-pharmacological prevention and treatment of lifestyle diseases, including hypertension, type 2 diabetes and osteoporosis.

A new study from the University of Southern Denmark shows that football is a surprisingly efficient type of physical training for female prediabetes patients, with impressive effects on cardiovascular health after 16 weeks of training for 55-70-year old women with no prior football experience.

Broad-spectrum improvements in cardiovascular, metabolic and musculoskeletal fitness

Considering that sporting activities are popular and that many of these imply intense training of variable forms, it is of great interest to study the effects of sports training in patients.

"More than 15 years of research on recreational football documents that it is indeed an effective and multifaceted type of training with a potential for simultaneous broad-spectrum improvements in cardiovascular, metabolic and musculoskeletal fitness", explains professor Peter Krustrup, head of the Sport and Health Sciences Research Unit, Department of Sports Science and Clinical Biomechanics at the University of Southern Denmark (SDU).

His conclusion is backed up by 3 recent meta-analyses, covering 31 scientific studies. However, only a few of these deal with the fitness and health effects of football for female patient groups.

Recreational football combined with dietary guidance

In a new study headed by professors Magni Mohr and Peter Krustrup, researchers investigated the short-term effects on cardiovascular health of football for 55-70-year-old women with prediabetes and compared the effects with age-matched men. The study was conducted on the Faroe Islands in close cooperation with the University of the Faroe Islands and included subjects recruited from a Faroese cohort from the Department of Occupational and Public Health.

For both genders, dietary advice alone was compared to dietary advice and 1-hour football training twice a week for 16 weeks. The study results were published in European Journal of Applied Physiology earlier this week.

"Football is top training for cardiovascular health, and indeed also for women with prediabetes. The present results show impressive simultaneous improvements of football training and dietary advice in blood pressure, fat percentage, cholesterol and aerobic fitness for the women, providing clinically relevant enhancement of the cardiovascular health profile", says professor Peter Krustrup.

Fitness effect even greater for women than for men

In general, the fitness and health effects are somewhat smaller for women participating in exercise programmes with fixed time, especially when it comes to blood pressure and fat loss. However, this was not the case in the present study.

Professor Magni Mohr follows up:

"Interestingly, the exercise intensity as well as the training effects were similar in women and men, and for aerobic fitness the improvements were even greater in women. This clearly emphasizes that middle-aged and elderly women can benefit to the same degree as men, even so women with no prior experience with football".

Relevant exercise for people who suffer from diabetes

This is especially relevant for patients with type 2 diabetes and individuals with prediabetes who normally suffer from multiple pathophysiological conditions.

"The results from our study confirm investigations of other patient groups and emphasize that football training is an intense, effective and versatile type of training. Football scores a true health hat-trick as training type for participants of both genders and across the lifespan", Magni Mohr concludes.