Drug used for PTSD may worsen nightmares, not reduce suicidal thoughts

Public Release: 19-Nov-2018

Medical College of Georgia at Augusta University

AUGUSTA, Ga. (Nov. 19, 2018) – Nightmares and insomnia often accompany posttraumatic stress disorder and increase suicide risk.

A small study looking at whether the drug prazosin, best known for treating high blood pressure but also used to treat PTSD-related sleep problems, can reduce suicidal thoughts has yielded surprising results.

They indicate it may actually worsen nightmares and insomnia and doesn’t reduce suicidal thinking, investigators report in the Journal of Clinical Psychopharmacology.

“I think we have to view this as not the final word on this, but it raises questions,” says Dr. W. Vaughn McCall, chair of the Department of Psychiatry and Health Behavior at the Medical College of Georgia at Augusta University.

McCall is currently seeking input from PTSD experts across the country but says a likely consensus could be that prazosin may help some, but may not be a good choice when suicide is an active concern.

Two larger studies in active and retired military personnel yielded mixed results as well, the first in active duty military showed it helped with nightmares and sleep quality and a follow-up study just published this year on military veterans with chronic PTSD indicated it was no better than placebo.

McCall’s pilot study is the first in which all participants had suicidal thoughts or actions.

“It did not seem to do much for suicidal ideation and that was somewhat disappointing, but the thing what was mind-blowing was that is actually worsened nightmares,” says McCall. “Maybe it’s not for everybody.” He notes that with PTSD, a patient’s nightmares often focus on the trauma that produced their disorder.

Two study participants required emergency inpatient psychiatric care, but there were no suicide attempts or deaths over the study course.

“We need to reconcile how is it that we had 10 years of data saying prazosin is good for nightmares in PTSD, a big study this February indicating it has essentially no affect and now a smaller study showing it can worsen some aspects,” McCall says. “We need to know what it all means.”

The latest study led by McCall looked at a total of 20 seriously psychiatrically ill patients, two with wartime PTSD with the remainder mostly civilian females who experienced sexual assault. All had active suicidal thoughts, some had previous suicide attempts and most were taking antidepressants and/or had them prescribed as part of evaluation for the study. For eight weeks, they took bedtime doses of the short half-life prazosin with the idea of helping avoid nightmares and, by association, suicidal thoughts. They were assessed weekly for relevant factors such as severity of suicidal thoughts, nightmares, insomnia, depression and PTSD.

One reason for the unexpected findings of the study could be the severity of participants’ PTSD as indicated by the their suicidal thoughts, McCall says of his study. The once daily dose may also have been problematic in impacting suicidal thoughts, McCall notes.

There was no significant impact on blood pressure, likely because of the drug’s short half-life, and no suicide attempts or deaths.

A result of PTSD can be too much noradrenaline, also known as norepinephrine, a stress hormone and neurotransmitter that is key to the body’s fight or flight response. Its increase ideally is a short-term reaction that constricts blood vessels so we can adeptly respond to some threat. Prazosin readily enters the central nervous system where it blocks the action of norepinephrine.

“What trauma does in part is put your brain on edge so you are always ready for the next bad thing,” McCall says. “We use terms like hypervigilance, meaning you are always scanning the environment and PTSD patients often sit with their back to the wall so they can see the door. People who are over-diligent by day probably don’t sleep well at night,” he notes.

The work of McCall and others has delineated a clear association between insomnia, nightmares and suicidal thoughts and behavior.

McCall reconfirmed in 2013 in The Journal of Clinical Sleep Medicine the link between insomnia and nightmares and how losing hope of ever getting another good night’s sleep itself is a risk factor for suicide.

Earlier studies looking at prazosin’s ability to help when PTSD appears responsible include a 26-week trial in 271 military veterans with chronic PTSD who had frequent nightmares. The study published earlier this year in the Journal of the American Medical Association failed to show any benefit of prazosin over placebo in reducing the frequency and intensity of trauma-related nightmares. New or worsening suicidal thoughts occurred in about 8 percent of participants taking prazosin versus 15 percent taking placebo. The study, led by Dr. Murray A. Raskind, vice chair of psychiatry and behavioral sciences at the University of Washington and director of the VA Northwest Network Mental Illness Research Education and Clinical Center at the VA Puget Sound Health Care System, took place at 13 VA medical centers.

Five years earlier, Raskind led another study of the drug in active duty soldiers returning from Iraq and Afghanistan with combat PTSD and nightmares. The drug, administered midmorning and at night for 15 weeks, showed it was actually effective compared with placebo in the 67 soldiers for combat nightmares, overall sleep quality, and generally reducing the impact of their PTSD.

McCall’s study used the same dosing schedule as the previous larger studies but with only the nighttime dose. Six participants completed the entire course of the trial, and investigators suspected that the weekly visits required for the study may have been arduous for some.

Currently the antidepressants sertraline and paroxetine are the only PTSD drug therapies that have Food and Drug Administration approval and neither are widely effective, McCall says.

###

The American Foundation for Suicide Prevention funded the research.

Click to view the study https://journals.lww.com/psychopharmacology/fulltext/2018/12000/A_Pilot,_Randomized_Clinical_Trial_of_Bedtime.15.aspx.

DOWNLOADS: Click to download a high-resolution photo of Dr. W. Vaughn McCall https://augustauniversity.app.box.com/s/umrhos1mrry6dl8668drjqwkau9nsh7t/file/349411720555 or https://augustauniversity.app.box.com/s/umrhos1mrry6dl8668drjqwkau9nsh7t/file/349428888172

Regeneration in the digestive tract / Antibiotics leave permanent traces in the gut

Public Release: 6-Nov-2018

 

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

The human gut is teeming with billions of beneficial bacteria. Therapies that use antibiotics often destroy most of them. Whether and how the intestinal flora will subsequently recover has been investigated by a research team that included scientists from the MDC. The results have been published in the scientific journal Nature Microbiology.

The human digestive tract houses a universe of tiny organisms. There are roughly as many bacteria in the gut as there are people living on earth. These microorganisms almost always serve the well-being of their host. They help to digest food, produce vitamins, and train the immune system. In addition, their very presence helps stem the spread of pathogens.

But the intestinal microcosm, also known as the microbiome, is sensitive to disruptions. “When thrown out of balance, there is a risk of infection, excess weight, and diabetes, as well as inflammatory and neurological diseases,” says Dr. Sofia Forslund, who in May this year switched from the European Molecular Biology Lab (EMBL) in Heidelberg to the Max Delbrück Center for Molecular Medicine (MDC) in Berlin to study the complex interactions between humans and microbiomes.

Antibiotics leave permanent traces in the gut

In a study published recently in Nature Microbiology, Forslund, together with colleagues from Denmark, Germany, and China, investigated how broad-spectrum antibiotic therapy affects the interaction of gut bacteria. “We were able to show that the microbiome had almost completely recovered six months after drug administration,” says the Swedish researcher. But only “almost”: “Some sensitive bacterial species disappeared completely,” says Forslund.

In the four-day study, the team led by MDC researchers and two scientists from the University of Copenhagen administered a cocktail of three antibiotics (meropenem, gentamicin, and vancomycin) to twelve healthy young men who had agreed to participate. These drugs are mainly used when more common antibiotics no longer work, due to the bacteria already having become resistant to them.

Some types of bacteria survived the drug administration

The researchers then studied their subjects’ microbiomes for six months. By means of DNA sequencing – a method used to determine the structure of the genetic material – they determined which bacterial species were present in the men’s guts, and which genes were present in the bacteria. The team also paid particular attention to resistance genes, with which the microbes defend themselves against drugs. “Our study is probably the first to investigate the influence of antibiotics on bacterial gene activity,” says Forslund.

It was first shown that the gut had not become completely sterile despite the administration of three potent antibiotics, reports the researcher. Among the remaining bacteria, the team even discovered some previously unknown species that have not yet been characterized. Other microbes shrank and turned into spores – a life form in which bacteria can persist for many years in precarious conditions without losing their original properties.

More and more disease-causing pathogens initially appeared

The subsequent repopulation of the gut was gradual. “Similar to when a forest slowly recovers after a fire,” says Forslund. However, according to the researcher, bacteria with disease-causing properties, such as Enterococcus faecalis and Fusobacterium nucleatum, initially appeared more frequently. At the same time, the team was able to identify many virulence factors in the microorganisms – structures and metabolites that are more harmful to humans. “This observation explains why most antibiotics cause gastrointestinal disturbances,” says Forslund.

Over time, however, the intestinal flora normalized again. Bad microbes were increasingly replaced by good bacteria such as the lactic acid-producing bifidobacteria that are instrumental in keeping pathogens away. After six months, the subjects’ microbiome was nearly the same as before. However, more than a few of the earlier bacterial varieties were missing. “As expected, the number of resistance genes in the bacteria also increased,” reports Forslund. Surprisingly, it was not the case that the bacterial species that reappeared most rapidly after antibiotic administration also had the most resistance genes. “This genetic material seems more likely to play a long-term role in gut repopulation,” says the researcher.

The lung microbiome will also be investigated further

“Given the apparently permanent loss of individual species and the increased number of resistance genes, the study shows once again how important it is to administer antibiotics with care,” Forslund emphasizes, adding: “It must also be further explored how to increase future success rates in protecting the sensitive microbiome from damage caused by antibiotics.”

The scientist plans to contribute to this research. For example, the MDC is currently running an observational study through which Forslund wants to find out how longer-term antibiotic treatments affect gut biodiversity – and whether a greater depletion of species increases the risk of obesity and metabolic diseases. She would also like to investigate how often gut bacteria exchange their resistance genes during antibiotic administration. A study investigating the influence of these drugs on the lung microbiome is already in the planning stage.

###

Albert Palleja et al. (2018): “Recovery of gut microbiota of healthy adults following antibiotic exposure.” Nature Microbiology 3. doi:10.1038/s41564-018-0257-9 (Publication available upon request.)

The Max Delbrück Center for Molecular Medicine (MDC)

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC’s mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent, and fight it better and more effectively. In these efforts the MDC cooperates with the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. http://www.mdc-berlin.de

The composition of gut bacteria almost recovers after antibiotics

Public Release: 23-Oct-2018

University of Copenhagen The Faculty of Health and Medical Sciences

The trillions of bacteria in the human gut affect our health in multiple ways including effects on immune functions and metabolism. A rich and diverse gut microbiota is considered to promote health providing the human host with many competences to prevent chronic diseases. In contrast, poor diversity of the gut ecosystem is a characteristic feature of chronic diseases including obesity, diabetes, asthma and gut inflammatory disorders.

Due the general bacterial-killing nature of antibiotics, it has been speculated that repetitive use of antibiotics deprives people of a rich gut bacterial environment and through this lead to adverse health effects.

Now, an international team of researchers led from the University of Copenhagen and Steno Diabetes Center Copenhagen report when 3 antibiotics were given to young healthy men for 4 days it caused an almost complete eradication of gut bacteria, followed by a gradual recovery of most bacterial species over a period of six months.

After the six months, however, the study participants were still missing nine of their common beneficial bacteria and a few new potentially non-desirable bacteria had colonized the gut. The findings are published today in Nature Microbiology.

“We show that the gut bacterial community of healthy adults are resilient and able to recover after short-term simultaneous exposure to three different antibiotics However, our findings also suggest that exposure to broad-spectrum antibiotics may dilute the diversity of the intestinal bacterial ecosystem. Antibiotics can be a blessing for preserving human health but should only be used based upon clear evidence for a bacterial cause of infection,” explains study lead , Professor Oluf Pedersen, Novo Nordisk Foundation Center for Basic Metabolic Research.

Is the missing beneficial gut microbes in the Western world due to over usage of antibiotics?

The study is a four-day intervention with three broad-spectrum so-called “last-resort” antibiotics in 12 adult healthy men. The method with a cocktail of three antibiotics was designed to mimic actual treatments in intensive care units.

The gut is a reservoir of hundreds of different bacterial species with antibiotic-resistant genes. This was confirmed in the study as these bacterial genes were the initiating force that led to the replenishment of bacteria in the gut.

“In this case, it is good that we can regenerate our gut microbiota which is important for our general health. The concern, however, relates to the potentially permanent loss of beneficial bacteria after multiple exposures to antibiotics during our lifetime. There is evidence that Western populations have a considerably lower diversity of their gut microbiota that native people living in certain parts of Africa and Amazonas. One possible explanation for this may be the widespread use of antibiotics in treatment of infectious diseases,” says Oluf Pedersen.

###

Study investigators were from Denmark, China and Germany and the study was funded among others by the Danish Diabetes Association and the Novo Nordisk Foundation.

How to help protect yourself from vaccine administration injury

Public Release: 23-Oct-2018

 

University of Waterloo

A study by researchers at the University of Waterloo reiterates the need for health care professionals, including pharmacists, to take certain precautions to minimize the risk of their patients suffering shoulder injury related to vaccine administration (SIRVA).

SIRVA is an uncommon and understudied phenomenon that people may experience after receiving an improperly administered vaccination. It occurs when an injection is administered too high in the arm, and the vaccine is delivered to the shoulder capsule instead of the deltoid muscle.

“With flu season underway and flu vaccinations widely available, both the public and health care providers should understand how to recognize and respond to SIRVA,” said Kelly Grindrod, a professor in the School of Pharmacy at Waterloo. “There are strategies we can adopt to decrease the likelihood of experiencing SIRVA.

“When going for your flu shot, wear a sleeveless shirt or a shirt where the sleeves can easily be rolled up. Don’t pull the neck of your shirt down as this can lead to a vaccine being injected into the shoulder instead of the arm. Putting your hand on your hip with your elbow out and away from the body will also help relax the deltoid muscle where the injection is going.”

It is common to experience a dull muscle ache after a vaccine injection, but that pain disappears within a few days. By contrast, SIRVA will result in pain that begins within 48 hours of vaccine administration and does not improve with over-the-counter painkiller medications

“In patients who experience SIRVA, months may pass by, and patients will still complain of increasing pain, weakness, and impaired mobility in the injected arm. Simple actions like lifting your arm to brush your teeth can cause pain,” said Grindrod. “It’s important that we learn to recognize these signs of SIRVA so that we can access appropriate treatment.”

People experiencing these symptoms should talk to their doctor. An ultrasound scan is necessary to diagnose SIRVA and determine the level and type of damage. Treatment includes a corticosteroid injection to the shoulder or physiotherapy.

Though SIRVA is fairly uncommon, it also often goes undiagnosed. Improved awareness about SIRVA is necessary for health care providers as well as patients. Grindrod and co-authors conducted a review of the literature to develop resources that teach health care providers about SIRVA and how to avoid it by using proper vaccination landmarking techniques.

The article, Getting it in the right spot: Shoulder injury related to vaccine administration (SIRVA) and other injection site events, recently appeared in the Canadian Pharmacists Journa

Researchers engineer dual vaccine against anthrax and plague

Public Release: 16-Oct-2018

American Society for Microbiology

Washington, DC – October 16, 2018 – A team of researchers has now engineered a virus nanoparticle vaccine against Bacillus anthracis and Yersinia pestis, tier 1 agents that pose serious threats to national security of the United States. B. anthracis and Y. pestis are the pathogens that cause anthrax and plague, respectively. Using bacteriophage T4, the scientists developed the vaccine by incorporating key antigens of both B. anthracis and Y. pestis into one formulation. Two doses of this vaccine provided complete protection against both inhalational anthrax and pneumonic plague in animal models. Even when animals were threatened with lethal doses of both anthrax lethal toxin and Y. pestis CO92 bacteria, the vaccine was shown to be effective. The study is published in mBio, an open-access journal of the American Society for Microbiology.

“This dual anthrax-plague vaccine is a strong candidate for stockpiling against a potential bioterror attack involving either one or both of these biothreat agents,” the researchers noted in the study. Their results demonstrate that T4 nanoparticle is a novel platform for developing multivalent vaccines against pathogens of high public health concern.

###

The American Society for Microbiology is the largest single life science society, composed of more than 30,000 scientists and health professionals. ASM’s mission is to promote and advance the microbial sciences.

ASM advances the microbial sciences through conferences, publications, certifications and educational opportunities. It enhances laboratory capacity around the globe through training and resources. It provides a network for scientists in academia, industry and clinical settings. Additionally, ASM promotes a deeper understanding of the microbial sciences to diverse audiences.

Higher levels of urinary fluoride associated with ADHD in children

Public Release: 10-Oct-2018

University of Toronto

Higher levels of urinary fluoride associated with Attention Deficit Hyperactivity Disorder (ADHD) in children

Higher levels of urinary fluoride during pregnancy are associated with more ADHD-like symptoms in school-age children, according to University of Toronto and York University researchers.

“Our findings are consistent with a growing body of evidence suggesting that the growing fetal nervous system may be negatively affected by higher levels of fluoride exposure,” said Dr. Morteza Bashash, the study’s lead author and researcher at the Dalla Lana School of Public Health.

The study, “Prenatal Fluoride Exposure and Attention Deficit Hyperactivity Disorder (ADHD) Symptoms in Children at 6-12 Years of Age in Mexico City,” published today in Environment International, analyzed data from 213 mother-child pairs in Mexico City that were part of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project, which recruited pregnant women from 1994 to 2005 and has continued to follow the women and their children ever since.

Tap water and dental products have been fluoridated in communities in Canada and the United States (as well as milk and table salt in some other countries) by varying amounts for more than 60 years to prevent cavities. In recent years, fierce debate over the safety of water fluoridation — particularly for children’s developing brains — has fueled researchers to explore the issue and provide evidence to inform national drinking water standards.

The research team — including experts from the University of Toronto, York University, the National Institute of Public Health of Mexico, University of Michigan, Indiana University, the University of Washington and Harvard School of Public Health — analyzed urine samples that had been obtained from mothers during pregnancy and from their children between six and 12 years of age to reconstruct personal measures of fluoride exposure for both mother and child.

The researchers then analyzed how levels of fluoride in urine related to the child’s performance on a variety of tests and questionnaires that measure inattention and hyperactivity, and provide overall scores related to ADHD. Analyses were adjusted for other factors known to impact neurodevelopment, such as gestational age at birth, birthweight, birth order, sex, maternal marital status, smoking history, age at delivery, education, socioeconomic status and lead exposure.

“Our findings show that children with elevated prenatal exposure to fluoride were more likely to show symptoms of ADHD as reported by parents. Prenatal fluoride exposure was more strongly associated with inattentive behaviours and cognitive problems, but not with hyperactivity,” said Bashash.

This work builds off of previous research the team published on this population demonstrating that higher levels of urine fluoride during pregnancy are associated with lower scores on tests of IQ and cognition in the school-age children.

ADHD is the most common psychiatric disorder diagnosed in childhood, affecting between five and nine per cent of all school-aged children.

“The symptoms of ADHD often persist into adulthood and can be impairing in daily life,” said Christine Till, Associate Professor of Psychology at York University and co-author on the study.

“If we can understand the reasons behind this association, we can then begin to develop preventive strategies to mitigate the risk,” said Till, who is also the principal investigator of another National Institutes of Health-funded grant examining fluoride exposure in a large Canadian sample of pregnant women.

###

The National Institute of Environmental Health Sciences, part of the National Institutes of Health (NIH), funded this study.

Fingerprint drug screen test works on the living and deceased

Public Release: 8-Oct-2018

 

University of East Anglia

IMAGE

IMAGE: A revolutionary drug test can detect four classes of drugs in traces of sweat found in a fingerprint. And the technology works on both the living and deceased.

Credit: Intelligent Fingerprinting

A revolutionary drug test developed from research carried out at the University of East Anglia can detect four classes of drugs in traces of sweat found in a fingerprint. And the technology works on both the living and deceased.

New research published in the Journal of Analytical Toxicology shows how the Intelligent Fingerprinting Drug Screening System enables the detection of amphetamines, cannabis, cocaine and opiates from a single fingerprint sample in just ten minutes.

The technology also works when used by UK coroners to detect drugs in the sweat of fingerprint samples gathered from deceased individuals.

Founded in 2007, Intelligent Fingerprinting is a spin-out company from UEA. The Drug Screening System works by analysing the sweat from a fingerprint sample.

Unlike conventional screening methods which require the collection of saliva or urine samples, the technique is non-invasive, dignified and non-biohazardous.

Its use in coroner mortuaries demonstrates the value of the system, which is also being used in drug rehabilitation centres and workplaces. Studies are also underway for its use in airport screening and for offender management applications within prisons and probation services.

Emeritus Prof David Russell, from UEA’s School of Chemistry, was a co-author of the research and is Intelligent Fingerprinting’s Founder and Chief Scientific Officer.

He said: “This new research highlights how our lateral flow drug screening cartridge can screen rapidly for drug use in individuals using a fingerprint sample with a sample collection time of only five seconds, and a total analysis time of ten minutes.

“Our study also showed how our technology is being used by coroners to assist in gaining early understanding of the possible cause of death, and to inform potential further post-mortem activities or quickly facilitate police investigations.

“We matched the coroners’ drug test results obtained using our fingerprint drug screen with a second sample tested in laboratory conditions, achieving excellent correlation in terms of accuracy,” he added.

“We also compared our results with toxicological analysis of blood and urine samples, with a good correlation of results.”

“This important research demonstrates how there is sufficient sweat present in a subject’s fingerprint, regardless of whether the person is alive or dead, to enable our fingertip-based drug screening system to detect the presence of four major drugs of abuse at the same time,” added Intelligent Fingerprinting’s Dr Paul Yates.

“The results from our coroner service trials also clearly demonstrate how our non-invasive fingerprint screen is simple to use, hygienic and offers an ideal complementary screening approach for the growing number of sectors that require a rapid and flexible drug test.”

‘Drug screening using the sweat of a fingerprint: lateral flow detection of Δ9-tetrahydrocannabinol, cocaine, opiates and amphetamine’ is published in the Journal of Analytical Toxicology.

Recovering from a heart attack? Hold the antibiotics

 

University of Wisconsin-Madison

MADISON – The community of microorganisms that live in the human gut has been shown to confer all kinds of health benefits. Now, an international team of researchers has shown in mice that a healthy gut microbiome is important for recovery after a heart attack.

Writing today (Oct. 8, 2018) in the journal Circulation, a team led by surgeon Patrick Hsieh of the Institute of Biomedical Sciences at Academia Sinica in Taipei, Taiwan, in collaboration with researchers from the University of Wisconsin-Madison, reports on experiments that show mice recovering from heart attacks are more likely to die if treated with antibiotics, a common intervention in hospitalized patients.

“This is a new thing to add to the list of potential complications” for recovery from a heart attack, says Timothy Kamp, a UW-Madison professor of medicine and cardiologist who contributed to the new study.

It is common, Kamp explains, for hospitalized patients to be dosed with broad spectrum antibiotics to treat a variety of infections, and some of these patients have heart attacks. But antibiotics can be indiscriminate and eliminate not only bad microbial players, but also the microbes we depend on to stay healthy, including the trillions of fungi and bacteria that help make up the gut microbiome.

Working in collaboration with microbiome expert and UW-Madison Professor of Bacteriology Federico Rey, Hsieh and Kamp treated mice with antibiotics to deplete the gut microbiome a week prior to experimentally inducing myocardial infarction or heart attack.

The depleted microbiome, the team found, tamps down the production of a set of three short-chain fatty acids, which are produced as the gut’s community of microorganism’s metabolizes food and which act as important chemical messengers to the body’s immune system. The diminished response, says Hsieh, “impacts the immune response and the repair response after myocardial infarction.”

Conversely, when the mouse microbiome is restored through a fecal transplant, the researchers observed an uptick in mouse physiological well-being and survival. And in mice that had their microbiomes boosted through the use of probiotics or other interventions prior to a heart attack, increased cardioprotective effects and survival were the hallmark effects. Previous studies in healthy mice have shown that the microbiome influences gene expression and the deployment of the short-chain fatty acids that help regulate immune response.

The current study showed that production of a small set of short-chain fatty acids was diminished by a depleted microbiome, but there likely are many more players – perhaps thousands – that may also be affected and that play a role in the immune response to a heart attack, says Kamp.

The research also showed that heart attacks themselves influence the health of the microbiome: “We found changes after myocardial infarction even without any antibiotics,” notes Rey. “Your microbiome changes as a result of a heart attack.”

However, the key finding – that a depleted microbiome and its diminished production of short-chain fatty acids blunts recovery from a heart attack – suggests that clinical intervention to manipulate the microbiome through a more nuanced use of antibiotics and supplementing it with probiotics will help human patients recover faster and more robustly from heart attacks, says Kamp. He adds that the study also identifies the short-chain fatty acids themselves as a potential therapeutic target to bolster a favorable immune response in the context of cardiovascular disease, one of the leading causes of death in industrialized societies. “The immune system and inflammation play a role in repair from a heart attack. We’ve known about the relationship between the microbiome and immune response. Now we’re getting at how that relationship works after a heart attack.”

###

Terry Devitt (608) 262-8282, trdevitt@wisc.edu

The study was supported by a grant from the University of Wisconsin-Madison’s Microbiome Initiative administered by the Office of the Vice Chancellor for Research and Graduate Education.

In Health Affairs: Cardiac devices up to six times more expensive in the US than Germany

 

Health Affairs

While much has been written about drug prices, less attention has been paid to medical devices, which account for 6 percent of US health care spending and 7 percent in European Union (EU) countries. In a new study appearing in the October issue of Health Affairs, the first systemic comparison of prices of cardiac implants, Martin Wenzl and Elias Mossialos of the London School of Economics and Political Science used survey data to compare prices for cardiac implants between the US, France, Germany, Italy, and the UK in the years 2006-14. They found that prices were typically highest in the US, where some prices were as much as six times those paid in Germany. For example, in 2014, the mean prices of a drug-eluting stent and a dual-chamber pacemaker were $340 and $1,400 in Germany, compared to $1,400 and $4,200 in the US. The authors also observed that prices varied within all countries except France. They conclude that factors at the health system level, including incentives for hospitals to contain costs, may help explain price variation.

###

Health Affairs is the leading peer-reviewed journal at the intersection of health, health care, and policy. Published monthly by Project HOPE, the journal is available in print, online, and on mobile phones. Additional and late-breaking content is found at http://www.healthaffairs.org.

Reclassification recommendations for drug in ‘magic mushrooms’

Public Release: 26-Sep-2018

If phase III clinical trials are successful, researchers suggest categorizing the drug as schedule IV

Johns Hopkins Medicine

In an evaluation of the safety and abuse research on the drug in hallucinogenic mushrooms, Johns Hopkins researchers suggest that if it clears phase III clinical trials, psilocybin should be re-categorized from a schedule I drug–one with no known medical potential–to a schedule IV drug such as prescription sleep aids, but with tighter control.

The researchers summarize their analysis in the October print issue of Neuropharmacology.

“We want to initiate the conversation now as to how to classify psilocybin to facilitate its path to the clinic and minimize logistical hurdles in the future,” says Matthew W. Johnson, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “We expect these final clearance trials to take place in the next five years or so.”

Following the Controlled Substances Act of 1970, any drug with the potential for abuse is categorized based on criteria that take into account whether the drug has accepted medical use, and its safety and the potential for abuse. Although preliminary research studies suggest that psilocybin may be effective for smoking cessation and for disorders such as cancer-specific depression and anxiety, it must clear phase III clinical trials before the Food and Drug Administration can be petitioned to reclassify it.

Studies in animals and humans both show low potential for abuse, the researchers say. When rats push a lever to receive psilocybin, they don’t keep pushing the lever like they do for drugs such as cocaine, alcohol or heroin. When it comes to human studies, people who have used psilocybin typically report using it a few times across their lifetime.

As for safety, studies show it frequently falls at the end of the scales with the least harm to users and society, say the researchers. Psilocybin also is lowest in the potential for lethal overdose as there is no known overdose level.

“We should be clear that psilocybin is not without risks of harm, which are greater in recreational than medical settings, but relatively speaking, looking at other drugs both legal and illegal, it comes off as being the least harmful in different surveys and across different countries,” says Johnson.

That being said, although psilocybin is relatively less harmful than other drugs and not prone to compulsive abuse, the researchers don’t recommend releasing psilocybin into patients’ hands even with a prescription. “We believe that the conditions should be tightly controlled and that when taken for a clinical reason, it should be administered in a health care setting monitored by a person trained for that situation,” says Johnson. The researchers foresee that the process for psilocybin use in the clinic would be similar to how an anesthesiologist prescribes and administers a drug, minimizing the potential for abuse or harm.

###

Additional authors include Roland Griffiths and Jack Henningfield of Johns Hopkins and Peter Hendricks of University of Alabama, Birmingham.

The analysis was funded by grants from Heffter Research Institute, Pinney Associates and National Institute of Drug Abuse (RO1DA03889).

COI: Griffiths and Henningfield consult for Hefftner Research Institute and Usona Institute.

The BMJ questions transparency of information surrounding safety of Pandemrix vaccine

Public Release: 20-Sep-2018

BMJ

  • A series of internal GlaxoSmithKline reports suggest possibility that serious safety signal had emerged for Pandemrix during 2009 H1N1 vaccine campaigns
  • Data indicated large discrepancies in rate of adverse event reporting for Pandemrix as compared to other GSK pandemic influenza vaccines
  • Manufacturer and some public health bodies received reports but did not make them public
  • Why did questions around the vaccine’s safety not emerge earlier?
  • Is the vaccine safety monitoring system fit for purpose?

An investigation published by The BMJ today raises fundamental questions about the transparency of information surrounding the safety of GlaxoSmithKline’s Pandemrix vaccine used in 2009-2010.

Eight years after the 2009 H1N1 “swine flu” outbreak, new information is emerging of a striking difference in the number and frequency of adverse events reported for three GSK pandemic vaccines approved and used across the world.

Internal safety reports from 2009 – unearthed as part of a lawsuit – suggest that GSK and public health officials were aware of a variety of serious adverse events logged in relation to Pandemrix, explains The BMJ‘s Associate Editor Peter Doshi.

But it would seem neither GSK nor health authorities made the information public, either during the H1N1 outbreak nor in the eight years since.

Doshi learned of the reports from a colleague, Tom Jefferson, who was hired as an expert witness in a lawsuit alleging that Pandemrix caused the sleep disorder narcolepsy.

Jefferson used the information to calculate adverse event rates per vaccine, which showed large differences between Pandemrix and other GSK pandemic vaccines.

The BMJ conducted its own analysis and found that Pandemrix had, proportionally, five times more adverse events reported than Arepanrix and another H1N1 vaccine manufactured by GSK.

The data are insufficient to draw cause-and-effect conclusions, but for Gillian O’Connor, the solicitor involved in the narcolepsy lawsuit, the disparity was “of such striking difference that any person contemplating taking the Pandemrix vaccine would be likely, if in receipt of this information, not to choose to have the Pandemrix vaccination.”

In many of the GSK reports, the company refers to having conducted “safety reviews.” The BMJ asked GSK for a copy of those reviews, but GSK did not provide them.

Instead, the company said it “continuously evaluated all available safety data and shared the data with the European Medicines Association (EMA) and other regulatory authorities where the vaccine was licensed so that the authorities could conduct their own independent assessments.”

The BMJ also asked GSK whether it ever notified healthcare providers about the discrepancies in rate of adverse events between its products, whether it considered pulling Pandemrix from the market, or considered recommending Arepanrix or another company’s vaccine. But GSK declined to answer these and all of The BMJ‘s questions, citing ongoing litigation.

The UK Department of Health also declined to comment on why it recommended Pandemrix over another company’s vaccine.

What the EMA knew – or could have known – about the comparative safety of GSK’s pandemic vaccines is hard to discern, writes Doshi. The EMA told The BMJ that it “does not perform comparative benefit and risk evaluations between products approved in the EU, or between EU products and products approved or used outside the EU.”

These events raise fundamental questions about the transparency of information, and question whether drug and vaccine safety monitoring (known as pharmacovigilance) is fit for purpose, writes Doshi.

For example, when do public health officials have a duty to warn the public over possible harms of vaccines detected through pharmacovigilance? How much detail should the public be provided with, who should provide it, and should the provision of such information be proactive or passive?

“If history were to repeat itself, does the public have a right to know?”

###

Peer-reviewed? Yes
Type of evidence: Investigation
Subjects: People

Sugar pills relieve pain for chronic pain patients

Public Release: 12-Sep-2018

Placebo benefits can be predicted by brain anatomy and psychological traits

Northwestern University

  • Doctors should consider treating chronic pain patients with sugar pills
  • Placebo pills relieve pain as effectively as drugs for half of chronic pain patients
  • Pain reduced by 30 percent
  • No need to fool patients, brain is primed to respond
  • Finding can result in vast cost savings for patients, health care system

CHICAGO — Someday doctors may prescribe sugar pills for certain chronic pain patients based on their brain anatomy and psychology. And the pills will reduce their pain as effectively as any powerful drug on the market, according to new research.

Northwestern Medicine scientists have shown they can reliably predict which chronic pain patients will respond to a sugar placebo pill based on the patients’ brain anatomy and psychological characteristics.

“Their brain is already tuned to respond,” said senior study author A. Vania Apkarian, professor of physiology at Northwestern University Feinberg School of Medicine. “They have the appropriate psychology and biology that puts them in a cognitive state that as soon as you say, ‘this may make your pain better,’ their pain gets better.”

There’s no need to fool the patient, Apkarian said.

“You can tell them, ‘I’m giving you a drug that has no physiological effect but your brain will respond to it,'” he said. “You don’t need to hide it. There is a biology behind the placebo response.”

The study was published Sept. 12 in Nature Communications.

The findings have three potential benefits:

  • Prescribing non-active drugs rather than active drugs. “It’s much better to give someone a non-active drug rather than an active drug and get the same result,” Apkarian said. “Most pharmacological treatments have long-term adverse effects or addictive properties. Placebo becomes as good an option for treatment as any drug we have on the market.”
  • Eliminating the placebo effect from drug trials. “Drug trials would need to recruit fewer people, and identifying the physiological effects would be much easier,” Apkarian said. “You’ve taken away a big component of noise in the study.”
  • Reduced health care costs. A sugar pill prescription for chronic pain patients would result in vast cost savings for patients and the health care system, Apkarian said.

How the study worked

About 60 chronic back pain patients were randomized into two arms of the study. In one arm, subjects didn’t know if they got the drug or the placebo. Researchers didn’t study the people who got the real drug. The other study arm included people who came to the clinic but didn’t get a placebo or drug. They were the control group.

The individuals whose pain decreased as a result of the sugar pill had a similar brain anatomy and psychological traits. The right side of their emotional brain was larger than the left, and they had a larger cortical sensory area than people who were not responsive to the placebo. The chronic pain placebo responders also were emotionally self-aware, sensitive to painful situations and mindful of their environment.

“Clinicians who are treating chronic pain patients should seriously consider that some will get as good a response to a sugar pill as any other drug,” Apkarian said. “They should use it and see the outcome. This opens up a whole new field.”

###

Other Northwestern authors are co-lead author Etienne Vachon-Presseau, Sara Berger, Taha Abdullah, Lejian Huang, Guillermo Cecchi, James Griffith and Thomas Schnitzer.

This study was funded by National Center for Complementary and Integrative Health grant AT007987 of the National Institutes of Health and the Canadian Institutes of Health Research and Fonds de Recherche Santé Québec.

More News at Northwestern Now

Find experts on our Faculty Experts Hub

Follow @NUSources for expert perspectives

http://news.feinberg.northwestern.edu/tag/press-release/

Breast cancer screening does not reduce mortality

Public Release: 12-Sep-2018

A Norwegian-Danish study shows that breast cancer mortality is indeed declining, but not due to screening for breast cancer. Associate Professor Henrik Støvring from Denmark thinks it is time to consider alternatives to mammography screening.

Aarhus University

Fewer and fewer women die from breast cancer in recent years but, surprisingly, the decline is just as large in the age groups that are not screened. The decline is therefore due to better treatment and not screening for breast cancer.

This is shown by a major Danish-Norwegian study, Effect of organised mammography screening on breast cancer mortality: A populationbased cohort study in Norway, which has just been published in the scientific journal International Journal of Cancer.

In the study, the researchers followed all Norwegian women aged 30-89 and identified those who developed breast cancer in the period 1987-2010, before subsequently comparing the number of deaths before and after the screening programme was introduced.

As Associate Professor Henrik Støvring from Aarhus University, Denmark, notes, the result does not favour the breast cancer screening programme. This conclusion can also be transferred directly to Denmark (and elsewhere), where all women aged 50-69 are offered mammography screening – which is an X-ray examination of the chest – every second year. The Danish screening programme was progressively introduced from the early 1990s and was offered nationally to everyone from 2007, three years after the Norwegians, who have supplied data for the Danish-Norwegian research project.

“The important result is that we do not find a beneficial effect of breast cancer screening any longer. The original randomised trials examining breast cancer screening were conducted way back in the 1980s, and they showed an effect, but the fact is that the better the treatment methods become, the less benefit screening has,” says Henrik Støvring, who is associate professor at the Department of Public Health with biostatistics and screening programmes as his particular areas of expertise.

Here he points towards one of the paradoxes of screening – the popular but erroneous belief that if breast cancer patients who have been screened ‘live longer’ than other breast cancer patients, then screening works. The problem is that with screening, medical doctors detect cancerous tumours earlier than they would otherwise have done, and thus move the point of diagnosis forward in time. But even if someone who has been screened lives longer as a patient, it is not certain that their life as a whole will be longer. It is important to account for this fact, and the new study shows that screening does not lead to women living longer overall – and this is the study’s most important finding.

“The women who are invited to screening live longer because all breast cancer patients live longer, and they do so because we now have better drugs and more effective chemotherapy, and because we have cancer care pathways, which means the healthcare system reacts faster than it did a decade ago. But it does not appear that fewer women die of breast cancer as a result of mammography screening,” says Henrik Støvring.

He also points out that it is not always beneficial for a woman to be diagnosed with a tiny cancerous growth of e.g. a millimetre in diameter at a mammography. Some of these small nodules are so slow-growing that the woman would have died a so-called natural death with undiagnosed cancer, if she had not been screened.

“Now what happens is these women are instead given a diagnosis which isn’t going to make anyone happier. Such a breast cancer diagnosis both makes life more difficult and costs a lot of money, but does not ultimately make a difference. The problem is that we are not currently able to tell the difference between the small cancer tumours that will kill you and those that will not,” says Henrik Støvring.

Here he addresses the issue of overdiagnosis which is a growing problem in all Western countries where the approach to medicine and examinations is extensive and where national screening programmes are prevalent. A problem that was last week discussed in Copenhagen, Denmark, where 450 researchers from thirty countries attended the Preventing Overdiagnosis 2018 conference.

Even though the research results challenge the current health policy in Denmark, Norway and the rest of the Western world, Henrik Støvring is not in the business of telling Danish politicians that they should stop the national screening programme here and now:

“It’s certainly not my task to decide how the research results should be used, but my suggestion would nonetheless be that we should get together and begin to investigate whether it would beneficial to do something other than screening and whether this could have a better effect. If a doctor could instead examine women’s breasts with his or her hands, what is known as palpation, at regular intervals, then we would avoid much of the overdiagnosis,” says Henrik Støvring.

###

The research results – more information

The study is a cohort study with follow-up of all Norwegian women aged 30-89 in the period 1987-2010.

Henrik Støvring’s collaborators have been: Mette H. Møller, MSc in Public Health, Aarhus University; Mette Lise Lousdal, PhD student, Department of Public Health, Aarhus University; and Professor Ivar S. Kristiansen, Oslo University in Norway.

Aspirin found not to prolong healthy aging

Public Release: 17-Sep-2018

 

Large, international study shows daily low-dose aspirin has no effect on healthy life span in older adults

Rush University Medical Center

Taking a low-dose aspirin daily does not prolong healthy living in older adults, according to findings from the ASPirin in Reducing Events in the Elderly (ASPREE) trial published online Sept. 16 in three papers in the New England Journal of Medicine.

The large clinical trial, which began in 2010, aimed to determine the risks and benefits of daily low-dose aspirin in healthy older adults without previous cardiovascular events, dementia or physical disability, and who were free of medical conditions requiring aspirin use. The results showed that aspirin did not extend healthy independent living (life free of dementia or persistent physical disability). Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up of study participants.

“This work is a key milestone in the more than a decade-long engagement in this large-scale clinical trial in the United States and Australia,” said Dr. Raj C. Shah, an associate professor of family medicine with the Rush Alzheimer’s Disease Center in Chicago.

Shah served as principal investigator of the ASPREE trial at Rush University Medical Center, which was an enrollment site for the study through the patient-oriented research team of the Rush Alzheimer’s Disease Center. Shah also served on the governance of the entire study as a member of its International Steering Committee, and as co-U.S. investigator with Dr. Anne Murray at the Berman Center in Minneapolis, Minnesota.

“The results will have a significant impact on guidelines about aspirin use for prevention and in daily clinical conversations between clinicians and their older, healthy patients regarding whether aspirin should or should not be used for achieving disability-free longevity,” said Shah.

Rush helped recruit under-represented groups and reduce barriers to study participation

The international, randomized, double-blind, placebo-controlled trial enrolled 19,114 older people (16,703 in Australia and 2,411 in the United States). Study participants were enrolled at 70 years of age or older, with 65 as the minimum age of entry for African-American and Hispanic individuals in the United States because of their higher risk for dementia and cardiovascular disease. They were followed for an average of 4.7 years to determine outcomes.

Rush researchers provided key national input into the recruitment and retention strategies for participants who are under-represented in aging research, with a special focus on African-American and Hispanic older adults. The Rush team also developed and implemented innovative, in-home assessments to reduce the barriers for continued participation in a study that involved evaluations for up to seven years.

The team of scientists was led by John J. McNeil, MBBS, PhD, head of the Department of Epidemiology and Preventive Health at Monash University, Melbourne, Australia, and Dr. Anne M. Murray, director of the Berman Center for Outcomes and Clinical Research at Hennepin Healthcare in Minneapolis. The research was supported in part by the National Institute on Aging and the National Cancer Institute, both parts of the National Institutes of Health (U01AG029824). The Australian component of the study also received funding from the Australian National Health and Medical Research Council and Monash University. Aspirin and placebo were supplied by Bayer, which had no other involvement with the study.

“Clinical guidelines note the benefits of aspirin for preventing heart attacks and strokes in persons with vascular conditions such as coronary artery disease,” said NIA Director Dr. Richard J. Hodes. “The concern has been uncertainty about whether aspirin is beneficial for otherwise healthy older people without those conditions. This study shows why it is so important to conduct this type of research, so that we can gain a fuller picture of aspirin’s benefits and risks among healthy older persons.”

Taking aspirin did not affect onset of dementia or physical disability

In the total study population, treatment with 100 mg of low-dose aspirin per day did not affect survival free of dementia or disability. Among the people randomly assigned to take aspirin, 90.3 percent remained alive at the end of the treatment without persistent physical disability or dementia, compared with 90.5 percent of those taking a placebo. Rates of physical disability were similar, and rates of dementia were almost identical in both groups.

The group taking aspirin had an increased risk of death compared to the placebo group: 5.9 percent of participants taking aspirin and 5.2 percent taking placebo died during the study. This effect of aspirin has not been noted in previous studies, and caution is needed in interpreting this finding.

The higher death rate in the aspirin-treated group was due primarily to a higher rate of cancer deaths. A small increase in new cancer cases was reported in the group taking aspirin, but the difference could have been due to chance.

Aspirin was associated with greater risk of bleeding

The researchers also analyzed the ASPREE results to determine whether cardiovascular events took place. They found that the rates for major cardiovascular events — including coronary heart disease, nonfatal heart attacks, and fatal and nonfatal ischemic stroke — were similar in the aspirin and the placebo groups. In the aspirin group, 448 people experienced cardiovascular events, compared with 474 people in the comparably-sized placebo group.

Significant bleeding — a known risk of regular aspirin use — also was measured. The investigators noted that aspirin was associated with a significantly increased risk of bleeding, primarily in the gastrointestinal tract and brain. Clinically significant bleeding — hemorrhagic stroke, bleeding in the brain, gastrointestinal hemorrhages or hemorrhages at other sites that required transfusion or hospitalization — occurred in 361 people (3.8 percent) on aspirin and in 265 (2.7 percent) taking the placebo.

As would be expected in an older adult population, cancer was a common cause of death, and 50 percent of the people who died in the trial had some type of cancer. Heart disease and stroke accounted for 19 percent of the deaths, and major bleeding for 5 percent.

“The increase in cancer deaths in study participants in the aspirin group was surprising, given prior studies suggesting aspirin use improved cancer outcomes,” said Dr. Leslie Ford, associate director for clinical research, National Cancer Institute Division of Cancer Prevention. “Analysis of all the cancer-related data from the trial is under way and until we have additional data, these findings should be interpreted with caution.”

Findings do not apply to patients with cardiovascular conditions

“Continuing follow-up of the ASPREE participants is crucial, particularly since longer term effects on risks for outcomes such as cancer and dementia may differ from those during the study to date,” said Dr. Evan Hadley, director of NIA’s Division of Geriatrics and Clinical Gerontology. “These initial findings will help to clarify the role of aspirin in disease prevention for older adults, but much more needs to be learned. The ASPREE team is continuing to analyze the results of this study and has implemented plans for monitoring participants.”

As these efforts continue, Hadley emphasized that older adults should follow the advice from their own physicians about daily aspirin use. It is important to note that the new findings do not apply to people with a proven indication for aspirin such as stroke, heart attack or other cardiovascular disease. In addition, the study did not address aspirin’s effects in people younger than age 65. Also, since only 11 percent of participants had regularly taken low-dose aspirin prior to entering the study, the implications of ASPREE’s findings need further investigation to determine whether healthy older people who have been regularly using aspirin for disease prevention should continue or discontinue use.

###

Disclaimer: AAAS and EurekAlert! are not responsible for the

Sugar pills relieve pain for chronic pain patients

Public Release: 12-Sep-2018

 

Placebo benefits can be predicted by brain anatomy and psychological traits

Northwestern University

  • Doctors should consider treating chronic pain patients with sugar pills
  • Placebo pills relieve pain as effectively as drugs for half of chronic pain patients
  • Pain reduced by 30 percent
  • No need to fool patients, brain is primed to respond
  • Finding can result in vast cost savings for patients, health care system

CHICAGO — Someday doctors may prescribe sugar pills for certain chronic pain patients based on their brain anatomy and psychology. And the pills will reduce their pain as effectively as any powerful drug on the market, according to new research.

Northwestern Medicine scientists have shown they can reliably predict which chronic pain patients will respond to a sugar placebo pill based on the patients’ brain anatomy and psychological characteristics.

“Their brain is already tuned to respond,” said senior study author A. Vania Apkarian, professor of physiology at Northwestern University Feinberg School of Medicine. “They have the appropriate psychology and biology that puts them in a cognitive state that as soon as you say, ‘this may make your pain better,’ their pain gets better.”

There’s no need to fool the patient, Apkarian said.

“You can tell them, ‘I’m giving you a drug that has no physiological effect but your brain will respond to it,'” he said. “You don’t need to hide it. There is a biology behind the placebo response.”

The study was published Sept. 12 in Nature Communications.

The findings have three potential benefits:

  • Prescribing non-active drugs rather than active drugs. “It’s much better to give someone a non-active drug rather than an active drug and get the same result,” Apkarian said. “Most pharmacological treatments have long-term adverse effects or addictive properties. Placebo becomes as good an option for treatment as any drug we have on the market.”
  • Eliminating the placebo effect from drug trials. “Drug trials would need to recruit fewer people, and identifying the physiological effects would be much easier,” Apkarian said. “You’ve taken away a big component of noise in the study.”
  • Reduced health care costs. A sugar pill prescription for chronic pain patients would result in vast cost savings for patients and the health care system, Apkarian said.

How the study worked

About 60 chronic back pain patients were randomized into two arms of the study. In one arm, subjects didn’t know if they got the drug or the placebo. Researchers didn’t study the people who got the real drug. The other study arm included people who came to the clinic but didn’t get a placebo or drug. They were the control group.

The individuals whose pain decreased as a result of the sugar pill had a similar brain anatomy and psychological traits. The right side of their emotional brain was larger than the left, and they had a larger cortical sensory area than people who were not responsive to the placebo. The chronic pain placebo responders also were emotionally self-aware, sensitive to painful situations and mindful of their environment.

“Clinicians who are treating chronic pain patients should seriously consider that some will get as good a response to a sugar pill as any other drug,” Apkarian said. “They should use it and see the outcome. This opens up a whole new field.”

###

Other Northwestern authors are co-lead author Etienne Vachon-Presseau, Sara Berger, Taha Abdullah, Lejian Huang, Guillermo Cecchi, James Griffith and Thomas Schnitzer.

This study was funded by National Center for Complementary and Integrative Health grant AT007987 of the National Institutes of Health and the Canadian Institutes of Health Research and Fonds de Recherche Santé Québec.

More News at Northwestern Now

Find experts on our Faculty Experts Hub

Follow @NUSources for expert perspectives

http://news.feinberg.northwestern.edu/tag/press-release/

Vicious circle leads to loss of brain cells in old age

Public Release: 31-Aug-2018

Researchers at the University of Bonn determine how dangerous inflammations in the brain are caused

University of Bonn

IMAGE

IMAGE: Dr. Andras Bilkei-Gorzo and his colleagues have determined how endocannabinoids attenuate inflammatory reactions in the brain.

Credit: © Photo: Kerstin Nicolai/Uni Bonn

The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. However, it appears to act also as a kind of “sensor” with which neurons measure and control the activity of certain immune cells in the brain. A recent study by the University of Bonn at least points in this direction. If the sensor fails, chronic inflammation may result – probably the beginning of a dangerous vicious circle. The publication appears in the journal Frontiers in Molecular Neuroscience.

The activity of the so-called microglial cells plays an important role in brain aging. These cells are part of the brain’s immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.

This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled. “We know that so-called endocannabinoids play an important role in this”, explains Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn. “These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells.”

Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. “However, microglial cells have virtually no CB1 and very low level of CB2 receptors,” emphasizes Bilkei-Gorzo. “They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals – why this is the case, has been puzzling so far.”

Neurons as “middlemen”

The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen – a certain group of neurons, because this group has a large number of CB1 receptors. “We have studied laboratory mice in which the receptor in these neurons was switched off,” explains Bilkei-Gorzo. “The inflammatory activity of the microglial cells was permanently increased in these animals.”

In contrast, in control mice with functional CB1 receptors, the brain’s own defense forces were normally inactive. This only changed in the present of inflammatory stimulus. “Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells,” said Bilkei-Gorzo. “However, we cannot yet say whether this is also the case in humans.”

This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulatory the other major glial cell type, the astroglial cells.

During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects: “Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running.”

It may be possible to break this vicious circle with drugs in the future. It is for instance hoped that cannabis will help slow the progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator – even in low doses free from intoxicating effect. Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.

###

Publication: Frank Ativie, Joanna A. Komorowska, Eva Beins, Önder Albayram, Till Zimmer, Andreas Zimmer, Dario Tejera, Michael Heneka and Andras Bilkei-Gorzo: Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons In?uences Microglial Activity; Frontiers in Molecular Neuroscience; https://doi.org/10.3389/fnmol.2018.00295

Contact:

Dr. Andras Bilkei-Gorzo
Institute of Molecular Psychiatry
University of Bonn
Tel. +49 (0)228-6885317
E-mail: abilkei@uni-bonn.de

Hormone therapy can make prostate cancer worse, study finds

Public Release: 4-Sep-2018

 

Cedars-Sinai Medical Center

LOS ANGELES (Sept. 4, 2018) — Scientists at Cedars-Sinai have discovered how prostate cancer can sometimes withstand and outwit a standard hormone therapy, causing the cancer to spread. Their findings also point to a simple blood test that may help doctors predict when this type of hormone therapy resistance will occur.

Prostate cancer is the second-leading cause of cancer death in men, behind lung cancer, killing nearly 30,000 in the U.S. each year, according to the American Cancer Society. In its early stages, the most common type, adenocarcinoma, is curable and generally responds well to therapies, including those that target androgen – a male sex hormone that stimulates tumor growth.

However, in certain patients, the cancer becomes resistant to androgen-targeted therapy, and the cancer recurs or spreads. One possible reason for that resistance, the study indicated, appears to be that the therapy causes some adenocarcinoma cells to become neuroendocrine cancer-type cells – a rare type that normally appears in fewer than 1 percent of prostate cancer patients.

“This transformation is a problem because neuroendocrine prostate cancer is especially aggressive, metastasizes more readily and is more resistant to both androgen-targeted therapy and chemotherapy,” said Neil Bhowmick, PhD, co-director of the Cancer Biology Program at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai. He is senior author of the study, published in the Journal of Clinical Investigation, and Rajeev Mishra, PhD, former project scientist in his laboratory, is the lead author.

Bhowmick said about one-fourth of the patients who receive androgen-targeted therapy may relapse with tumors that show features of neuroendocrine prostate cancer and develop treatment-resistant disease, according to published research.

To learn more about this process, the investigators examined how cancer cells interact with the supporting cells near the tumor, referred to as the tumor microenvironment, in laboratory mice. They found these interactions raised the level of the amino acid glutamine, turning the supporting cells into “factories” that supplied fuel for the cancer cells.

“While glutamine is known to spur cancer growth, its role in prostate cancer cells to trigger reprogramming of adenocarcinoma cells into neuroendocrine cancer cells is a new and important finding,” said Roberta Gottlieb, MD, professor of Medicine and vice chair of translational medicine in the Department of Biomedical Sciences at Cedars-Sinai. Gottlieb was a co-author of the study.

The team also examined how androgen-targeted therapy affected the cancer microenvironment.

“To our surprise, we found this type of therapy further changed the cellular environment in a way that caused adenocarcinoma cells in the prostate to transform into neuroendocrine cancer-type cells,” said Bhowmick, professor of Medicine and Biomedical Sciences.

As the final step in validating the findings in mice, investigators compared levels of glutamine in the plasma of small groups of patients – one with treatment-responsive prostate cancer and the other with treatment-resistant prostate cancer. They found that levels of glutamine were higher in the second group.

This finding has potential implications for treating prostate cancer patients, said Edwin Posadas, MD, co-director of the Translational Oncology Program at the cancer institute and associate professor and clinical chief of the Division of Hematology/Oncology in the Department of Medicine at Cedars-Sinai.

“The study raises the possibility that a simple blood test measuring glutamine might be able to pinpoint when androgen-targeted therapy is failing in a prostate cancer patient and even predict when therapy resistance will occur,” said Posadas, who co-authored the study. He said the team is designing a new study to test this hypothesis.

###

Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA 108646 and CA 098912 and the U.S. Department of Veterans Affairs under award number BX001040.

New research: Financial disclosure lacking in publication of clinical trials

Public Release: 30-Aug-2018

Oregon Health & Science University

A substantial proportion of pharmaceutical industry payments to authors of oncology clinical trials published in major scientific journals are not disclosed, new research shows. The publications focused on clinical trials that tested new cancer drugs.

The new findings will be published as a research letter in the journal JAMA Oncology.

Authors of the research letter examined the federal Open Payments Database to determine payments to oncologists who authored studies in high-impact journals. They then cross-checked the information to determine whether the authors properly disclosed the funding when the results of their clinical trials were published in scientific journals. Depending on the journal, almost half of total funding was not disclosed.

“It’s the honor system,” said co-author Erick Turner, M.D., associate professor of psychiatry in the OHSU School of Medicine and senior scholar with the Center for Ethics in Health Care at OHSU in Portland, Oregon. “The journals ask the authors to make these disclosures, but there’s no legal force behind it.”

Previous studies have investigated funding disclosures among the authors of clinical practice guidelines. However, this is the first study to examine financial conflict of interest in the publication of clinical trials that underpin FDA approval of new oncology drugs.

Payments from pharmaceutical companies have been shown to change physician prescribing practices, researchers noted.

“We know that pharmaceutical companies sponsor trials of their own drugs. That’s not a surprise,” said lead author Cole Wayant, D.O., Ph.D., researcher at Oklahoma State University. “But what is a surprise, and what warrants concern, is that this funding is often not disclosed in the publication of clinical trials that form the basis of FDA approvals and clinical practice guidelines.”

The researchers identified 344 oncologist-authors of clinical trials associated with oncology drugs approved between Jan. 1, 2016, and Aug. 31, 2017. Cumulatively, the 344 oncologist authors received a total of $216 million in four categories of payments: Speaking fees and other general payments; research for study coordination; research grants, and ownership through stock payments.

The authors then compared disclosure of financial conflict of interest in clinical trials published in six high-impact scientific journals: The New England Journal of Medicine, The Lancet, The Lancet Oncology, The Lancet Haematology, the Journal of Clinical Oncology, and JAMA Oncology. Almost a third of the oncologist-authors (a total of 110) did not fully disclose payments, the study found.

“In clinical trials of FDA-approved oncology drugs, bias, either real or potential, is more concerning because these oncology drugs are often associated with marginal improvement in survival but exorbitant costs,” the authors wrote.

Antibiotic side effects in kids lead to nearly 70,000 ER visits in the US each year

Public Release: 23-Aug-2018

Pediatric Infectious Diseases Society

The use of antibiotics drives the development of antibiotic resistance, a major threat to public health worldwide. But these drugs also carry the risk of harm to individual patients, including children. According to a new analysis published in the Journal of the Pediatric Infectious Diseases Society, antibiotics led to nearly 70,000 estimated emergency room visits in the U.S. each year from 2011-2015 for allergic reactions and other side effects in children. The study helps quantify the risk posed by specific antibiotics in children across different age ranges.

“For parents and other caregivers of children, these findings are a reminder that while antibiotics save lives when used appropriately, antibiotics also can harm children and should only be used when needed,” said lead author Maribeth C. Lovegrove, MPH, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention. “For health care providers, these findings are a reminder that adverse effects from antibiotics are common and can be clinically significant and consequential for pediatric patients.”

For their analysis, researchers used nationwide estimates for outpatient antibiotic prescriptions and data from a nationally representative sample of hospitals for emergency room visits attributed to the use of antibiotics by children aged 19 and younger. Most of the visits (86 percent) were for allergic reactions, such as a rash, pruritus (itching), or angioedema (severe swelling beneath the skin). The risk of a visit varied by child age and type of antibiotic, but for most antibiotics, children aged 2 or younger had the highest risk of an adverse drug event. Forty-one percent of visits involved children in this age group. Amoxicillin was the most commonly implicated antibiotic in adverse drug events among children aged 9 or younger, while sulfamethoxazole/trimethoprim was most commonly implicated among children 10-19 years old.

Antibiotics are among the most commonly prescribed medications for children, but prior research has suggested that nearly a third, if not more, of outpatient pediatric prescriptions for antibiotics are unnecessary. Efforts to reduce antibiotic overprescribing have largely focused on reducing antibiotic resistance. However, studies have shown that these longer-term societal risks are not always prioritized when clinicians are making decisions about treatment.

“By considering available data on the immediate risks to individual patients, clinicians, and parents and caregivers, can better weigh the risks and benefits of antibiotic treatment,” Lovegrove said.

The researchers were not able to determine which antibiotic prescriptions were unnecessary or inappropriate in the study, because data for antibiotic indications, doses, and durations of therapy were not available. The study also likely underestimates how often children experience adverse side effects from antibiotics because the analysis includes only adverse drug events that resulted in a visit to an emergency room. Adverse drug events treated in other settings, such as an urgent care facility or a doctor’s office, or cases for which no health care was sought, were not included. Also, adverse events that are less likely to be diagnosed in the emergency room setting (e.g., Clostridium difficile infections that can cause severe diarrhea after antibiotic use) were not included.

###

Fast Facts

  • Antibiotics are among the most commonly prescribed medications in children, but they can lead to adverse drug events and should be used only when needed.
  • From 2011-2015, antibiotic use in children led to nearly 70,000 estimated emergency room visits each year for allergic reactions and other side effects.
  • The risk of a visit varied by child age and type of antibiotic used, but for most antibiotics, children aged 2 or younger had the highest risk of an adverse drug event.

Editor’s Note: The study was funded by the Centers for Disease Control and Prevention, and is embargoed until 1:05 a.m. ET on Thursday, Aug. 23. For an embargoed copy, please contact Terri Christene Phillips, MSA (cphillips@idsociety.org, 703-299-9865).

The Journal of the Pediatric Infectious Diseases Society is dedicated to perinatal, childhood, and adolescent infectious diseases. The journal, which recently received its first Impact Factor, publishes original research articles, clinical trial reports, guidelines, and topical reviews, with particular attention to global pediatric communities. It is the official journal of the Pediatric Infectious Diseases Society (PIDS).

PIDS membership encompasses leaders across the global scientific and public health spectrum, including clinical care, advocacy, academics, government, and the pharmaceutical industry. From fellowship training to continuing medical education, research, regulatory issues and guideline development, PIDS members are the core professionals advocating for the improved health of children with infectious diseases both nationally and around the world, participating in critical public health and medical professional advisory committees that determine the treatment and prevention of infectious diseases, immunization practices in children, and the education of pediatricians. For more information, visit http://www.pids.org.

One of the most popular ADHD drugs may cause hallucinations and other psychotic symptoms

Public Release: 22-Aug-2018

Exeley Inc.

In the scientific article recently published in Scandinavian Journal of Child and Adolescent Psychiatry and Psychology, Erica Ramstad and others reviewed the existing evidence between various psychotic symptoms such as hallucinations, problems with concentration or anxiety with methylphenidate, a drug commonly prescribed as a treatment for attention deficit hyperactivity disorder (ADHD) and narcolepsy.

Methylphenidate is a stimulant that increases the activity of the central nervous system, helps to combat fatigue, improves attention and maintains alertness. Its medial use medical use began in 1960 and continues to grow since, reaching global consumption of 2.4 billion doses in 2013. Clinical studies confirmed safety and effectiveness of the drug and proved that its long-term usage reduces abnormalities in brain structure and function usually associated with ADHD syndrome.

Currently around around 5.3% children and adolescents worldwide suffer from ADHD condition. Psychostimulants, including methylphenidate, are first-choice drug treatment. Ramstad and others examined whether methylphenidate increases the risk of psychotic symptoms in children and adolescents affected with the illness. Although the amount and quality of existing data did not allow them to draw any strong conclusions, their research suggests that possible adverse symptoms may affect around 1.1% to 2.5% of ADHD patients treated with methylphenidate.

The article and its findings are of great importance for patients, physicians and caregivers who should be aware of possible adverse effects of the drug. In case of appearance of psychotic symptoms during the methylphenidate medication, clinicians should be able to address the problem, reduce or stop stimulant medication and ensure proper treatment.

###

The original article is fully available for reading at: https://www.exeley.com/sj_child_adolescent_psychiatry_psychology/doi/10.21307/sjcapp-2018-003

DOI: 10.21307/sjcapp-2018-003

About SJCAPP journal:

The Scandinavian Journal of Child and Adolescent Psychiatry and Psychology (SJCAPP) is an Open Access, scientific journal covering a broad scope of high value articles in the field of child and adolescent psychiatry and psychology. The journal publishes quantitative and qualitative research on: diagnosis, assessment, psychotherapeutic and psychopharmacological treatments, behaviour, cognition, epidemiology, development, training, cross cultural issues, neuroscience and genetic aspects related to mental disorders in children, adolescents and families.

https://www.exeley.com/journal/sj_child_adolescent_psychiatry_psychology

About Exeley:

Exeley Inc. is a New York based company that focuses on offering innovative publishing services to Open Access publications worldwide. Amongst the technological solutions delivered, the functionalities include responsive webpage design, full-text XML, integration with social media sites and performance metrics including altmetrics.

https://www.exeley.com

The dark side of antibiotic ciprofloxacin

Public Release: 25-Jul-2018

Baylor College of Medicine

The use of ciprofloxacin and other antibiotics of the class of fluoroquinolones may be associated with disruption of the normal functions of connective tissue, including tendon rupture, tendonitis and retinal detachment. These observations reported in a number of journals resulted in the drugs currently having a black box warning physicians and patients of the potential deleterious side effects.

These studies also suggested that other types of connective tissues might be involved.

“A natural tissue to worry about is the aorta, a blood vessel that relies heavily on having a sound connective tissue component – called the extracellular matrix – to maintain its integrity,” said first author Dr. Scott A. LeMaire, director of research in the division of cardiothoracic surgery, vice-chair for research and professor of surgery and of molecular physiology and biophysics at Baylor College of Medicine.

Two retrospective clinical studies looked at the possible association between fluoroquinolones and cardiovascular problems.

“They found that patients who received fluoroquinolones had a higher risk for aneurysms (formation of balloon-like areas in the aorta that weaken the integrity of the vessel), ruptures or dissections (tears in the wall) than patients who did not receive the antibiotics. This has raised important concerns,” LeMaire said.

Although the retrospective clinical studies point at an association between fluoroquinolone antibiotics and increased risk of aortic diseases, they do not prove that the antibiotics cause the problems. To determine whether a cause-effect association exists, LeMaire and his colleagues worked with a mouse model of human aortic aneurysms and dissections (ADD).

Ciprofloxacin increases risk of tears and rupture in mouse aortas

“In our study, mice with normal or moderately stressed aortas received either ciprofloxacin or placebo and after four weeks we looked at their aortas,” said senior author Dr. Ying H. Shen, director of the Aortic Diseases Research Laboratory and associate professor of surgery at Baylor College of Medicine.

The results showed that normal, unstressed mice treated with ciprofloxacin did not show significant negative effects on the aorta. In mice with moderately stressed aortas that had received the placebo, 45 percent developed AAD, 24 percent developed aortic dissection and none had rupture. On the other hand, 79 percent of the mice with moderately stressed aortas that received antibiotic developed AAD, 67 percent had aortic dissection, and 15 percent had fatal rupture. These results were similar in males and females.

“Our study suggests that in this model of moderately stressed mouse aortas, ciprofloxacin exposure results in the disease progressing more rapidly and more severely, which is exactly the concern,” Shen said.

The researchers then looked deeper into the effects of ciprofloxacin on mouse aortas searching for insights into the antibiotic’s mechanism of action. Compared with the aortas from stressed mice treated with the placebo, the aortic tissue of stressed mice treated with the antibiotic showed more destruction and fragmentation of elastic fibers; decreased activity of LOX, a key enzyme involved in stabilizing the extracellular matrix; increased activity of MMP enzymes involved in extracellular matrix degradation; and enhanced activation of cellular pathways that lead to cell death.

Separate laboratory experiments on human aortic smooth muscle cells revealed that sustained ciprofloxacin exposure reduced the expression of LOX while enhancing the expression of MMP and inducing cell death. In these experimental settings, the antibiotic is disrupting the natural processes that maintain the integrity of the extracellular matrix that is essential for normal aortic function.

“Our findings support the concerns raised by previous retrospective clinical studies and suggest that ciprofloxacin and other antibiotics of the same class should be used with caution in patients with aortic dilatation,” Shen said.

“If we consider the clinical data and our experimental results that prove causation in a reliable model of AAD, I believe we have enough evidence for changing guidelines on the use of fluoroquinolone antibiotics for people who have an aneurysm or are at risk for getting an aneurysm,” LeMaire said. “I am hopeful that these guidelines can be changed in short order.”

Read all the details of this study in JAMA Surgery.

###

Other contributors of this work include Lin Zhang, Pingping Ren, Wei Luo, Alon R. Azares, Chen Zhang, Yidan Wang, Chris Guardado and Joseph S. Coselli.

The researchers are affiliated with Baylor College of Medicine, the Texas Heart Institute and Baylor College of Medicine’s Cardiovascular Research Institute.

This study was supported by an award from the Roderick D. MacDonald Research Fund at Baylor St. Luke’s Medical Center (17RDM004).

Changes in bacterial mix linked to antibiotics increase risk for type 1 diabetes

Public Release: 24-Jul-2018

NYU Langone Health / NYU School of Medicine

A single course of antibiotics early in childhood may increase risk for Type 1 diabetes. This is the finding of a study in mice led by researchers from NYU Medical School and published online July 24 in the journal eLife.

The study centered on the intestinal microbiome, the mix of bacterial species that live in the digestive tract, and that co-evolved with humans to play roles in nutrition and immunity. As rates of children’s exposure to antibiotics has increased in recent decades – with each child receiving nearly three courses on average in the first two years of life – the number of patients with type 1 diabetes has doubled, say the study authors.

In prior work, and using mice that have an unusually high rate of type 1 diabetes, the research team had found that exposure to multiple courses of antibiotics accelerated onset of this disease. The current study finds that even a single antibiotic course significantly increased risk and severity.

The normal mix of inherited microbes is thought to “educate” the founding immune system, with evolution choosing microbes that decrease the sensitivity of immune cells, making them less likely to mistakenly attack the body’s own cells, say the authors. In autoimmune diseases like type 1 diabetes, immune cells that normally control invading microbes instead destroy insulin-producing cells in the pancreas.

Patients with type 1 diabetes produce little or no insulin, the hormone that controls the level of sugar in the blood. In the current study, the onset of disease was determined by measuring blood sugar, and by marking when levels rose to extremely high levels due to the lack of insulin.

“Our findings confirm earlier work showing that antibiotics can increase risk for type 1 diabetes,” says lead study author Xuesong Zhang, PhD, assistant professor of Medicine at NYU School of Medicine. “Even a single early life course may perturb the intestinal microbiome in ways that lead to long-term consequences in the intestinal wall, including immune cell changes and damage to the pancreas.”

Senior study investigator Martin Blaser, M.D., director of the Human Microbiome Program at NYU School of Medicine, said the results “are a model of the pervasive effects that antibiotic courses may have on children, causing immune systems to develop abnormally on the way to serious illness.”

The research team used genomic and statistical techniques to analyze the millions of pieces of bacterial DNA in samples taken from the study mice. Past studies had already matched key DNA sequences to known bacterial species, enabling the team to define each mouse’s microbiome, and to watch the effect of antibiotics on each.

Specifically, the study found that four bacterial species groups (taxa) – Enterococcus, Blautia, Enterobacteriaceae, and Akkermansia – were significantly more abundant in the guts of mice treated with the single course of antibiotics, and likely involved in driving progression of type 1 diabetes. While normally harmless, such species, called pathobionts, cause disease when environmental factors like antibiotics alter the normal balance. Past studies had found that human children who later developed type 1 diabetes were more likely to have had altered gut microbiota representation of Blautia and Akkermansia mucinophila early in life, with corresponding changes to their immune systems.

The shift in dominant species seen with antibiotics was accompanied by a shift in active bacterial genes and in chemical compounds produced by the bacteria. This in turn caused changes in gene expression patterns in the intestinal wall, say the authors. Many of these genes are known to influence the type of immune cell activation that damages pancreatic islets.

In addition, populations of four different taxa – S24-7, Clostridiales, Oscillospira, and Ruminococcus – were significantly smaller in mice treated with antibiotics in comparisons with normal mice during the developmental post-birth time window previously shown to be critical to educating the immune system. The results suggest that these taxa may be protective against Type 1 diabetes, and could be a focus of future development of probiotics, for instance, that seek to restore healthy species in newborns.

The current study focused on male mice simply because it examined mechanisms found to be important in the autoimmune development regardless of gender.

The authors say their findings support the hypothesis that, by diminishing particular beneficial bacteria, one early exposure to antibiotics permits the emergence of other species that change immunological development and worsen pancreatic damage.

###

Along with Blaser and Zhang, study authors from the NYU School of Medicine departments of Medicine and Microbiology were Jackie Li, Michelle Badri, Thomas Battaglia, Timothy Borbet, Sandy Ng, Rachel Sibley, Shawn Jindal, Victoria Ruiz, Alexandra Livanos, and Kelly Ruggles. Other NYU authors were Hyunwook Koh and Huilin Li from the Department of Population Health at NYU School of Medicine, as well as Richard Bonneau of New York University’s Center for Data Science.

Authors from other institutions were Kimberly Krautkramer and John Denu from the Department of Biomolecular Chemistry at the University of Wisconsin School of Medicine and Public Health; Yuanyuan Li, Wimal Pathmasiri. and Susan Jenkins Sumner of the Nutrition Research Institute at the University of North Carolina at Chapel Hill School of Public Health; Robin Shields-Cutler, Ben Hillmann, Gabriel Al-Ghalith, and Dan Knights of the BioTechnology Institute, Computer Science and Engineering, University of Minnesota, St. Paul; Arlin Rogers Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, and Angelique Wout, Nabeetha Nagalingam, Anthony Williamson, and Marcus Rauch of the Janssen Prevention Center London, London, UK.

These study was supported by National Institute of Health grants 5T35DK007421, R37GM059785, F30 DK108494, T32GM008692, and R01DK110014, as well as by Janssen Labs London (15-A0-00-00-0039-29-01), the TransAtlantic Networks of Excellence Program of Fondation Leducq, and by the C & D fund.

Most common shoulder operation is no more beneficial than placebo surgery

Public Release: 19-Jul-2018

One of the most common surgical procedures in the Western world is probably unnecessary, suggests a new study

University of Helsinki

The Finnish Shoulder Impingement Arthroscopy Controlled Trial (FIMPACT) compared surgical treatment of shoulder impingement syndrome to placebo surgery. Two years after the procedure the study participants, both those in the group who underwent surgery and the ones in the placebo group, had equally little shoulder pain and were equally satisfied with the overall situation of their shoulder.

“These results show that this type of surgery is not an effective form of treatment for this most common shoulder complaint. With results as crystal clear as this, we expect that this will lead to major changes in contemporary treatment practices,” said the study’s principal investigators chief surgeon Mika Paavola and professor Teppo Järvinen from the Helsinki University Hospital and University of Helsinki.

Shoulder problems are very common and place a significant burden on the health care system. The most common diagnosis for shoulder pain that requires treatment is shoulder impingement, and the most common surgical treatment is decompression through keyhole surgery (i.e., arthroscopy Merriam Webster Dictionary: a minimally invasive surgical procedure involving visual examination of the interior of a joint with an arthroscope to diagnose or treat various conditions or injuries of a joint and especially to repair or remove damaged or diseased tissue or bone).

“With nearly 21,000 decompression surgeries done in UK every year, and ten times that many in the United States, the impact of this study is huge,” explained adjunct professor Simo Taimela, the research director of the Finnish Centre for Evidence-Based Orthopedics (FICEBO) at the University of Helsinki.

This research confirms previous randomised studies showing that keyhole decompression surgery of the shoulder does not alleviate the symptoms of patients any better than physiotherapy. Paradoxically, however, the number of decompression surgeries has increased significantly, even though solid proof of the impact of the surgery on the symptoms has been lacking.

The FIMPACT study involved 189 patients suffering from persistent shoulder pain for at least three months despite receiving conservative treatment, physiotherapy and steroid injections. Patients were randomised to receive one of three different treatment options, subacromial decompression surgery, placebo surgery (diagnostic arthroscopy, which involved arthroscopic examination of the shoulder joint but no therapeutic procedures) or supervised exercise therapy.

No one involved in the study – including the patients, the persons involved in their care after surgery, and the researchers who analysed the results – knew which patient was in the decompression or placebo group.

Two years after the start of the study, patients were asked about shoulder pain and other symptoms they had experienced, as well as their satisfaction with the treatment and its results. The patients in the decompression or placebo groups were also asked which group they believed they had been in – actual surgery or placebo.

Overall, shoulder pain was substantially improved in all three groups from the start of the trial. However, decompression surgery offered no greater benefit to shoulder pain than placebo surgery. The patients in the diagnostic arthroscopy group were no more likely than those in the decompression group to guess that they had had a placebo procedure.

The group that received exercise therapy also improved over time, to the point that patients who initially had decompression surgery were only slightly more improved than those who had physiotherapy only. Although this latter finding could be interpreted as evidence to support decompression surgery, the authors did not find the difference in improvement to be clinically significant.

“Based on these results, we should question the current line of treatment according to which patients with shoulder pain attributed to shoulder impingement are treated with decompression surgery, as it seems clear that instead of surgery, the treatment of such patients should hinge on nonoperative means,” Järvinen states. “By ceasing the procedures which have proven ineffective, we would avoid performing hundreds of thousands useless surgeries every year in the world”, Järvinen points out. “Fortunately, there seems to be light at the end of the tunnel as the NHS in England just released a statement that they will start restricting funding for ‘unnecessary procedures’ and the list includes subacromial decompression. We applaud this initiative and encourage other countries to follow this lead”.

“We have to spend taxpayers’ money responsibly. If we are spending money on procedures that are not effective, that money is deprived from treatments that are clinically effective and would provide benefits to patients. One component in becoming more efficient is to make sure we are not undertaking unnecessary procedures”, Dr. Taimela concludes.

The FIMPACT research project includes the Helsinki and Tampere University Hospitals in Finland. The study is published in The BMJ on 19 July 2018.

###

FIMPACT study is one of the main research projects of the Finnish Centre for Evidence-Based Orthopedics (FICEBO. FICEBO is housed primarily at the Department of orthopaedics and traumatology at the Helsinki University Hospital and the University of Helsinki. FICEBO is internationally known as one of the leading research groups on the impact and benefits of musculoskeletal disabilities, and especially on its’ studies that use the placebo surgery design. In 2013 FICEBO published a placebo-surgery controlled FIDELITY study that showed that the most common orthopaedic procedure, arthroscopic partial resection of knee meniscus, was no more effective than placebo surgery in alleviating knee pain in middle aged or older persons.

Study: ADHD drugs do not improve cognition in healthy college students

Public Release: 19-Jul-2018

Medication may also impair working memory, researchers at URI, Brown University report

University of Rhode Island

KINGSTON, R.I., July 19, 2018 — Contrary to popular belief across college campuses, attention deficit hyperactivity disorder (ADHD) medications may fail to improve cognition in healthy students and actually can impair functioning, according to a study by researchers at the University of Rhode Island and Brown University.

Study co-investigators Lisa Weyandt, professor of psychology and a faculty member with URI’s George and Anne Ryan Institute for Neuroscience, and Tara White, assistant professor of research in behavioral and social sciences at Brown University, had anticipated different findings. “We hypothesized that Adderall would enhance cognition in the healthy students, but instead, the medication did not improve reading comprehension or fluency, and it impaired working memory,” she said. “Not only are they not benefitting from it academically, but it could be negatively affecting their performance.”

This first-ever multisite pilot study of the impact of so-called “study drugs” on college students who do not have ADHD comes at a time when use of prescription stimulants such as Adderall, Ritalin and Vyvanse is common among young adults who believe the drugs will improve their academic performance. Research by Weyandt and others has estimated that 5 to 35 percent of college students in the United States and European countries without ADHD illegally use these controlled substances, buying or receiving them from peers, friends, or family.

Results of the new study, published last month in the journal Pharmacy, show that the standard 30 mg dose of Adderall did improve attention and focus — a typical result from a stimulant — but that effect failed to translate to better performance on a battery of neurocognitive tasks that measured short-term memory, reading comprehension and fluency.

Weyandt has a theory about why working memory would be adversely affected by the medication. Brain scan research shows that a person with ADHD often has less neural activity in the regions of the brain that control executive function — working memory, attention, self-control. For people with ADHD, Adderall and similar medications increase activity in those regions and appear to normalize functioning. “If your brain is functioning normally in those regions, the medication is unlikely to have a positive effect on cognition and my actually impair cognition. In other words, you need to have a deficit to benefit from the medicine,” Weyandt said.

Participants in the study also reported their perceived effects of the drug and its impact on their emotions, with students reporting significant elevation of their mood when taking Adderall.

In contrast to the small, mixed effects on cognition, the drug had much larger effects on mood and bodily responses, increasing positive mood, emotional ratings of the drug effect, heart rate and blood pressure. “These are classic effects of psychostimulants,” said White. “The fact that we see these effects on positive emotion and cardiovascular activity, in the same individuals for whom cognitive effects were small or negative in direction, is important. It indicates that the cognitive and the emotional impact of these drugs are separate. How you feel under the drug does not necessarily mean that there is an improvement in cognition; there can be a decrease, as seen here in young adults without ADHD.”

The physical effects from the drugs, such as increased heart rate and blood pressure, were expected, and underscored the difference with cognition. “They are subjecting themselves to physiological effects but do not appear to be enhancing their neurocognition,” Weyandt said. She stressed, however, that the findings are based on a pilot study and need to be replicated with a substantially larger sample of college students.

The researchers recruited students from both universities, eliminating individuals who had taken ADHD medications or other drugs. After rigorous health screenings, 13 students participated in two five-hour sessions at White’s lab at Brown and at Memorial Hospital in Pawtucket.

In the double-blind study, in which neither researchers nor participants know who is receiving the placebo and who is receiving the study medication, each student received Adderall in one session and the placebo in the other. This allowed the researchers to see the effects of the medication vs. placebo in individuals and across the group.

Given the important and unexpected results from the study, Weyandt and White plan to apply for federal funding to continue the research with a larger group of healthy college students.

###

This research was supported by grants from the Rhode Island Neuroscience Collaborative, the Brown (now Carney) Institute for Brain Science, the George and Anne Ryan Institute for Neuroscience and the Norman Prince Neurosciences Institute at Rhode Island Hospital as well as divisions within the National Institutes of Health and the National Science Foundation.

Anticonvulsant drugs ineffective for low back pain and can cause harm, despite increased prescribing

Public Release: 3-Jul-2018

Canadian Medical Association Journal

Anticonvulsant drugs are increasingly being used to treat low back pain, but a new study in CMAJ (Canadian Medical Association Journal) finds they are ineffective and can have adverse effects.

“Clinically, the prescription of anticonvulsants for back and neck pain, including radicular pain in primary care, has increased by 535% in the last 10 years,” writes Dr. Oliver Enke, University of Sydney, Sydney Medical School Nepean, Kingswood, Australia, with coauthors, citing data from a recent study on prescribing trends for back pain.

Low back pain affects millions of people and is the number one cause of disability. Clinical practice guidelines usually recommend nonpharmacologic treatments and nonopioid pain relievers rather than stronger analgesics such as anticonvulsants.

The study findings are based on high and moderate-quality evidence from 9 placebo-controlled randomized trials that found a lack of evidence of benefit from anticonvulsants and more adverse events from some of these drugs.

“We have shown, with mostly high- and moderate-quality evidence, that common anticonvulsants are ineffective for chronic low back pain and lumbar radicular pain, and are accompanied by increased risk of adverse events,” write the authors.

These findings support recent guidelines from the United States and the United Kingdom that do not recommend the use of anticonvulsants.

“Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis” is published July 3, 2018.

Antidepressants may increase risk of death by 20 percent for those COPD

Public Release: 26-Jun-2018

 

Serotonergic antidepressants increase respiratory-related adverse events for those with chronic obstructive pulmonary disease, study suggests

St. Michael’s Hospital

TORONTO, June 26, 2018 – Antidepressant use in people with chronic obstructive pulmonary disease (COPD) is associated with a 20 per cent increase in likelihood of death and a 15 per cent increase in likelihood of hospitalization due to related symptoms, finds a new study led by researchers at St. Michael’s Hospital.

Published today in the European Respiratory Journal, the research suggests that amongst adults with COPD, new users of serotonergic antidepressants – a specific class of the medication – have higher rates of hospitalization, emergency room visits, and mortality related to respiratory conditions, as well as death overall versus non-users of the medications. While the study does not show cause and effect, it suggests strong association.

“We were not surprised by these findings, as there are biological reasons why antidepressants could lead to respiratory issues,” said Dr. Nicholas Vozoris, a scientist in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital and the lead author. “These drugs can cause sleepiness, vomiting and can negatively impact immune system cells. This increases the likelihood of infections, breathing issues, and other respiratory adverse events, especially in patients with COPD.”

COPD is a progressive lung disease that causes increasing breathlessness. It affects more than 10 per cent of those aged 40 and older worldwide. Because of the nature of the disease, upwards of 70 per cent of those with COPD also struggle with symptoms of low mood and anxiety, said Dr. Vozoris, who is also an assistant professor in the Department of Medicine at the University of Toronto and a respirologist at St. Michael’s.

Using health administrative databases from the Institute of Clinical Evaluative Sciences (ICES), Dr. Vozoris and his team studied 28,360 new users of serotonergic antidepressants with COPD aged 66 and older and matched them to an equivalent amount of non-users. The analysis revealed that among older adults with COPD, new users of this class of medication have modest, but significant, increases in rates of breathing-related death and all causes of death. The research showed a strong association, but not a definite cause and effect.

“The study results should not cause alarm among those who use these medications, but rather increase caution among patients and physicians,” Dr. Vozoris said. “I hope our study encourages increased awareness when prescribing these medications and monitoring for adverse side effects. Also, because there is this association, we as physicians should give thought to psychotherapy and pulmonary rehabilitation as non-drug related treatment.”

Dr. Vozoris plans to continue to study other classes of medications used for treatment of psychological issues in patients with COPD to build a more complete picture of medication risks.

###

This research was funded by the University of Toronto and supported by the Institute of Clinical Evaluative Sciences.

About St. Michael’s Hospital

St. Michael’s Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in more than 29 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, care of the homeless and global health are among the Hospital’s recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Centre, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael’s Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto.

Media contact

For more information or for an interview with Dr. Vozoris, please contact:

Ana Gajic
Senior Communications Advisor
St. Michael’s Hospital
Phone: 416-864-5960 or 416 458 0629
Gajica@smh.ca
Inspired Care. Inspiring Science.
http://www.stmichaelshospital.com
Follow us on Twitter: http://www.twitter.com/stmikeshospital

One-third of US adults may unknowingly use medications that can cause depression

Public Release: 12-Jun-2018

 

Polypharmacy on the rise

University of Illinois at Chicago

IMAGE

IMAGE: This is Dima Qato.

Credit: UIC/Jenny Fontaine

A new study from University of Illinois at Chicago researchers suggests that more than one-third of U.S. adults may be using prescription medications that have the potential to cause depression or increase the risk of suicide, and that because these medications are common and often have nothing to do with depression, patients and health care providers may be unaware of the risk.

The researchers retrospectively analyzed medication use patterns of more than 26,000 adults from 2005 to 2014, which were collected as part of the National Health and Nutrition Examination Survey. They found that more than 200 commonly used prescription drugs — including hormonal birth control medications, blood pressure and heart medications, proton pump inhibitors, antacids and painkillers — have depression or suicide listed as potential side effects.

Published in the Journal of the American Medical Association, the study is the first to demonstrate that these drugs were often used concurrently and that concurrent use, called polypharmacy, was associated with a greater likelihood of experiencing depression. Approximately 15 percent of adults who simultaneously used three or more of these medications experienced depression while taking the drugs, compared with just 5 percent for those not using any of the drugs, 7 percent for those using one medication and 9 percent for those taking two drugs simultaneously.

The researchers observed similar results for drugs that listed suicide as a potential side effect. These findings persisted when the researchers excluded anyone using psychotropic medications, considered an indicator of underlying depression unrelated to medication use.

“The take away message of this study is that polypharmacy can lead to depressive symptoms and that patients and health care providers need to be aware of the risk of depression that comes with all kinds of common prescription drugs — many of which are also available over the counter,” said lead author Dima Qato, assistant professor of pharmacy systems, outcomes and policy in the UIC College of Pharmacy. “Many may be surprised to learn that their medications, despite having nothing to do with mood or anxiety or any other condition normally associated with depression, can increase their risk of experiencing depressive symptoms, and may lead to a depression diagnosis.”

Qato notes that the study also shows an important trend of increasing polypharmacy for medications with depression, particularly suicidal symptoms, as a potential adverse effect. This makes the need for awareness of depression as a potential side effect even more pressing.

The researchers found use of any prescription medication with a potential depression adverse effect increased from 35 percent in the 2005 to 2006 period to 38 percent in the 2013 to 2014 period. Approximate use of antacids with potential depression adverse effects, like proton pump inhibitors and H2 antagonists, increased from 5 percent to 10 percent in the same period. Use of three or more drugs concurrently increased from 7 percent to 10 percent, approximately.

For prescription drugs with suicide listed as a potential side effect, usage increased from 17 percent to 24 percent, and use of three or more drugs concurrently increased from 2 percent to 3 percent.

“People are not only increasingly using these medicines alone, but are increasingly using them simultaneously, yet very few of these drugs have warning labels, so until we have public or system-level solutions, it is left up to patients and health care professionals to be aware of the risks,” Qato said.

Qato says that solutions worth further study may include updating drug safety software to recognize depression as a potential drug-drug interaction, so that health care professionals, including pharmacists, are more likely to notice if a patient is using multiple medications that may increase risk. Or, including evaluation of medication use in the depression screening and diagnostic tools used by doctors and nurses and recommended by the U.S. Preventive Services Task Force, especially when it comes to persistent or treatment-resistant depression.

“With depression as one of the leading causes of disability and increasing national suicide rates, we need to think innovatively about depression as a public health issue, and this study provides evidence that patterns of medication use should be considered in strategies that seek to eliminate, reduce or minimize the impact of depression in our daily lives,” Qato said.

Co-authors on the study are Katharine Ozenberger of UIC and Columbia University’s Mark Olfson. Qato and Olfson both noted financial disclosures potentially relevant to the study

Millions could have incorrect statin, aspirin and blood pressure prescriptions

Public Release: 4-Jun-2018

Stanford Medicine

More than 11 million Americans may have incorrect prescriptions for aspirin, statins and blood pressure medications, according to a study led by researchers at the Stanford University School of Medicine.

Their findings are based on an updated set of calculations — known as pooled cohort equations, or PCEs — that are used to determine the risk of a heart attack or stroke.

The PCEs are the foundation for cardiovascular-disease-prevention guidelines in the United States. They help physicians decide whether to prescribe aspirin, blood pressure or statin medications, or some combination of these, by estimating the risk a patient may have for a heart attack or stroke. Most physicians calculate a patient’s risk using a PCE web calculator or a smartphone app; the equations are also built into many electronic health records so that a patient’s risk is automatically calculated during an office visit.

But there has been debate over whether the PCEs are based on outdated data and therefore putting some patients at risk for over- or under-medication.

“We found that there are probably at least two major ways to improve the 2013 equations,” said Sanjay Basu, MD, PhD, assistant professor of primary care outcomes research at the School of Medicine and a core faculty member at Stanford Health Policy. “The first was well-known: that the data used to derive the equations could be updated.”

Old equations

For example, he said, one of the main data sets used to derive the original equations had information from people who were 30-62 years old in 1948, and who would therefore be 100 to 132 years old in 2018 — that is, likely dead. The older equations were often estimating people’s risk as too high, possibly by an average of 20 percent across risk groups.

“A lot has changed in terms of diets, environments and medical treatment since the 1940s,” Basu said. “So, relying on our grandparents’ data to make our treatment choices is probably not the best idea.”

Basu is the senior author of the study, which will be published June 5 in the Annals of Internal Medicine. The lead author is Steve Yadlowsky, a graduate student in electrical engineering at Stanford.

Furthermore, the researchers found that the old data may not have had a sufficient sample of African-Americans. For many African-Americans, physicians may have been estimating the risks of heart attacks or strokes as too low.

“So while many Americans were being recommended aggressive treatments that they may not have needed according to current guidelines, some Americans — particularly African-Americans — may have been given false reassurance and probably need to start treatment given our findings,” Basu said.

The researchers have updated the PCEs with newer data in an effort to substantially improve the accuracy of the cardiovascular risk estimates. The National Institutes of Health, which maintains and updates the cohort data, approved the updated equations.

Updating statistical methods

A second improvement to the equations, the authors found, was to update the statistical methods used to derive the equations.

“We found that by revising the PCEs with new data and statistical methods, we could substantially improve the accuracy of cardiovascular disease risk estimates,” the authors wrote.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

###

Basu is a member of Stanford Bio-X and the Child Health Research Institute.

Researchers from the University of Michigan, University of Washington and University of Mississippi also contributed to the study.

The study was supported by the National Institutes of Health (grants DP2MD010478, U54MD010724, K08HL121056 and P30DK092926) and a Stanford University graduate fellowship.

Stanford’s Department of Medicine also supported the work.

The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children’s Health. For information about all three, please visit http://med.stanford.edu.

Drug companies selling more ‘lifestyle,’ less ‘symptom’

Public Release: 15-May-2018

 

University of South Florida (USF Health)

TAMPA, Fla. (May 15, 2018)- Prescription drug commercials are getting longer and providing less factual information. A study published in the Annals of Family Medicine finds that the majority of these ads focus on lifestyle improvements made post-medication rather than side-effects and the negative emotions associated with certain health issues.

The team of researchers lead by the University of South Florida in Tampa compared prescription drug commercials from 2016 to results from a related study conducted in 2004. They found 56.9% of ads portrayed actors as regaining control and social approval, along with improved endurance in physical activities such as bicycling and hiking. That’s up from 39.5% of ads monitored in the previous research.

“Direct-to-consumer advertising continues to promote prescription drugs above educating the population,” said lead author Janelle Applequist, PhD, assistant professor at the University of South Florida Zimmerman School of Advertising and Mass Communications. “Such expansive promotion of drug benefits could imply off-label outcomes and encourage an inappropriately broad population to seek the advertised drug.”

While the commercials were 30-percent longer, they contained significantly less information about the medical condition in itself. The percentage of ads that explain associated risk factors dropped 26 percent to 16 percent and the condition’s prevalence went from 25 percent to 16 percent. Few ads emphasized the importance of combining the medication with improved diet and exercise.

The researchers come to this conclusion after monitoring the networks ABC, NBC, CBS and FOX during primetime hours for 13 weeks. During that time, they say the networks aired 868 prescription drug commercials, 61 if you remove duplicates.

Dr. Applequist says these findings prove a need for policymakers to take regulatory action in order to ensure pharmaceutical ads promote health and disease awareness above product endorsement.

Oral antibiotics linked to increased kidney stone risk for several years after use

PUBLIC RELEASE: 10-MAY-2018

Risk appears to be highest among children

AMERICAN SOCIETY OF NEPHROLOGY

Highlights

  • Use of oral antibiotics was linked with an increased risk of developing kidney stones.
  • Risk decreased over time but was still elevated several years after antibiotic use.
  • Risk was highest for young patients.

Washington, DC May 10, 2018) — The potential to promote antibiotic resistance in bacteria isn’t the only reason to avoid using antibiotics when possible. A new study reveals that antibiotics are also linked with an increased risk of developing kidney stones, with the greatest risk among children. The findings appear in an upcoming issue of the Journal of the American Society of Nephrology (JASN).

For reasons that are unclear, the prevalence of kidney stones–or nephrolithiasis–has increased 70% over the last 30 years, with the most disproportionate increase experienced by children and adolescents. Because perturbations in bacterial communities residing in the intestines and urinary tract have been associated with nephrolithiasis, a team led by Gregory Tasian MD, MSc, MSCE and Michelle Denburg MD, MSCE (The Children’s Hospital of Philadelphia) examined whether the use of antibiotics might affect individuals’ risk of developing the condition.

For their study, the investigators determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based study within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. The team matched 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at the date of diagnosis (termed the index date).

Exposure to any one of five different antibiotic classes 3-12 months before the index date was associated with nephrolithiasis. Risks were increased 2.3-times, 1.9-times, 1.7-times, 1.7-times, and 1.3-times for sulfas, cephalosporins, fluoroquinolones, nitrofurantoin/methenamine, and broad-spectrum penicillins, respectively. The risk of nephrolithiasis decreased over time, but it remained elevated at 3-5 years after the antibiotic prescription. Also, the risk was greatest for exposures at younger ages. Previous research has shown that children receive more antibiotics than any other age group, and 30% of antibiotics prescribed during ambulatory care visits are inappropriate.

“These findings demonstrate that exposure to certain antibiotics is a novel risk factor for kidney stones and that the risk may be greatest when exposure to these antibiotics occurs at younger ages,” said Dr. Tasian. “Consequently, these results suggest that the risk of nephrolithiasis may be decreased by reducing inappropriate antibiotic exposure and choosing alternative antibiotics, particularly for those patients who are at increased risk of stone formation.”

###

Study co-authors include Thomas Jemielita, PhD, David S. Goldfarb, MD, Lawrence Copelovitch, MD, Jeffrey Gerber MD, PhD, MSCE, and Qufei Wu, MS.

Disclosures: The authors have no conflicts of interest to declare.

The article, entitled “Oral Antibiotic Exposure and Kidney Stone Disease,” will appear online at http://jasn.asnjournals.org/ on May 10, 2018, doi: 10.2215/ASN.2017111213.

The content of this article does not reflect the views or opinions of The American Society of Nephrology (ASN). Responsibility for the information and views expressed therein lies entirely with the author(s). ASN does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies.

Since 1966, ASN has been leading the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients. ASN has nearly 18,000 members representing 112 countries. For more information, please visit http://www.asn-online.org or contact the society at 202-640-4660.

Spinal surgery for osteoporosis no better for pain relief than injections

PUBLIC RELEASE: 9-MAY-2018

Results do not support surgery as standard pain treatment for osteoporotic fractures

BMJ

Vertebroplasty (surgery to repair spinal fractures) is no more effective for pain relief than a sham (placebo) procedure in older patients with osteoporosis, finds a trial published by The BMJ today.

The researchers say their results “do not support vertebroplasty as standard pain treatment in patients with osteoporotic vertebral fractures.”

Osteoporosis is a disease in which bones become weak and more likely to break. Fractures caused by osteoporosis most often occur in the spine and are called vertebral compression fractures. Long term, these fractures can lead to deformity, breathing problems, and loss of height.

Vertebroplasty involves injecting a special cement into the fractured bone to stabilise it and to relieve pain. But previous studies have reported conflicting results and there is ongoing debate about its benefits, risks, and cost-effectiveness.

To try to resolve this uncertainty, researchers in the Netherlands and the USA compared pain relief in patients undergoing vertebroplasty or a ‘sham’ procedure, where patients are given local anaesthetic injections, but no bone cement.

The trial involved 180 adults aged older than 50 years, with 1-3 painful vertebral compression fractures of up to nine weeks old. Participants were randomly assigned to either vertebroplasty (91 patients) or the sham procedure (89 patients).

The main (primary) outcome measure was mean reduction in pain scores at one day, one week, and one, three, six, and 12 months after the procedure. Other (secondary) outcomes were differences in quality of life and disability over 12 months.

Pain was measured using a visual analogue scale (VAS) ranging from 0 (no pain) to 10 (severe pain). Clinically significant pain relief was defined as a decrease of 1.5 points in VAS score from the start of the study (baseline).

The mean reduction in VAS pain score was statistically significant in both groups at all follow-up points after the procedure, compared with baseline. However, these changes in VAS scores did not differ significantly between the groups over the 12 month follow-up period.

Vertebroplasty had no effect on quality of life or on disability.

“Percutaneous vertebroplasty to treat patients with acute osteoporotic vertebral compression fractures did not result in statistically significant more pain relief than a sham procedure during 12 months’ follow-up,” say the researchers.

They point to some study limitations, such as lack of an untreated control group and limited generalisability to other treatments. However, strengths over previous trials included larger patient groups and longer follow-up.

They believe there is a place for vertebroplasty “when efficacy outweighs the risks,” but conclude that these results “do not support using percutaneous vertebroplasty as standard pain treatment in patients with acute osteoporotic vertebral compression fractures.”

This trial suggests that vertebroplasty “should not be offered to patients with three or fewer painful osteoporotic vertebral fractures of less than 6-9 weeks’ duration,” says Evan Davies, consultant spinal surgeon at Southampton General Hospital, in a linked editorial.

However, questions remain on its place in the management of chronic painful fractures, and, more specifically, whether cement augmentation has any role in the prevention of long term morbidity and mortality, he adds.

These are fruitful areas for further research, he writes, In the meantime, early vertebroplasty – before nine weeks – “should probably be considered only in exceptional circumstances for patients with vertebral osteoporotic fractures.”

Noise throws the heart out of rhythm

Public Release: 3-May-2018

 

Mainz University Medical Center publishes new results on noise pollution from the Gutenberg Health Study

Johannes Gutenberg Universitaet Mainz

IMAGE

IMAGE: Noise throws the heart out of rhythm.

Credit: Photomontage realized by Peter Pulkowski, Mainz University Medical Center

With an increasing level of noise, the incidence of atrial fibrillation also increases dramatically. Scientists from the Department of Cardiology at the Mainz University Medical Center were able to prove this with data from the Gutenberg Health Study. They found that the incidence of atrial fibrillation in subjects with extreme noise annoyance reactions increases to 23 percent, compared to just 15 percent without this environmental impact. Looking at the proportion of sources of extreme noise pollution, aircraft noise came first with 84 percent during the day and 69 percent during sleep. These results from the Gutenberg Health Study were published recently in the renowned International Journal of Cardiology.

Noise annoyance is a very important indicator in order to decide which noise levels may be considered significant or unacceptable and may be even harmful for our health. Anger, disturbed sleep, exhaustion, and stress symptoms due to noise permanently impair wellbeing, health, and the quality of life. “We have already been able to prove the connection between noise and vascular disease in several studies in healthy volunteers and patients with established coronary artery disease as well as in in preclinical studies. To date, there has been no explicit study being published which addresses to what extent noise annoyance can cause cardiac arrhythmia,” emphasized Professor Thomas Münzel, Director of Cardiology I at the Department of Cardiology at the Mainz University Medical Center and senior author of the study.

The effects of noise pollution have been a subject of research within the framework of the Gutenberg Health Study (GHS). The GHS is one of the world’s largest studies of its kind, including more than 15.000 men and women aged 35 to 74 from the state capital of Rhineland-Palatinate and the district of Mainz-Bingen.

The researchers investigated the relationship between different noise sources during the day and at night during sleep and the most common arrhythmia in the general population, i.e., atrial fibrillation. The study found that increasing annoyance is associated with a significant increase in the frequency of atrial fibrillation. This grew up to 23 percent in subjects experiencing extreme noise annoyance, while only 15 percent experienced no noise annoyance at all. In this context, it has been shown that aircraft noise accounts for the largest share of extreme noise pollution: 84 percent during the day and 69 percent during sleep. The aircraft noise annoyance affected 60 percent of the population, more than every second in the Mainz-Bingen region. Thus, it clearly outperformed other noise sources such as road, rail, or neighborhood noise.

“The study shows for the first time that noise annoyance caused by various noise sources during the day and night is associated with an increased risk of atrial fibrillation,” concluded study leader Omar Hahad, research associate at the Deparment Cardiology, Cardiology I. “Overall, we were able to demonstrate a stronger influence of annoyance caused by nocturnal noise on the heart rhythm.”

The study leaders, however, point out that noise annoyance was measured, not physical noise. Since this is a cross-sectional study, no statements can be made with respect to a causal relationship.

Participants in the GHS study were asked to rate how much they had been harassed in recent years by road, rail, construction, trade, neighborhood noise and aircraft noise, both day and night. Noise annoyance was recorded using internationally accepted, standardized questionnaires. Atrial fibrillation was diagnosed on the basis of the medical history (anamnestic) and / or on the study ECG.

“The relationship between noise annoyance and atrial fibrillation is an important finding that may also explain why noise can lead to more strokes. However, one must not forget that noise also leads to damage to health without the need for an anger reaction,” said Professor Thomas Münzel.

In addition, the impact of the night-time ban introduced by Frankfurt am Main airport (11 p.m. to 5 a.m.) in October 2011 on the aircraft noise reported by the participants was examined. “Interestingly, there was a significant increase in aircraft noise after the introduction of the no-fly ban, both during the day and at night,” commented Münzel. “This could be due to the fact that in spite of the ban on night flights altogether the number of flight movements has not decreased and the flight movements have been concentrated more in the marginal hours of 10 p.m. to 11 p.m. and 5 a.m. to 6 a.m.” The authors conclude that, for example, the total ban on scheduled aircraft movements at the Frankfurt Airport has to be expanded from 11 p.m. to 5 a.m. to 10 p.m. to 6 a.m., in accordance with the definition of nighttime in Germany.

Daily aspirin doubles the risk of melanoma in men

Public Release: 3-May-2018

Daily aspirin linked to higher risk in men

Women taking daily aspirin do not have higher risk in the same population

Northwestern University

  • Results surprising because aspirin is often reported to decrease risk of certain cancers
  • Men who take daily aspirin may benefit from periodic skin exams by the dermatologist
  • ‘This does not mean men should stop aspirin therapy’

CHICAGO — Men who take once-daily aspirin have nearly double the risk of melanoma compared to men who are not exposed to daily aspirin, reports a new Northwestern Medicine study.

Women, however, do not have an increased risk in this large patient population.

“Given the widespread use of aspirin and the potential clinical impact of the link to melanoma, patients and health care providers need to be aware of the possibility of increased risk for men,” said senior study author Dr. Beatrice Nardone, research assistant professor of dermatology at Northwestern University Feinberg School of Medicine.

She suggested increasing patient education about sun exposure, avoiding tanning beds and getting skin checks by a dermatologist, particularly for individuals who are already at high risk for skin cancers.

“This does not mean men should stop aspirin therapy to lower the risk of heart attack,” she stressed.

Almost half of people age 65 and over reported taking aspirin daily or every other day, according to a 2005 study. In 2015, about half of a nationwide survey of U.S. adults reported regular aspirin use.

The study was published April 27 in the Journal of the American Academy of Dermatology.

Nardone was surprised at the results because aspirin is reported to reduce risk of gastric, colon, prostate and breast cancer. And some previous studies have reported a reduced risk in aspirin-exposed men and an increased risk in aspirin-exposed women. Nardone attributed this to variability of the research methods used in studies that look for associations and risks for cancers.

Among the numerous possibilities, one reason men may be more vulnerable could be related to males (human and animal species) expressing a lower amount of protective enzymes, like superoxide dismutase and catalase, compared to females, Nardone speculated.

“These lower levels of protective enzymes suggest that a higher level of resulting oxidative cellular damage in men might contribute to the possibility of developing melanoma,” said Nardone, who is an investigator for the Research on Adverse Drug Events and Reports Program at Northwestern.

The study collected medical record data comprising almost 200,000 patients who were aspirin-exposed or aspirin-unexposed (control group), ages 18-89, with no prior history of melanoma and with a follow-up time of at least five years.

For the aspirin-exposed patient population, the study included only patients who had at least one year of once-daily aspirin exposure at a dose of 81 or 325 mg occurring between January 2005 and December 2006 in order to allow for at least five years of follow-up data to detect if melanoma occurred over time. Out of a total of 195,140 patients, 1,187 were aspirin exposed. Of these 1,187 patients, 26 (2.19 percent) (both men and women) had a subsequent diagnosis for melanoma compared to 1,676 (0.86 percent) in aspirin-unexposed (men and women) patients.

When the groups were separated into men and women, men exposed to aspirin had almost twice the risk for diagnosis of melanoma (adjusted relative risk: 1.83) compared to men in the same population who were not exposed to aspirin.

###

Other Northwestern authors include Kelsey Orrell, Ahuva D. Cices, Nicholas Guido, Sara Majewski, Erin Ibler, Thy Huynh, Stephanie Rangel, Anne Laumann, Mary Martini, Alfred Rademaker and Dennis West.

The Northwestern Medicine Enterprise Data Warehouse (NMEDW) was used as a data source. The NMEDW, is supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant Number UL1TR001422.

Kids exposed to general anesthestic have poorer development, literacy and numeracy scores

Public Release: 26-Apr-2018

 

University of Sydney

The new finding published today in Pediatric Anesthesia, is based on a data-linkage study of over 210,000 children in New South Wales, Australia.

The 211,978 children included in the study were born in New South Wales at 37-plus weeks’ gestation without major congenital anomalies or neurodevelopmental disability. Of these, researchers had data on their school entry developmental assessment in 2009, 2012, or their Grade-3 school test results in 2008-2014.

The researchers compared the developmental and school results of children exposed to general anaesthesia during hospital procedures (37,880) up to 48 months of age to same-aged children with no exposure to general anaesthesia or hospitalisation (197,301).

Key findings

Compared to children unexposed to general anaesthesia, those exposed to general anaesthesia had a:

  • 17 per cent increased risk of poor child development
  • 34 per cent increased risk of lower numeracy scores on school tests
  • 23 per cent increased risk of lower reading scores on school tests.

When the researchers restricted their analyses to children who’d had only one hospitalisation involving a procedure requiring general anaesthesia, they found no increased risk for poor development or reduced reading scores, however the risk of poor numeracy scores remained.

“There are many reasons why a child requires surgery or investigation, and, in some cases, this may be lifesaving or unavoidable,” said the study’s senior author, Professor Natasha Nassar of the University of Sydney.

“For these children, our findings suggest that it is important to follow-up and monitor their literacy and numeracy skills when they reach school, and ensure early intervention, if required.”

Co-author Dr Justin Skowno, a clinical lecturer at the University of Sydney and senior staff specialist in Paediatric Anaesthesia at the Children’s Hospital, Westmead said:

“Determining exactly what is causing this effect is not easy.

“The children receiving a general anaesthetic in this study also had surgery, and often had other associated medical conditions.

“There are some procedures where alternative approaches or management may be possible, but the majority of surgeries in young infants and children cannot easily be postponed.”

“Parents can certainly discuss with their doctor and explore whether these procedures can be avoided, combined with other procedures, delayed to older ages or treated with alternatives to surgery, or other methods of sedation,” said Dr Skowno.

The researchers say further investigation of the specific effects of general anaesthesia on numeracy skills, underlying health conditions that prompt the need for surgery or diagnostic procedures is required, particularly among children exposed to previous or long duration of general anaesthesia or with repeated hospitalisations.

Measures of development, literacy and numeracy

Child development was obtained from the Australian version of the Early Development Instrument (AvEDI), a nationwide triennial assessment of child development. It includes results from teachers’ assessment of five developmental domains: physical health and well-being, emotional maturity, communication skills and general knowledge, language, and cognitive skills (numeracy and literacy) and social competence.

Based on national percentiles, children with domain scores in the bottom 10 percent are classified as developmentally vulnerable in that domain. Children who are vulnerable in 2 or more domains are classified as developmentally high risk.

###

Children’s Grade 3 school performance was ascertained from the NSW Department of Education National Assessment Program-Literacy and Numeracy (NAPLAN) conducted in public schools in 2009- 2014. NAPLAN tests cover 5 domains: reading, writing, spelling, grammar and punctuation, and numeracy.

One in every six deaths in young adults is opioid-related: Study

 

Rate of opioid-related deaths in Ontario has tripled in past fifteen years, with most significant increase in young adults

St. Michael’s Hospital

IMAGE

IMAGE: Dr. Tara Gomes is a researcher at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital and the Institute for Clinical Evaluative Sciences (ICES).

Credit: St. Michael’s Hospital

TORONTO, April 26, 2018 – One out of every six deaths among young adults in Ontario is related to opioids, suggests a study led by researchers at St. Michael’s Hospital and the Institute for Clinical Evaluative Sciences (ICES).

The study, published today in the Journal of Addiction Medicine, found that the rate of opioid-related deaths nearly tripled in Ontario from 2000 to 2015, with one in every 133 deaths in Ontario related to opioid use by 2015. However, this number varied importantly by age group. The study expands on earlier research from Dr. Tara Gomes, which showed that one in 170 deaths in Ontario was related to opioid use in 2010.

“It is striking to see that despite the efforts put into harm reduction, proper prescribing practices, and education around opioid use, the number of opioid-related deaths continues to rise,” said Dr. Gomes, a scientist in the Li Ka Shing Knowledge Institute of St. Michael’s. “The other alarming fact is how this crisis is increasingly impacting our youth and young adults.”

Researchers reviewed all deaths in Ontario where prescribed or illicit opioids were determined to be a contributing factor between 2000 and 2015. In the last five years examined in this study (2010 to 2015), the most dramatic increase in opioid-related deaths occurred among those aged 15 to 24 years. By 2015, more than 1 in 9 deaths in this age group were opioid-related – up from 1 in 15 deaths five years earlier.

Dr. Gomes, who is also an ICES scientist, and her team found that a total of 29,410 years of potential life were lost prematurely due to opioid-related causes in 2015, which exceeds the years of life lost prematurely annually from diseases such as pneumonia, HIV/AIDS and influenza in the most recent data available.

“These shifting patterns show us that we have to better understand the dynamics of drug use in younger populations who are succumbing to opioid-related deaths,” Dr. Gomes said. “We can only truly understand this by talking directly to affected communities to learn what they need to create a safer environment in which to live.”

###

This study was funded by grants from the Ontario Ministry of Health and Long-Term Care and the Ontario Strategy for Patient-Oriented Research Support Unit, and was supported by ICES.

About St. Michael’s Hospital

St. Michael’s Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in more than 29 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, care of the homeless and global health are among the Hospital’s recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Centre, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael’s Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto.

About the Institute for Clinical Evaluative Sciences

The Institute for Clinical Evaluative Sciences (ICES) is an independent, non-profit organization that uses population-based health information to produce knowledge on a broad range of health care issues. Our unbiased evidence provides measures of health system performance, a clearer understanding of the shifting health care needs of Ontarians, and a stimulus for discussion of practical solutions to optimize scarce resources. ICES knowledge is highly regarded in Canada and abroad, and is widely used by government, hospitals, planners, and practitioners to make decisions about care delivery and to develop policy. For the latest ICES news, follow us on Twitter: @ICESOntario

Media contacts:

Ana Gajic
Senior Communications Advisor | Communications and Public Affairs
GajicA@smh.ca
(o) 416-864-5960 or (c) 416-458-0629

Deborah Creatura
Media Advisor, ICES
deborah.creatura@ices.on.ca
(o) 416-480-4780 or (c) 647-406-5996

Common class of drugs linked to dementia even when taken 20 years before diagnosis

Public Release: 25-Apr-2018

 

Regenstrief Institute

INDIANAPOLIS – The largest and most detailed study of the long-term impact of anticholinergic drugs, a class of drugs commonly prescribed in the United States and United Kingdom as antidepressants and incontinence medications, has found that their use is associated with increased risk of dementia, even when taken 20 years before diagnosis of cognitive impairment.

An international research team from the US, UK and Ireland analyzed more than 27 million prescriptions as recorded in the medical records of 40,770 patients over age 65 diagnosed with dementia compared to the records of 283,933 older adults without dementia.

The researchers found greater incidence of dementia among patients prescribed anticholinergic antidepressants, anticholinergic bladder medications and anticholinergic Parkinson’s disease medications than among older adults who were not prescribed these drugs.

Dementia increased with greater exposure to anticholinergic medications.

“Anticholinergic Medication and Risk of Dementia: Case-control Study” is published in BMJ (formerly the British Medical Journal) an international peer-reviewed medical journal.

“Anticholinergics, medications that block acetylcholine, a nervous system neurotransmitter, have previously been implicated as a potential cause of cognitive impairment,” said Regenstrief Institute and Indiana University Center for Aging Research investigator Noll Campbell, PharmD, MS, a co-author of the new BMJ study. “This study is large enough to evaluate the long-term effect and determine that harm may be experienced years before a diagnosis of dementia is made.” Dr. Campbell is also an assistant professor of pharmacy practice at Purdue University College of Pharmacy.

“These findings make it clear that clinicians need to carefully consider the anticholinergic burden of their patients and weigh other options,” said study co-author Malaz Boustani, M.D., MPH, a Regenstrief Institute and IU Center for Aging Research investigator. Dr. Boustani is the founder of the Indiana Clinical and Translational Science Institute’s IU Center for Health Innovation and Implementation Science and the Richard M. Fairbanks Professor of Aging Research at IU School of Medicine.

“Physicians should review all the anticholinergic medications – including over-the-counter drugs – that patients of all ages are taking and determine safe ways to take individuals off anticholinergic medications in the interest of preserving brain health,” Dr. Boustani said.

The study, which was led by the University of East Anglia and funded by the Alzheimer’s Society, both in the UK, utilized data from the Clinical Practice Research Datalink which includes anonymized diagnosis, referral and prescription records for more than 11 million patients from 674 primary care practices across the UK. The data is broadly representative of the UK population in terms of age, sex and ethnicity.

“This research is really important because there are an estimated 350 million people affected globally by depression. Bladder conditions requiring treatment are estimated to affect over 13 percent of men and 30 percent of women in the UK and US,” said study lead researcher George Savva, PhD, visiting researcher at University of East Anglia’s School of Health Sciences.

“We don’t know exactly how anticholinergics might cause dementia,” said study co-author Chris Fox, MD, professor of clinical psychiatry at UEA’s Norwich Medical School and a consultant psychiatrist. “Further research is needed to understand possible reasons for this link. In the meantime, I strongly advise patients with any concerns to continue taking their medicines until they have consulted their doctor or pharmacist.”

Study co-author Ian Maidment, PhD, senior lecturer in clinical pharmacy at Aston University in the UK, said: “With many medicines having some anticholinergic activity, one key focus should be de-prescribing. Clinical staff, patients and carers need to work together collaboratively to limit the potential harm associated with anticholinergics.”

###

In addition to Regenstrief Institute, IU, Purdue, University of East Anglia and Aston University investigators, collaborators included researchers from the University of Aberdeen, the Royal College of Surgeons in Ireland, Newcastle University, and the University of Cambridge.

Commonly prescribed heartburn drug linked to pneumonia in older adults

Public Release: 24-Apr-2018

American Geriatrics Society

Researchers at the University of Exeter have found a statistical link between pneumonia in older people and a group of medicines commonly used to neutralize stomach acid in people with heartburn or stomach ulcers. Although proton-pump inhibitors (PPIs) are still a valuable group of medicines, research is indicating that PPIs are not as completely safe for older people as previously thought.

PPIs are medicines commonly prescribed to reduce gastric (stomach) acid production and to protect the stomach. Approximately 40 percent of older adults receive PPIs, although according to some experts, up to 85 percent of people who receive PPI prescriptions may not need them.

Researchers say people should not stop using their PPI medication, but should discuss with their prescribing healthcare professional whether the PPIs are still needed. Just stopping PPIs could be dangerous as PPIs may be useful, for example, to prevent stomach bleeds in some people.

Once thought to be relatively harmless, PPIs have more recently been linked to increased rates for certain health concerns like fractures, cardiovascular disease, and some bacterial infections. The association between PPI use and pneumonia was studied because stomach acid helps to prevent infections spreading from the gut in some individuals. Since pneumonia is a major cause of death for older adults, it is important for healthcare providers to understand the links between PPIs and pneumonia.

The Exeter team designed a study to look at statistical links in medical records between long-term PPI use and pneumonia in older adults. Their study was published in the Journal of the American Geriatrics Society.

David Melzer, Professor of Epidemiology and Public Health at the University of Exeter Medical School, said: “This study shows that there was a higher rate of pneumonia in older people who received PPIs over a two year period. Caution is needed in interpreting the findings as our study is based on analyzing data from medical records, so other factors may be involved. However, our study adds to growing evidence that PPIs are not quite as safe as previously thought, although they are still a very useful class of medication for certain groups of patients.”

The researchers used information from Clinical Practice Research Datalink (CPRD) for England, a large database containing records from many primary care practices in the U.K. They selected patients 60-years-old and older who had taken prescribed PPIs regularly and who also had previous regular medical records. The researchers identified more than 75,000 older adults who were treated with PPIs.

As with all prescription medications, regularly review your use of medicines like PPIs with your healthcare providers to make sure each prescription is still needed.

This summary is from “Proton-Pump Inhibitors and Long-Term Risk of Community?Acquired Pneumonia in Older Adults.” It appears online ahead of print in the Journal of the American Geriatrics Society. The study authors are Jan Zirk-Sadowski, PhD; Jane A. Masoli, MBChB; Joao Delgado, PhD; Willie Hamilton, MD; W. David Strain, MD; William Henley, PhD; David Melzer MBBCh, PhD; and Alessandro Ble, MD.

###

About the Health in Aging Foundation

This research summary was developed as a public education tool by the Health in Aging Foundation. The Foundation is a national non-profit established in 1999 by the American Geriatrics Society to bring the knowledge and expertise of geriatrics healthcare professionals to the public. We are committed to ensuring that people are empowered to advocate for high-quality care by providing them with trustworthy information and reliable resources. Last year, we reached nearly 1 million people with our resources through HealthinAging.org. We also help nurture current and future geriatrics leaders by supporting opportunities to attend educational events and increase exposure to principles of excellence on caring for older adults. For more information or to support the Foundation’s work, visit http://www.HealthinAgingFoundation.org.

About the Journal of the American Geriatrics Society

Included in more than 9,000 library collections around the world, the Journal of the American Geriatrics Society (JAGS) highlights emerging insights on principles of aging, approaches to older patients, geriatric syndromes, geriatric psychiatry, and geriatric diseases and disorders. First published in 1953, JAGS is now one of the oldest and most impactful publications on gerontology and geriatrics, according to ISI Journal Citation Reports®. Visit wileyonlinelibrary.com/journal/JGS for more details.

About the American Geriatrics Society

Founded in 1942, the American Geriatrics Society (AGS) is a nationwide, not-for-profit society of geriatrics healthcare professionals that has–for 75 years–worked to improve the health, independence, and quality of life of older people. Its nearly 6,000 members include geriatricians, geriatric nurses, social workers, family practitioners, physician assistants, pharmacists, and internists. The Society provides leadership to healthcare professionals, policymakers, and the public by implementing and advocating for programs in patient care, research, professional and public education, and public policy. For more information, visit AmericanGeriatrics.org.

Study predicts 2018 flu vaccine will have 20 percent efficacy

Public Release: 19-Apr-2018

Rice U. study finds egg adaptations will limit efficacy of new flu vaccine

Rice University

IMAGE

IMAGE: Michael Deem and Melia Bonomo.

Credit: Jeff Fitlow/Rice University

A Rice University study predicts that this fall’s flu vaccine — a new H3N2 formulation for the first time since 2015 — will likely have the same reduced efficacy against the dominant circulating strain of influenza A as the vaccine given in 2016 and 2017 due to viral mutations related to vaccine production in eggs.

The Rice method, known as pEpitope (pronounced PEE-epih-tope), was invented more than 10 years ago as a fast, inexpensive way of gauging the effectiveness of proposed flu vaccine formulations. The latest pEpitope study, which is available online this week in Clinical Infectious Diseases, suggests pEpitope is a more accurate predictor of vaccine efficacy than long-relied-upon ferret tests, particularly for data gathered in the past decade. The pEpitope method accounts for 77 percent of what impacts efficacy of the vaccine in humans.

pEpitope is a computational method that measures critical differences in the genetic sequences of flu strains. In the new study, the method accurately predicted vaccine efficacy rates for more than 40 years of flu records. These included the past two flu seasons in which vaccines offered only limited protection against the most widely circulating strain of influenza A.

“The vaccine has been changed for 2018-19, but unfortunately it still contains two critical mutations that arise from the egg-based vaccine production process,” said Michael Deem, Rice’s John W. Cox Professor in Biochemical and Genetic Engineering and professor of physics and astronomy. “Our study found that these same mutations halved the efficacy of flu vaccines in the past two seasons, and we expect they will lower the efficacy of the next vaccine in a similar manner.”

Full efficacy data for the 2017-2018 flu season are still being compiled, but pEpitope has predicted it will be around 19 percent against H3N2, the type of influenza A that infected most people in the U.S. in each of the past two years. The Food and Drug Administration chose the same vaccine formulation in 2017 and 2016, in part because the dominant circulating strain stayed the same. In 2016, the vaccine had an efficacy of 20 percent, almost identical to the efficacy of 19 percent predicted by pEpitope.

Efficacy is the measure of how effective a vaccine is at protecting the overall population. A 20 percent efficacy means that in a population, 20 percent fewer vaccinated people will get the flu compared to the unvaccinated people.

Annual flu vaccines are formulated to protect against one type of influenza B and two strains of influenza A, one H3N2 strain and one H1N1 strain. The H and N refer to hemagglutinin and neuraminidase, two proteins that cover the outside of invading flu particles that can cause infection when inhaled. The human immune system targets these particles for destruction based on their H and N sequences, and flu viruses constantly evolve the sequence of amino acids in these proteins to evade detection.

Most flu vaccines are produced with a decades-old process that involves culturing viruses in hundreds of millions of chicken eggs. Because the strain of flu that infects people is often difficult to grow in eggs, vaccine producers must make compromises to produce enough egg-based vaccine in time for fall flu shots. Unintended effects of this process have reduced vaccine efficacy against H3N2 the past two years, Deem said.

“Very often there are egg adaptations,” he said. “There were a couple of these in the vaccine strain the past two seasons that wound up making it a little bit different from the actual circulating virus strain.”

While other papers have examined these mutations using expensive and time-consuming experiments on live ferrets and laboratory cell cultures, Deem and Melia Bonomo used the pEpitope method to rapidly calculate how much the egg-passage mutations would decrease vaccine efficacy in humans.

“In fact, it’s pretty substantial,” said Bonomo, a doctoral student in applied physics. “The original strain used as a reference for the vaccine was basically a perfect match to the dominant circulating strain, and the predicted efficacy would have been around 47 percent. We found that the mutations in two amino acids out of more than 300 in one key region of the hemagglutinin protein were enough to lower efficacy to 19 percent against all circulating strains.”

Deem said egg adaptations like those that reduced the efficacy of vaccines in 2016 and 2017 are unavoidable as long as flu vaccines are produced in eggs. He and Bonomo compared the efficacy of the egg-based vaccine with an experimental vaccine produced from insect cells via reverse genetics. The cell-based vaccine, which did not have the egg-passage mutations, had a predicted efficacy of 47 percent, the average value of a perfectly matched H3N2 vaccine, Deem said.

For decades, scientists have relied upon ferret models to gauge how flu viruses and flu vaccines will behave in people. But Deem said ferret studies over the past 10 years have been considerably less predictive of human effects than they were in the preceding three decades, and it is unclear why.

“It’s been apparent over the last 10 years that egg adaptations have affected the efficacy of flu vaccines,” he said. “It’s also been apparent that the ferrets have done a really bad job of predicting the reduction of the efficacy due to the egg adaptations. Additionally, it’s been difficult to get data from ferrets because the ferrets’ immune systems have not recognized the vaccines particularly well over the past 10 years.”

Deem said the ferret-based measures are one-third as predictive as the pEpitope method that has consistent performance over decades of flu data.

“When we look at our model over all data and over the last 10 years, we get the same answer,” Deem said. “Whether we use the last 10 years of data or the last 50 years, our theory is very robust.”

###

The research was funded by the National Science Foundation via Rice’s Center for Theoretical Biological Physics and by the Welch Foundation.

High-resolution IMAGES are available for download at:

http://www.laughlin.af.mil/News/Art/igphoto/2001819271/
CAPTION: Even in years when flu vaccines have reduced efficacy, experts say flu shots are a safe and easy way to reduce one’s chances of getting sick and spreading the flu. (U.S. Air Force photo/Senior Airman Areca T. Wilson)

http://news.rice.edu/files/2018/04/0418_FLU-mdmb-lg-17n89h3.jpg
CAPTION: Michael Deem and Melia Bonomo (Photo by Jeff Fitlow/Rice University)

The DOI of the Clinical Infectious Diseases paper is: 10.1093/cid/ciy323

A copy of the paper is available at: https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciy323/4972858

Related research from Rice:

New way of predicting dominant seasonal flu strain — Nov. 15, 2010

Rice researchers seek better vaccine procedure — Sept. 8, 2009

Better by design: Engineering flu vaccines — March 17, 2009

This release can be found online at news.rice.edu.

Follow Rice News and Media Relations via Twitter @RiceUNews

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,879 undergraduates and 2,861 graduate students, Rice’s undergraduate student-to-faculty ratio is 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for quality of life and for lots of race/class interaction and No. 2 for happiest students by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance. To read “What they’re saying about Rice,” go to http://tinyurl.com/RiceUniversityoverview.

Post-surgical opioids can, paradoxically, lead to chronic pain

Public Release: 16-Apr-2018

 

Rats given morphine experienced pain-reactivity for three weeks longer, inflammatory changes in spinal cord

University of Colorado at Boulder

Giving opioids to animals to quell pain after surgery prolongs pain for more than three weeks and primes specialized immune cells in the spinal cord to be more reactive to pain, according to a new study by the University of Colorado Boulder.

The authors say the paradoxical findings, if replicated in humans, could have far-reaching implications for patient pain management and add a new wrinkle to the conversation about the national opioid epidemic.

“This indicates that there is another dark side of opiates that many people don’t suspect,” said senior author Linda Watkins, a professor in the Department of Psychology and Neuroscience. “It shows that trauma, including surgery, in combination with opiates can lead to chronic pain.”

For the study, Watkins and co-author Peter Grace, then an assistant research professor at CU Boulder, performed exploratory abdominal surgery, or laparotomy, on male rats. A similar procedure is done tens of thousands of times annually in the United States in humans, and opiates are routinely used after surgery.

“Opiates are really effective for acute pain relief. There is no drug that works better. But very little research has been done to look at what it is doing in the weeks to months after it’s withdrawn,” said Grace, now an assistant professor at MD Anderson Cancer Center in Houston.

In one experiment, half the rats were given the equivalent of what would be a “moderate” dose of morphine in people for seven days postsurgery. Half were given a saline solution.

In another experiment, the rats were given morphine for eight days and then tapered off by day 10. In a third, the animals were given morphine until day 10 and then it was abruptly withdrawn.

Before and after the treatments, the researchers measured the animal’s sensitivity to touch as well as activity of genes that express inflammatory proteins in the spinal cord.

They found that rats given morphine experienced postoperative pain for more than three weeks longer. The longer they received morphine, the longer their pain lasted. And gradual tapering made no difference.

“This tells us that this is not a phenomenon related to opioid withdrawal, which we know can cause pain. Something else is going on here,” Grace said.

Watkins describes that something as a “one-two hit” on specialized immune system cells called glial cells in the central nervous system. The first hit, the surgery, stimulates what she calls the “not me, not right, not OK” receptor, Toll-like receptor 4 on the cells, igniting the release of a cascade of inflammatory proteins and “priming” them to be on guard for a second hit.

Morphine, which also stimulates that receptor, is the second hit.

“With that second hit, the primed glial cells respond faster, stronger and longer than before, creating a much more enduring state of inflammation and sometimes local tissue damage,” she said.

In a previous study, published in the Proceedings of the National Academy of Sciences in 2016, the researchers showed that just a few days of treatment with opiates to treat peripheral nerve pain, such as sciatica, could exacerbate and prolong pain for months in animals, in part by increasing expression of inflammatory genes.

A few small studies in humans have associated postsurgical opioid administration with chronic pain as much as one year later.

“An unusually high number of people end up with postoperative chronic pain. This new study lends insight into one explanation for that,” Watkins said.

The researchers, acknowledging that animal studies cannot directly translate to humans, are now calling for more clinical studies on opioids and chronic pain.

More than 50 million U.S. adults experience chronic pain, according to the National Institutes of Health.

Watkins is also studying novel compounds that could be given with opioids to mute the exaggerated immune response they are believed to trigger, as well as alternative painkillers, including cannabinoids, for pain.

“There is surely a dark side in terms of addiction when it comes to opioids, but this is a very different idea–that we think we are treating the pain with these drugs and we may actually be prolonging it,” she said.

###

Lisa Marshall, CU Boulder media relations
lisa.marshall@colorado.edu
303-492-3115

New affordable hepatitis C combination treatment shows 97 percent cure rate

Public Release: 12-Apr-2018

 

Results support a public health approach to hepatitis C

Drugs for Neglected Diseases Initiative

 

IMAGE

IMAGE: STORM-C-1 : SVR12 rates overall and per pre-defined sub groups-Intend to treat analysis.

Credit: DNDi

PARIS, 12 April 2018 – An affordable hepatitis C combination treatment including the new drug candidate ravidasvir has been shown to be safe and effective, with extremely high cure rates for patients, including hard-to-treat cases, according to interim results from the Phase II/III STORM-C-1 trial presented by the non-profit research and development organisation Drugs for Neglected Diseases initiative (DNDi) at the International Liver Conference in Paris.

“The results indicate that the sofosbuvir/ravidasvir combination is comparable to the very best hepatitis C therapies available today but it is priced affordably and could allow an alternative option in countries excluded from pharmaceutical company access programs,” said Bernard Pécoul Executive Director, DNDi.

The trial using medicines produced by Egyptian drug manufacturer Pharco Pharmaceuticals was run by DNDi and co-sponsored by the Malaysian Ministry of Health, in ten sites in Malaysia and Thailand. Agreements signed in 2016 and 2017 enabling the trials and patient scale-up in Malaysia set out a target price of US$300 for a 12-week treatment, an almost 100% drop from existing treatment prices in Malaysia.

“As hepatitis C has become a major public health concern in Malaysia, it is crucial to increase access to treatment for the benefit of the nation,” said Datuk Dr Noor Hisham Abdullah Director General of Health, Ministry of Health, Malaysia. In September 2017, the government of Malaysia issued a “government-use” license on sofosbuvir patents to allow 400,000 people living with hepatitis C in Malaysia to access generic HCV regimens in public hospitals.

DNDi conducted the STORM-C-1 open label trial to assess the efficacy, safety, tolerance and pharmacokinetics of the drug candidate ravidasvir combined with sofosbuvir. 301 chronically infected adults were treated with the ravidasvir/sofosbuvir combination for 12 weeks for patients without cirrhosis of the liver, and for 24 weeks for those with compensated cirrhosis. In accordance with international standards defining cure for HCV treatments, 12 weeks after treatment completion, 97% of those enrolled were cured (95% CI: 94.4-98.6). Cure rates were very high even for the hardest-to-treat patients: people with liver cirrhosis (96% cured), people living with HIV using their usual treatment (97%), people infected with genotype 3 (97%) including those with cirrhosis (96%), and people who had been exposed to previous HCV treatments (96%). Importantly, patients combining several of these risk factors were cured, and no unexpected safety signals were detected.

“From a treatment provider perspective, this is very exciting as we have been waiting for a simple, affordable, robust treatment tolerated by all patients groups, including those whose treatment outcomes are currently poorer, like patients under antiretroviral therapy,” said Pierre Mendiharat, Deputy Operations Director for Médecins Sans Frontières / Doctors Without Borders (MSF). “This will be crucial to expand treatment to the most vulnerable categories of patients in developing countries.”MSF and DNDi are working together to increase access to care and treatment for HCV patients in key low- and middle-income countries, through the STORM-C project financed by MSF’s Transformational Investment Capacity (TIC) initiative.

Over 71 million people live with hepatitis C worldwide, a disease which causes 400,000 deaths a year. Although highly effective treatments have existed for a number of years, less than three million people are on treatment, with more people infected every year than are put on treatment. The World Health Organization aims for 80% of people diagnosed with HCV to be put on treatment by 2030.

Ravidasvir is an oral NS5A inhibitor licensed to DNDi by Presidio Pharmaceuticals. Most people enrolled in the DNDi trial in Malaysia and Thailand had genotype 1 (42% of participants) or genotype 3 (53%), thereby confirming the combination’s effectiveness for those two additional genotypes. Further trials are planned to document the efficacy and safety of the combination in patients infected with the other HCV genotypes and in particularly vulnerable groups, to enable a public health approach to the treatment of hepatitis C.

“Pharco is proud to enable a public health approach to hepatitis C treatment by providing affordable treatments. We look forward to future collaboration in additional clinical trials to confirm the safety and efficacy of ravidasvir,” said Dr. Sherine Helmy, CEO, Pharco.

###

Media Contacts

DNDi: media@dndi.org or Ilan Moss +1 646 266 5216, imoss@dndi.org

Poster reference: Isabelle Andrieux-Meyer, Tan Soek Siam,Nicolas Salvadori, François Simon, Tim R. Cressey, Hajiah Rosaida Hi Mohd Said, Muhammad Radzi Abu Hassan, Haniza Omar, Hoi-Poh Tee, Chan Wah Kheong, Goh Khean Lee, Sharifah Faridah Syed Omar, Adeeba Kamarulzaman, Suresh Kumar, Satawat Thongsawat, Kanawee Thetket, Anchalee Avihingsanon, Suparat Khemnark, Sombat Thanprasertsuk, Jean-Michel Piedagnel, Sasikala Siva, Nur Asimah, Nelson Da Silva, Jennifer Brenner, Bernard Pecoul, Marc Lallemant, Shahnaz Murad. Safety and efficacy of ravidasvir plus sofosbuvir 12 weeks in non-cirrhotic and 24 weeks in cirrhotic patients with hepatitis C virus genotypes 1, 2, 3 and 6: the STORM-C-1 phase II/III trial. International Liver Congress, Paris, April 11-15 2018, France. Poster LBP-032.

About DNDi

The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit R&D organization working to deliver new treatments for neglected patients, in particular sleeping sickness, Chagas disease, leishmaniasis, filaria, paediatric HIV/AIDS, and hepatitis C. http://www.dndi.org

‘Coffee filter’ helps make new cancer drug Z-endoxifen 1,000 times cheaper

Public Release: 5-Apr-2018

 

Thorough analysis of synthesis reveals much cheaper purification route

Eindhoven University of Technology

 

Making drugs cheaper doesn’t always require pricey investments. A joint initiative by researchers from Eindhoven University of Technology (TU/e), the Dutch company Syncom BV and the Antoni van Leeuwenhoek hospital proves just that. What started out as a Bachelor project at TU/e laid the foundation for a much cheaper production of the promising cancer drug Z-endoxifen.

Tamoxifen is known world-wide as a blockbuster chemotherapeutic drug for the treatment of breast cancer, but it is not always effective. Before it can exert its healing effect, the patient’s body must first convert it into the active component Z-endoxifen. Unfortunately, the conversion depends on the patient’s genes, which can lead to a variable therapeutic response in patients. By not administering Tamoxifen but Z-endoxifen directly, this genetic dependence is circumvented and the medicine therefore becomes more effective and less toxic due to lower dosing. This has also been demonstrated by clinical trials in the US.

The application of Z-endoxifen had quite a hurdle to overcome: the drug’s production was only feasible in small amounts, which led to the exorbitant price of about ten thousand euros per gram. Researchers from TU/e and Syncom have now overcome this hurdle with an improved method to produce Z-endoxifen. During a Bachelor project attentive researchers from TU/e recognized that the HPLC (high-pressure liquid chromatography) purification method used was not at all necessary. Especially on a larger scale HPLC can be particularly expensive.

The existing production method yields two variants (Z- and E-stereo isomers) of endoxifen in a 70:30 ratio, of which the latter is undesired. HPLC was necessary to remove the unwanted 30%. The researchers from Eindhoven made the seredipitous discovery that the ratio one step earlier in the process could be increased to 95:5 in favour of the preferred Z-isomer. At this purity a chemical process known as trituration is possible, which enables removal of the the remaining 5% unwanted E-isomer by paper filter, not unlike filtering coffee granules from your morning coffee. The Dutch company Syncom showed this to be the case, andtook the project to the next level by scaling up the production and rendering the synthesis more robust using a tailored protective group on the molecule. Finally, Prof Jos Beijnen’s group in Amsterdam proved that this new approach did indeed produce pure Z-endoxifen and that the alternative method of purification is effective.

For the next phase of clinical trials of Z-endoxifen, it is important that researchers are able to obtain sufficient quantities of the potential drug at a sufficiently low price. The retail price of pure Z-endoxifen is estimated to be approximately 75,000 euros per gram. By comparison, the invention from Eindhoven makes it possible to produce dozens of grams or even kilos of high purity at the same time, a lot easier, and at a cost of production that is 1,000 times lower. The big breakthrough means that if medical research groups want to do research into the effects of the drug, they are no longer dependent on expensive producers, but they can now produce the drug themselves and at a much lower cost.

Former bachelor student Daphne van Scheppingen worked on the synthesis of Z-endoxifen under the supervision of assistant professor Dr Lech-Gustav Milroy, in 2011. The aim of Van Scheppingen’s project was to synthesize 30-50 milligrams of Z-endoxifen for a collaboration with the research group of Prof Jos Beijnen of the Antoni van Leeuwenhoek hospital. At that time, the drug was still in pre-clinical development and still had to undergo clinical testing. Van Scheppingen and Milroy made the discovery through careful inspection of the final steps in an already existing synthesis route. These steps include the purification of a mixture of the synthesis products into the pure substance, and involved a much cheaper and simpler alternative purification method. Since the clinical testing had not yet been completed, the scientific interest in Z-endoxifen was still small. Since the the publication of the clinical trial data, the project has received a new impulse and the work has quickly been published. Bartjan Koning and Jan Koek of Syncom have scaled up the synthesis significantly to dozens of grams. This opens the doors to more research into the activity and selectivity of the cancer medication.

In order to make the drug available to patients, the newly discovered production method must be scaled up even further to industrial production (kilograms). The researchers expect that this will require approximately one year of R&D. More research is also needed on the effects of the drug, the so-called Phase II and III, which typically last between 1 and 6 years.

Why has mumps reemerged in the United States?

Public Release: 21-Mar-2018

 

American Association for the Advancement of Science

A recent resurgence in mumps cases in the U.S. may be due to weakening immune protection from the mumps vaccine, researchers report. They say the results of their modeling studies suggest that a booster dose at age 18 may help control outbreaks of the disease. Before the mumps vaccine was developed in 1967, more than 90% of children and youth in the United States experienced this painful and highly-contagious viral infection prior to the age of 20. After decades of declining mumps incidence due to the introduction of widespread vaccination, an increase in mumps cases was observed in 2006 in adolescents and young adults in the U.S. Seeking to determine if the mumps virus had evolved to escape the vaccine or if immunity from the vaccine naturally decreased over time – a distinction that helps to inform whether new vaccines are needed to control transmission – Joseph Lewnard and Yonatan Grad closely examined epidemiological data from six mumps vaccine effectiveness studies conducted in the United States and Europe. The scientists concluded that the mumps vaccine protects people for an average of 27 years (with a range of 16 to 51 years), and did not seem to be less effective against emerging mumps strains. Transmission models indicated that routine use of a booster dose at age 18 could help to maintain population immunity. The authors say their findings emphasize a need to conduct clinical trials that would measure the benefit of administering this booster dose.

###

Living human tracheas

Public Release: 14-Feb-2018

 

Case Western Reserve University researchers engineer natural windpipe replacement alternative to synthetic scaffolding now being used

Case Western Reserve University

Biomedical engineers at Case Western Reserve University are growing tracheas by coaxing cells to form three distinct tissue types after assembling them into a tube structure-without relying on scaffolding strategies currently being investigated by other groups.

Successful trials and further research and development could someday allow surgeons the option of replacing damaged or faulty trachea with a fully functional natural-tissue trachea in both adults and children, said Eben Alsberg, professor in Biomedical Engineering and Orthopaedic Surgery and director of the Alsberg Stem Cell & Engineered Novel Therapeutics (ASCENT) Lab at Case Western Reserve University.

“The unique approach we are taking to this problem of trachea damage or loss is forming tissue modules using a patient’s cells and assembling them like childhood toy Legos into a more complex tissue,” said Alsberg, who is leading the research.

This step toward building living windpipe structures from self-assembled modules is explained in detail in the most recent issue of Advanced Science.

Co-authors include: Marsha Rolle, an associate professor of biomedical engineering from Worcester Polytechnic Institute in Worcester, Massachusetts; Hannah Strobel, a WPI graduate student; Calvin Cotton, a professor of pediatrics and physiology and biophysics at Case Western Reserve; and nine researchers from Alsberg’s lab, including co-first authors Anna Dikina and Daniel Alt.

The research was supported by a $1.9 million grant from the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering.

The problem

The trachea, commonly called the windpipe, is the airway between the voice box and the lungs. Patients may need a rebuilt trachea because of tumor resection or an injury that results in tracheal stenosis, a narrowing or constricting of the windpipe, which inhibits breathing.

Damage to or loss of trachea tissue can be life-threatening or lead to a significantly reduced quality of life, Alsberg said.

Doctors have limited solutions for patients with damaged tracheas. If a portion of the trachea is damaged, for example, they can only surgically join the ends if less than half of the trachea is damaged in adults or less than 30 percent in children.

Other procedures, such as implanting a stent or simply clearing away tissue obstructing the airway, offer only short-term relief as the repaired tube tends to close off again after about a year.

Recent tissue-engineering approaches using synthetic or natural materials as scaffolding for cells have been met with challenges.

Difficulties have included uniformly seeding cells on the scaffolding, recreating the multiple different tissue types found in the native trachea, tailoring the scaffolding degradation rate to equal the rate of new tissue formation, and recreating important contacts between cells because of the intervening scaffold.

Improving upon current treatments

The trachea engineering strategy now being pursued at Case Western Reserve, however, wouldn’t have those problems because it doesn’t rely on a separate scaffold structure, Alsberg said.

According to Alsberg’s research, a new trachea replacement must do three critical things to function properly:

  1. maintain rigidity to prevent airway collapse when the patient breathes;
  2. contain immunoprotective respiratory epithelium, the tissue lining the respiratory tract, which moistens and protects the airway and functions as a barrier to potential pathogens and foreign particles;
  3. and integrate with the host vasculature, or system of blood vessels, to support epithelium viability.

The self-assembling rings developed by the Alsberg and Rolle labs meet all three of those requirements because they can fuse together to form tubes of both cartilage and “prevascular” tissue types. Prevascular refers to tissues potentially ready to participate in the formation of blood vessels, though not yet functional in that way.

The cartilage rings are formed by aggregating marrow-derived-stem cells in ring-shaped wells. Polymer microspheres containing a protein that induces the stem cells to become “chondrocytes,” or cells that form cartilage, are also incorporated into the cell aggregates.

Rolle said it is the combining of those two things-the self-assembled tissue ring modules and the polymer microspheres-that “makes it possible to create the complex multi-tissue structure that makes up the trachea.”

The prevascular rings are comprised of both these marrow-derived stem cells and endothelial cells, the thin layer of cells that line the interior of blood vessels.

The researchers then coat the tubes with epithelial cells to form multi-tissue constructs that satisfy all of those requirements: cartilage provides rigidity, epithelium serves the role of immunoprotection and the vascular network would ultimately permit blood flow to feed and integrate the new trachea tissue.

Using this method, Alsberg, Rolle and their team have been able to engineer highly elastic “neo-tracheas” of various sizes, including tissues similar to human trachea. When these tracheas were implanted under the skin in mice, there was evidence the prevascular structures could join up with the host vascular supply.

“The hope is that a surgeon could implant the tissue tube into the body and it will grow and incorporate into the existing tissue,” Alsberg said. “We’re excited about this approach, as it may have broad applicability to bottom-up engineering of many other complex tissues and organs.”

###

Case Western Reserve University is one of the country’s leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,100 undergraduate and 6,200 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.

Heroin vaccine blocks lethal overdose

Public Release: 13-Feb-2018

 

Scripps Research Institute

LA JOLLA, CA – Feb. 13, 2018 -Scientists at The Scripps Research Institute (TSRI) have achieved a major milestone toward designing a safe and effective vaccine to both treat heroin addiction and block lethal overdose of the drug. Their research, published today in the journal Molecular Pharmaceutics, shows how a new anti-heroin formulation that is safe in animal models remains stable at room temperature for at least 30 days. As a result, the vaccine is close to being ready for human testing.

“The heroin vaccine is one step closer to clinical evaluation,” says Candy S. Hwang, PhD, first author of the study and a research associate at TSRI.

According to the National Institute on Drug Abuse, 15,446 Americans died from heroin overdose between 2000 and 2016, and the mortality rates are increasing. Heroin abuse has been further fueled by a rise in prescription opioid abuse–studies show that opioid pain reliever users are 40 times more likely to abuse heroin.

The first formulation of the heroin vaccine was developed in 2013 by a team led by Kim D. Janda, PhD, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI. It has been shown to be effective–and safe–in both mouse and non-human primate models.

The vaccine works by training the immune system antibodies to recognize and bind to heroin molecules, blocking the drug from reaching the brain to cause a “high.” Researchers believe that blocking the high of heroin will help eliminate the motivation for many recovering addicts to relapse into drug use.

The heroin molecule does not naturally prompt an antibody response, so researchers attach it to a carrier protein that alerts the immune system to start making antibodies. Scientists also add an ingredient called an adjuvant to the vaccine, which boosts the immune response and makes the vaccine more effective.

Hwang says, “Our goal was to prepare a vaccine that could be advanced to clinical trials. As such, we were looking for the best combination of ‘hapten’ (the heroin molecule), carrier protein and adjuvant to keep the vaccine both stable for transport and storage but still efficacious.”

For the new study, the researchers investigated how 20 different carrier protein/adjuvant combinations worked, including shelf stability based on temperature and storage time and whether the formulation was a liquid or powder.

Their experiments in rodent models showed that the best vaccine formulation contained a carrier protein called tetanus toxoid (TT) and adjuvants called alum and CpG ODN. The discovery that alum worked best as an adjuvant was especially significant since alum is one of the few adjuvants used in vaccines already approved by the U.S. Food and Drug Administration. The researchers also found that there was no difference in how well it worked between the liquid and powder versions of this formulation.

Hwang notes that the best vaccine formulation showed protection against lethal doses of heroin. This is particularly important as many heroin addicts have succumb to overdose and death during their attempts to quit the drug.

With this new study, the researchers have shown that the vaccine is safe and effective in animal models, stable under clinical conditions and reliant on an already-approved adjuvant. The next step is to find a producer to make the vaccine on a large scale.

“We believe that a heroin vaccine would be tremendously beneficial for people who have a heroin substance use disorder but have found difficulty in trying to quit,” says Hwang.

###

In addition to Hwang and Janda, authors of the study, “Enhancing Efficacy and Stability of an Anti-Heroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality,” were Paul T. Bremer, Cody J. Wenthur, Beverly Ellis and Bin Zhou of The Scripps Research Institute; and Sam On Ho, SuMing Chiang and Gary Fujii of Molecular Express, Inc.

The study was supported by the National Institutes of Health (grants UH3DA041146, F32AI126628, F32DA043323, R42DA040422 and R44AI094770).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists–including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine–work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www.scripps.edu.

Chicken pox vaccine linked with shingles at the vaccination site in some children

cv

http://onlinelibrary.wiley.com/wol1/doi/10.1111/pde.13415/full

Public Release: 9-Feb-2018

Wiley

New research in Pediatric Dermatology reports several cases of shingles that developed at the original vaccination site in healthy children after they were immunized against chicken pox. Most of these cases were initially misdiagnosed as other skin rashes. While some of these patients underwent tests to help make the diagnosis, all of the children recovered without complications.

Infection with the varicella-zoster virus leads to chickenpox, or primary varicella. The virus then lies dormant and can later reactivate as shingles, or herpes zoster. The varicella-zoster vaccine is made of an attenuated live virus that prevents most people from getting chicken pox but rarely can reactivate and cause shingles.

The cases highlight the importance of recognizing shingles in vaccinated children.

“Shingles in healthy immunized children is rare, but when it occurs it may correlate to the original vaccination site,” said senior author Dr. Jennifer Huang, of Boston Children’s Hospital. “Recognizing vaccine-associated shingles may prevent unnecessary procedures or testing.”

Children Who Get Flu Vaccine Have Three Times Risk Of Hospitalization For Flu, Study Suggests (2009 Requested Repost)

 

Date: May 20, 2009

Source: American Thoracic Society

The inactivated flu vaccine does not appear to be effective in preventing influenza-related hospitalizations in children, especially the ones with asthma. In fact, children who get the flu vaccine are more at risk for hospitalization than their peers who do not get the vaccine, according to new research that will be presented on May 19, at the 105th International Conference of the American Thoracic Society in San Diego.

Flu vaccine (trivalent inactivated flu vaccine—TIV) has unknown effects on asthmatics.

“The concerns that vaccination maybe associated with asthma exacerbations have been disproved with multiple studies in the past, but the vaccine’s effectiveness has not been well-established,” said Avni Joshi, M.D., of the Mayo Clinic in Rochester, MN. “This study was aimed at evaluating the effectiveness of the TIV in children overall, as well as the children with asthma, to prevent influenza-related hospitalization.”

The CDC’s Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend annual influenza vaccination for all children aged six months to 18 years. The National Asthma Education and Prevention Program (3rd revision) also recommends annual flu vaccination of asthmatic children older than six months.

In order to determine whether the vaccine was effective in reducing the number of hospitalizations that all children, and especially the ones with asthma, faced over eight consecutive flu seasons, the researchers conducted a cohort study of 263 children who were evaluated at the Mayo Clinic in Minnesota from six months to 18 years of age, each of whom had had laboratory-confirmed influenza between 1996 to 2006. The investigators determined who had and had not received the flu vaccine, their asthma status and who did and did not require hospitalization. Records were reviewed for each subject with influenza-related illness for flu vaccination preceding the illness and hospitalization during that illness.

They found that children who had received the flu vaccine had three times the risk of hospitalization, as compared to children who had not received the vaccine. In asthmatic children, there was a significantly higher risk of hospitalization in subjects who received the TIV, as compared to those who did not (p= 0.006). But no other measured factors—such as insurance plans or severity of asthma—appeared to affect risk of hospitalization.

“While these findings do raise questions about the efficacy of the vaccine, they do not in fact implicate it as a cause of hospitalizations,” said Dr. Joshi. “More studies are needed to assess not only the immunogenicity, but also the efficacy of different influenza vaccines in asthmatic subjects.”

American Thoracic Society. “Children Who Get Flu Vaccine Have Three Times Risk Of Hospitalization For Flu, Study Suggests.” ScienceDaily. ScienceDaily, 20 May 2009. <www.sciencedaily.com/releases/2009/05/090519172045.htm

Influenza A vaccination associated with 6.3 times more aerosol shedding than non vaccinated

Editors Note (Ralph Turchiano: I encourage you to review the full study as I shall link it below. I am only highlighting the two outcomes that require urgent further investigation due to the rapid mutagenicity of H3N2 .

Study Quote # 1  “In adjusted models, we observed 6.3 (95% CI 1.9–21.5) times more aerosol shedding among cases with vaccination in the current and previous season compared with having no vaccination in those two seasons.”

Study Quote #2 “ The association of current and prior year vaccination with increased shedding of influenza A might lead one to speculate that certain types of prior immunity promote lung inflammation, airway closure, and aerosol generation. This first observation of the phenomenon needs confirmation. If confirmed, this observation, together with recent literature suggesting reduced protection with annual vaccination, would have implications for influenza vaccination recommendations and policies.

 

Full Text Link: http://www.pnas.org/content/early/2018/01/17/1716561115.full

mmm

VACC1

vac2

Dramatic FLU virus mutations may be due to antiquated vaccine manufacturing

Dramatic FLU virus mutations may be due to antiquated vaccine manufacturing

Dramatic FLU virus mutations may be due to antiquated vaccine manufacturing

Researchers discovered that by manufacturing the vaccine through the use of chicken eggs it had the unintentional consequence of causing dramatic mutations in the H3N2 Virus. These mutations the researchers speculate resulted in a equally dramatic decline in vaccine effectiveness

Prediction of influenza vaccine effectiveness for the influenza season 2017/18 in the US [version 1; referees: 1 approved]. F1000Research 2017, 6:2067 (doi: 10.12688/f1000research.13198.1)

A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine  (doi: /10.1371/journal.ppat.1006682)

Vaccine Resistant Flu strains are evolving as dominant strains

Public Release: 13-Dec-2017

How well will the flu vaccine work this winter?

University of Texas Medical Branch at Galveston

GALVESTON, Texas — The most effective way of preventing seasonal influenza is to be vaccinated each autumn. The reason that people are encouraged to get vaccinated annually is because flu virus can cause severe disease. One of the problems is that there are many different flu viruses circulating around the world and which ones circulate changes over time.

Each year, pharmaceutical companies produce vaccines against the flu viruses predicted to be dominant during the upcoming flu season. How well the vaccine works varies from year to year because of how much the circulating flu viruses evolve between the time that the vaccine is produced and the beginning of flu season. For this reason, in most years, the flu vaccine is 50 to 70 percent effective.

During the Australian 2017 flu season, the flu vaccine was only 10 percent effective because of the emergence of variant H3N2 that was “vaccine resistant”.

Scientists from UTMB and Biomed Protection have published this prediction almost two years in advance demonstrating that the prediction of flu vaccine efficacy may be possible. In their study, they predicted which H3N2 variants would become “vaccine resistant”, and this prediction has been now confirmed during the 2017 Australian flu season.

“It’s important every year that we monitor the Australian flu season because the following flu season in the U.S. and Europe could be similar,” said Slobodan Paessler, UTMB professor in the department of pathology. “When the flu vaccine isn’t terribly effective in Australia, U.S. and European health authorities prepare for a potentially severe flu season.”

In a new paper published in F1000 Research, Paessler and Veljko Velkovic, co-founder of Biomed Protection, used the same bioinformatics platform to determine how well the current seasonal flu vaccine might protect against H3N2 flu viruses isolated in the U.S and Australia between July and September 2017. Virus gene sequences from currently circulating strains were obtained from the Global Initiative on Sharing All Influenza Database.

The results published suggest that the current flu vaccine will work better during the 2018 U.S. flu season than the 2017 Australian flu season. In Australia, there were two groups of H3N2 viruses circulating, and the vaccine was projected to protect against the minority of viruses but not the majority viruses. In the U.S., the vaccine is projected to be effective against the majority H3N2 flu viruses so far.

Update: On December 8, The U.S. Centers for Disease Control laboratory has published a report showing that the flu vaccine is similar to the flu viruses afflicting people in the U.S. this season, suggesting that the flu vaccine should offer similar protection as past seasons.

“Nevertheless, this situation could change if any of the viruses from the minority group, which is not covered by the vaccine, were to become dominant,” said Paessler and Veljkovic. “For this reason, its very important that we closely monitor the evolution of the H3N2 flu viruses throughout the 2018 U.S. flu season.”

Recently, lack of effectiveness in the flu vaccine has been linked to a specific mutation generated during the vaccine production process. Paessler and Veljkovic analyzed the effect of the mutation and found that it is shifting the vaccine virus from the majority group to the minority group, potentially decreasing the vaccine’s effectiveness.

###

Rising levels of HIV drug resistance

Public Release: 30-Nov-2017

 

University College London

HIV drug resistance is approaching and exceeding 10% in people living with HIV who are about to initiate or reinitiate first-line antiretroviral therapy, according to the largest meta-analysis to date on HIV drug resistance, led by researchers at UCL and the World Health Organization (WHO) and funded by the Bill & Melinda Gates Foundation and the WHO.

The study, published today in The Lancet Infectious Diseases, looked at data for people who were beginning antiretroviral therapy, and found that resistance – particularly to one of the main types of first-line drug, NNRTIs – is increasing and those who exhibited drug resistance were more likely to have previously been exposed to antiretroviral drugs, often during pregnancy.

“Treatments for HIV have improved immensely in recent years, and close to 21 million people worldwide are now being treated with antiretroviral therapy. Yet to end the AIDS epidemic as a public health threat, minimising drug resistance will be one part of the response. Our findings show the importance of improving how we monitor drug resistance, and suggest we should review which drugs are included in first-line therapies,” said the study’s lead author, Professor Ravindra Gupta (UCL Infection & Immunity).

The researchers pulled together 358 datasets, including data from 56,044 adults across 63 low- to middle-income countries who were beginning first-line therapy for HIV from 1996 and 2016. The research was conducted by a team of 33 authors on five continents.

Current WHO treatment guidelines for first-line therapy recommend non-nucleoside reverse transcriptase inhibitors (NNRTI) in combination with nucleoside reverse transcription inhibitors (NRTI). The research team focused on studies that included data on the presence of drug-resistant mutations in the virus, most commonly resistant to NNRTI drugs.

The research team found that, from 2001-2016, the odds of drug resistance in low- to middle-income countries across Sub-Saharan Africa, Latin America and Asia were increasing. In particular, the yearly incremental increase in NNRTI resistance was greatest in Eastern Africa (29% annual increase) and in Southern Africa (23% annual increase, with an absolute increase of 1.8 percentage points from 2015 to 2016) and was the smallest in Asia (11% annual increase).

The study did not focus on high-income countries, but other studies have found that levels of drug resistance to NNRTIs in high-income countries were either plateauing or declining.

The study authors found drug resistance to be highest in Southern Africa, where 11.1% of people beginning first-line therapy had a virus with NNRTI drug-resistant mutations, compared to 10.1% in Eastern Africa, 7.2% in Western/Central Africa, and 9.4% in Latin America.

The study team also found that people starting therapy who self-report previous use of antiretroviral drugs are more likely to carry resistant virus, and are at greater risk of virological failure – that is, the risk the virus won’t be adequately kept under control by the HIV treatment.

Their data suggests that in some areas, 10-30% of people presenting for antiretroviral therapy have previously been exposed to antiretroviral drugs.

“Many people develop drug resistance after being treated by antiretroviral drugs if they stop taking their medication – often due to personal reasons, difficulty accessing treatment providers, or drug supply issues that are common in low income regions. When these individuals restart treatment at a later date, they are less likely to respond to therapy and may pass on the drug-resistant strains to other people,” explained Professor Gupta.

If no action is taken, drug resistance to NNRTIs exceeding 10% in people starting therapy could result in 890,000 more AIDS deaths and 450,000 more infections in Sub-Saharan Africa alone before 2030, as most people whose antiretroviral therapy is unsuccessful have a drug-resistant virus, according to prior research.

However, a way forward exists and is being proposed by the World Health Organization. In July 2017, WHO published a new HIV drug resistance report, based on drug resistance national surveys conducted in 11 countries in Africa, Asia and Latin America. The report’s findings concurred with this broader meta-analysis’ results and showed that in 6 of the 11 countries surveyed over 10% of people starting HIV treatment had drug resistant strains.

“If we are to combat HIV drug resistance, we must ensure countries can do a good job in monitoring and responding to it when needed,” said co-author Dr Silvia Bertagnolio of the World Health Organization. “New WHO guidelines and a global action plan aim to help make this happen.”

WHO’s guidelines on pre-treatment HIV drug resistance recommend that countries switch to more robust first-line treatment when levels of resistance reach 10%. The five-year Global Action Plan calls on all countries and partners to join efforts to prevent, monitor and respond to HIV drug resistance and to protect the ongoing progress towards the Sustainable Development Goal of ending the AIDS epidemic by 2030.