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Human herpesvirus 6 (HHV-6) infects almost all of the human population, but only very few will show any symptoms during their lifetime: HHV-6 is one of the most widespread viruses among the population. Between 95 and 100 percent of healthy adults have antibodies to the virus which means that they have been infected at some point in the past.

The virus hides in the genomic DNA

There are two types of the virus: HHV-6A and HHV-6B. HHV-6B primarily infects in infancy as sixth disease, whereas HHV-6A infections usually remain asymptomatic. After primary infection, the virus establishes lifelong latency by integrating with the cellular DNA.

The infection is generally harmless. Under certain circumstances, however, the virus can be reactivated - for example, after chlamydia infection, organ transplantation, immunodeficiency or when taking specific drugs.

Trigger of numerous diseases

While HHV-6 was long believed to have no negative impact on human health, scientists today increasingly suspect the virus of causing various diseases such as multiple sclerosis or chronic fatigue syndrome. Recent studies even suggest that HHV-6 might play a role in the pathogenesis of several diseases of the central nervous system such as schizophrenia, bipolar disorder, depression or Alzheimer's.

Dr. Bhupesh Prusty is responsible for these new insights. The scientist is a team leader at the Department of Microbiology of the University of Würzburg. Prusty has recently discovered a method which for the first time allows reactivation of human herpesvirus to be detected at an early stage.

MicroRNA molecules as markers

"Betaherpesviruses like human herpesvirus 6A, 6B and 7 integrate into subtelomeric ends of human chromosomes and acquire latency. This makes it difficult to recognize the early phase of viral activation based on an analysis of the viral DNA," Prusty points out the problem. Together with his team, the virologist has now discovered an alternative approach which could be a suitable biomarker for HHV-6 studies.

"We have identified several viral microRNA molecules which are produced both during active infection and viral activation," Prusty explains. MicroRNAs directly influence cell metabolism. The RNA assures the flow of genetic information from nuclear DNA into the cell where it is "translated" to proteins. The microRNAs have a regulatory function in this process. They can dock to RNA molecules and prevent them from being translated to proteins or initiate the degradation of RNA molecules. Prusty is certain that the detection of these viral microRNAs can serve as an ideal biomarker under clinical conditions.

Biopsies confirm hypothesis

The scientists were able to confirm their hypothesis by studying biopsies of a young woman who had died tragically as a result of drug-induced hypersensitivity syndrome (DRESS), a usually life-threatening condition which results in rash, organ failure and blood count anomalies.

Scientists have suspected for some time that these cases might have been caused by drugs that activate viruses but were unable to provide evidence for this theory. Prusty and his colleagues have now detected traces of HHV-6 DNA in the blood of the deceased - however different concentrations at various stages of the disease. At the time of death, for example, the viral load was very low while the opposite was true for the concentration of microRNA: "All biopsy samples showed a positive signal for this special type of RNA," Bhupesh Prusty says. This indicates the potential effectiveness of RNA as a viral biomarker for the detection of active viral infection in the body.

With this finding, Prusty and his team have demonstrated for the first time in experiments that some of the prescription drugs have the potential to reactivate HHV-6 with life-threatening consequences. Early detection of viral reactivation may therefore be helpful for further clinical interventions.

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In an analysis of all relevant studies, exposure to environmental toxins called per- and polyfluoroalkyl substances was linked to worse kidney function and other signs of kidney damage.

Washington, DC (September 13, 2018) -- Certain highly pervasive environmental pollutants may have a variety of negative effects on kidney health, according to an analysis of all relevant studies published on this topic to date. The findings, which appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN), point to the need for additional research to clarify and address these effects.

Per- and polyfluoroalkyl substances (PFAS) are a large group of manufactured non-biodegradable compounds used in industrial processes and consumer products, and they are everywhere in the environment. Humans are exposed to PFAS through contaminated soil, food, water, soil, and air. Recently, they have been detected on military bases, where they are used in aqueous fire-fighting foams, as well as in public water supplies from industrial contamination and in agricultural and crop products.

To investigate whether PFAS exposure may be affecting kidney health, John Stanifer, MD, MSc (Duke University) and his colleagues searched the medical literature for relevant studies. "The kidneys are very sensitive organs, particularly when it comes to environmental toxins that can get in our bloodstream. Because so many people are now exposed to these PFAS chemicals, and to the newer, increasingly-produced alternative PFAS agents such as GenX, it is critical to understand if and how these chemicals may be contributing to kidney disease," he said.

In the 74 studies identified, there were many adverse outcomes linked to PFAS exposure, including worse kidney function, derangements in the proximal tubules (the resorptive structure of the kidney), and dysregulated metabolic pathways linked to kidney disease. It was also particularly concerning that children are exposed to these chemicals to a greater extent than adults.

"By searching all the known studies published on the topic, we concluded that there are several potential ways in which these chemicals can cause kidney damage," said Dr. Stanifer. "Further, we discovered that there have already been multiple reports suggesting that these chemicals are associated with worse kidney outcomes."

Doctors and nurses are always grateful when they are given advance notice that a patient is about to seriously deteriorate (or 'crash', to use today's clinical vernacular). Recent years have seen important advances towards this goal in the form of what are known as 'Clinical Early Warning Scores.' These simple computational tools are intended to help predict future clinical deterioration, often related to the onset of sepsis. (Sepsis is a potentially life-ending condition that arises when the body's immune response to infection damages the patient's own organs.) The Open Anesthesia Journal is pleased to announce the publication of a clinical review on this important topic. Entitled Clinical Early Warning Scores: New Clinical Tools in Evolution and authored by Dr. D. John Doyle from the Department of General Anesthesiology at Cleveland Clinic, Abu Dhabi, this open-access peer-reviewed journal article will be valuable as a starting point for hospitals and clinics interested in launching their own clinical early warning initiative. The article also critically comments on the state of the art of early warning algorithms, and makes suggestions for further research initiatives. The full article may be retrieved free of charge at https://benthamopen.com/FULLTEXT/TOATJ-12-26.

Paris, France: Babies born very prematurely are more likely to harbour Ureaplasma bacteria, according to new research to be presented on Sunday at the European Respiratory Society International Congress [1].

Ureaplasma bacteria are often present in the birth canal but they are unusually small and difficult to detect. The bacteria can be passed on to babies during pregnancy or birth, and can cause a respiratory infection in newborns.

The new research shows that very premature babies who have Ureaplasma bacteria in the lungs at birth are more likely to develop respiratory problems during their first year of life and less likely to survive.

It also shows that a widely-available antibiotic that is effective against Ureaplasma in the lab can be given safely to premature babies and so could have a role in the treatment of premature babies in the future.

The work was presented by Rose Marie Viscardi MD, Professor of Paediatrics at the University of Maryland School of Medicine, Baltimore, USA. She says: "Research has already suggested a link between Ureaplasma infection, premature birth and a serious lung disease called bronchopulmonary dysplasia. Prematurely born babies with this condition may have long-term breathing problems such as asthma and they may require oxygen at home, respiratory medications, more doctor visits and they're more likely to be re-admitted to hospital.

"I have been studying the association between Ureaplasma respiratory infection and bronchopulmonary dysplasia for more than 20 years. A key question is whether this bacteria is causing ill health in newborns and, if so, whether eliminating the bacteria improves outcomes for these very small babies."

Professor Viscardi studied a group of 121 babies born between 24 and 28 months' gestation (around six months). Half of the babies were treated with a three-day course of azithromycin (20 mg per kg of the baby's weight per day), while the other half were given a placebo. All were tested for the presence of Ureaplasma bacteria in their noses and windpipes before and after treatment, and followed up for their first year of life.

The researchers found that 36% of all the babies in the study were Ureaplasma-positive, but this rose to 45% among the most premature babies born between 24 and 26 weeks' gestation.

Compared to babies without the infection or those who only had the bacteria detected in their nose, these very premature babies who had Ureaplasma in their windpipe at birth were less likely to survive (71% compared to 90% and 100%), and they were more likely to develop bronchopulmonary dysplasia and other respiratory problems during their first year of life (67% compared to 50% and 21%).

The study suggests that the three-day course of azithromycin treatment was safe for these premature babies and effective at eradicating Ureaplasma bacteria.

The researchers caution that this is a small study, but say the results also show that the likelihood of death or severe respiratory disease one year after birth was lower in babies treated with azithromycin compared to babies who were Ureaplasma-positive and treated with placebo (33% compared to 86%).

Professor Viscardi added: "We believe that Ureaplasma bacteria can interact with a mother's and baby's immune defences leading to a chronic infection with persistent inflammation. This can then lead to premature labour or early rupture of the membranes. In a premature baby, inflammation alters the development of the immature lung, contributing to the development of bronchopulmonary dysplasia.

"This study shows that Ureaplasma respiratory infection is very common in extremely premature infants and clinicians should consider testing for this infection in those newborns who are at risk. It also suggests that the three-day course of azithromycin is safe and effective. However, there is not yet enough evidence to recommend routine treatment of Ureaplasma respiratory infection and we are planning a larger clinical trial to address this question."

Professor Viscardi and her team will continue to follow the babies in this study and hope to conduct a larger trial to show whether azithromycin treatment improves outcomes in the longer-term.

Professor Tobias Welte of Hannover University in Germany is President-Elect of the European Respiratory Society and was not involved in the study. He said: "There is currently no consensus among neonatal specialists on whether to test for Ureaplasma, or whether to give treatment if the bacteria are detected. Ureaplasma are not picked up by routine tests for infections and require specialised lab tests. These bacteria are not considered dangerous in healthy people so many clinicians do not think treatment is necessary.

"However, this study suggests that in very premature babies this infection is linked with bronchopulmonary dysplasia and a higher risk of death. Larger clinical trials are needed to clarify the importance of detecting Ureaplasma in premature babies and to show whether treatment with antibiotics is beneficial. Until then, antibiotic treatment should not be used routinely."

Two new studies by scientists at Scripps Research are bringing Ebola virus's weaknesses into the spotlight, showing for the first time exactly how human and mouse antibodies can bind to the virus and stop infection--not only for Ebola virus, but for other closely related pathogens as well.

The research suggests antibodies like these could be key ingredients in versatile lifesaving therapeutics capable of neutralizing all members of the Ebolavirus genus.

"This is like understanding how to kill five or six birds with one stone," says Erica Ollmann Saphire, PhD, professor at Scripps Research and senior author of the new papers, published recently in mBio and the Journal of Infectious Diseases. "The different viruses in the Ebolavirus genus vary in their structure, but all these different viruses have the same outbreak potential. We need a therapeutic approach that can target them all."

A major challenge in treating what we call Ebola virus is that it isn't just one pathogen but five. Members of the genus Ebolavirus include Ebola virus, Sudan virus, Bundibugyo virus, Taï Forest virus and Reston virus. Each of these viruses is up to 50 percent different in amino acid sequence, making it tough to develop broad treatment strategies. For example, the Sudan and Bundibugyo viruses were responsible for 40 percent of Ebola cases before 2013, yet current experimental Ebola therapies can't neutralize them.

Adding to the threat, all members of the Ebolavirus genus could mutate to escape immune system defenses and fight off drug therapies.

The new research shows that antibodies that bind to a site on the viral "fusion loop" can neutralize all known ebolaviruses. The fusion loop is part of the machinery that the virus uses to fuse with human cells and initiate infection. Targeting this peptide could present an opportunity to develop a universal therapy for infections caused by all five members of the Ebolavirus genus.

For the mBio study, the researchers focused on a human antibody called ADI-15878. This antibody was found in the blood of an Ebola virus survivor and is the only human antibody ever found to neutralize all five members of the Ebolavirus genus.

So how does ADI-15878 do it?

Using a high-resolution structural technique called X-ray crystallography, the scientists modeled the interaction between the antibody and the viral glycoprotein (the protein that enables the virus to infect a cell). Ebola's glycoprotein is covered with sugars that help to mask the virus from detection by the body's immune system. The team observed that ADI-15878 binds directly to one of these sugars alongside a paddle-like structure on the fusion loop. Part of the antibody then dips down and binds into a pocket that is normally hidden by another part of the viral glycoprotein.

"It's really cool to see that this antibody has found a way to bind into a cryptic, conserved pocket despite the proximity of sugars and other pieces of the virus that effectively hide this region from the immune system" says mBio study first author Brandyn West, PhD, a research associate at Scripps Research.

The researchers hypothesize that this action locks two important parts of Ebola's fusion machinery together, making it impossible for the virus to get into human cells. The fusion loop is a key piece of the Ebola virus entry machinery, so its structure is what scientists refer to as highly conserved--meaning the virus can't easily mutate the fusion loop to escape immune detection without compromising the ability of the virus to infect cells. If antibodies targeting this structure were included in therapies or elicited through vaccines, these antibodies should provide broad protection.

But was ADI-15878 just a one in a million antibody from a lucky human survivor?

The second paper the lab published this week in the Journal of Infectious Diseases shows that such antibodies are not out of reach. In this work, the scientists showed that a mouse which had been sequentially immunized with Ebola virus and then Sudan virus also had a broadly protective antibody response. The researchers demonstrate that an antibody, termed 6D6, from this mouse binds to the same region as ADI-15878. The immunization study provides more evidence that this part of the fusion loop is a promising target for vaccine design and therapies.

"Both the human and mouse antibodies were able to neutralize all known types of Ebola," explains Jacob Milligan, PhD, research associate at Scripps Research and first author of the Journal of Infectious Diseases study.

It could be possible, the researchers say, for therapeutics to include antibodies that work like ADI-15878. Researchers working on Ebola vaccines could also design molecules that look like this region of the fusion loop. These molecules, called immunogens, teach the human immune system which piece of the virus to target.

"We're hot on the trail of immunogen design strategies to produce more of these neutralizing antibodies," Ollmann Saphire says.

Taking high dose folic acid supplements in later pregnancy (beyond the first trimester) does not prevent pre-eclampsia in women at high risk for this condition, finds a randomised controlled trial published by The BMJ today.

However, taking low dose folic acid supplements before and during early pregnancy to prevent birth defects, such as spina bifida, is still strongly recommended for all women, say the researchers.

Pre-eclampsia is a serious condition where abnormally high blood pressure and other complications develop during pregnancy. It affects about 3-5% of pregnancies and is dangerous for both mother and child.

Previous observational studies have shown a potential protective effect, but findings have been inconsistent, and there is currently no clear guidance for the use of high dose folic acid to prevent pre-eclampsia in women with risk factors for the condition.

So an international research team decided to conduct a randomised trial - the Folic Acid Clinical Trial (FACT) - to evaluate the effect of high dose folic acid supplementation beyond the first trimester of pregnancy on the risk of developing pre-eclampsia among pregnant women already at high risk for this condition.

They included 2,301 pregnant women who were between 8 and 16 weeks' pregnant at the start of the study and had at least one risk factor for pre-eclampsia (existing high blood pressure, pre-pregnancy diabetes, twin pregnancy, pre-eclampsia in a previous pregnancy, or a body mass index of 35 or more).

Women were randomised to receive either daily high dose (4 mg) folic acid or placebo in addition to up to 1.1mg of folic acid throughout pregnancy.

Information on personal characteristics and medical history was recorded and participants had a total of four follow-up visits during the study period.

After taking account of factors that could have affected the results, they found that pre-eclampsia occurred in 169 out of 1,144 (14.8%) women in the folic acid group and 156 out of 1,157 (13.5%) in the placebo group. There was no evidence of differences between the groups for any other adverse outcomes.

The researchers therefore conclude that high dose folic acid supplementation beyond the first trimester has no benefit for preventing pre-eclampsia. And they suggest that "high dose recommendation should now cease, and the search for an effective and acceptable strategy to prevent pre-eclampsia must continue."

In a linked editorial, Professor Lucy Chappell and colleagues stress that the lack of benefit reported in this trial "must not detract in any way from the importance of folic acid supplements for the prevention of neural tube defects."

However, they say these findings "are another disappointment in the long search for a more effective measure to prevent pre-eclampsia" and they call for continued efforts towards a global reduction in pre-eclampsia related deaths.

Half of clinical trials on the EU register have not reported results, despite rules requiring results to be posted within 12 months of completion, finds a study published by The BMJ today.

The findings show that, although compliance with EU rules has been poor overall, trials with commercial sponsors are substantially more likely to have posted results than trials with non-commercial sponsors, such as universities, hospitals, governments and charities. They also show that EU registry data commonly contain inconsistencies that might prevent even regulators assessing compliance.

The results of clinical trials are used by clinicians, patients, and policy makers to make informed choices about which treatments work best.

The European Commission therefore requires all trials conducted in Europe on medicinal products to report results directly on to the EU Clinical Trials Register (EUCTR) within 12 months of trial completion; but compliance has never been assessed.

So a team of researchers, led by Dr Ben Goldacre at the University of Oxford, set out to assess compliance with these rules, explore factors associated with non-compliance, rank sponsors by compliance, and create a website for live ongoing audit of compliance.

Of 7,274 trials where results were due, they found that 49.5% reported results.

Trials with a commercial sponsor were substantially more likely to post results than those with a non-commercial sponsor (68% v 11%), as were trials by a sponsor who conducted a large number of trials (78% v 18%). More recent trials were also more likely to report results.

Unexpectedly, the researchers also found extensive evidence of errors, omissions, and contradictory data in EUCTR - notably, that 29.4% of trials marked as "completed" gave no completion date, which prevents ascertainment of compliance with reporting requirements.

The paper also describes the development of the EU TrialsTracker website, available online at EU.trialstracker.net. This website gives detailed information on the trial reporting performance of every individual drug company, university and hospital conducting clinical trials in Europe.

It shows which sponsors are the best or worst at complying with the law, and gives detailed information on the individual trials that have failed to report results onto the trials register. The information on EU.trialstracker.net updates every month, so sponsors who report more trials will find their improved performance reflected on the website.

"To our knowledge this is the first study of compliance with European Commission requirements on trial reporting," say the researchers.

"We have found strong evidence that the European Commission guideline, requiring all trials' results to be reported on EUCTR within 12 months of completion, is commonly being breached. Sponsors doing fewer trials, and non-commercial sponsors such as universities, have particularly low reporting rates."

They conclude: "We hope that the accessible and timely information on the compliance status of each individual trial and sponsor provided by our EU.trialstracker.net will help to improve reporting rates".

People who have long-term raised blood pressure have an increased risk of aortic valve disease (AVD) - problems with the valve that controls how blood is pumped from the left ventricle of the heart out into the main artery, the aorta.

In a study of 5.4 million adults in the UK, published in the European Heart Journal [1] today (Thursday), researchers found that above a systolic blood pressure [2] of 115 mmHg, every additional 20 mmHg was associated with a 41% higher risk of aortic stenosis (AS) and a 38% higher risk of aortic regurgitation (AR) later in life. Compared to people who had a systolic blood pressure of 120 mmHg or lower, those with systolic blood pressure of 161 mmHg or higher had more than twice the risk of being diagnosed with AS and were nearly twice as likely to be diagnosed with AR during follow-up.

The findings suggest that controlling blood pressure, even at levels below the threshold currently defined for hypertension of 140/90 mmHg, may be a way to prevent these conditions [3]. "These findings collectively suggest that AS and AR might be partially preventable with potential implications on clinical practice guidelines for prevention of cardiovascular disease in general and valvular heart disease and hypertension in particular," write the authors of the EHJ paper.

AS is a condition in which the valve that opens and closes when blood is pumped out of the left ventricle becomes narrowed and stiff due to calcium building up. When this happens, the valve fails to work effectively, making it harder for the heart to pump blood to the rest of the body. AR occurs when the valve doesn't close properly, allowing some blood to leak back into the left ventricle.

During an average follow-up time of more than nine years, 20,680 (0.38%) of the 5.4 million patients in the study were diagnosed with AS alone and 6440 (0.12%) were diagnosed with AR alone. The average age at the time of diagnosis was 64 years and 57 years for AS and AR respectively.

Researchers, led by Kazem Rahimi, deputy director and associate professor of cardiovascular medicine at The George Institute for Global Health, University of Oxford, UK, analysed data from electronic health records for the UK Clinical Practice Research Datalink from January 1990 to December 2015. The CPRD database contains anonymised patient data from 674 general practices in the UK. The patients included in this analysis were aged between 30 and 90 years, and none had any known heart or blood vessel diseases at the time of their earliest blood pressure measurement.

An average of nearly seven blood pressure measurements per patient were taken during the study period, which helped to estimate the patient's actual blood pressure better. The ability to collect data over a long period of time, combined with the large number of patients, makes this the first study substantial enough to investigate the link between blood pressure and aortic valve disease and how it changes with age and with different blood pressure levels.

Professor Rahimi said: "The study shows that serious valvular heart diseases that are common at old age are not simply due to aging. Long-term exposure to higher blood pressure is a strong and potentially modifiable risk factor for aortic stenosis and regurgitation at every level of typical blood pressure, not only in those who are classified as having hypertension. Blood pressure should be considered as a major risk factor for aortic valve disease, much in the same way as we think of elevated blood pressure as a risk factor for atherosclerotic disease. The study suggests that the associations are causal, but this requires further confirmation."

Previous research has suggested that the mechanism involved in the link between blood pressure and AVD could be that higher blood pressure can cause cell damage leading to a loss of elasticity in the aorta and stiffening of the aortic valve.

Limitations of the study include the possibility that raised blood pressure may be an indication of an underlying problem with arterial stiffness that is caused by something else. To investigate this further, the researchers are carrying out a study that uses genetic indicators for higher blood pressure that are not affected by environmental factors. Another limitation is the use of data from a general practice registry, which might be prone to errors in measuring blood pressure, other factors that might affect the results, and patient outcomes.

In an editorial [4] to accompany the research paper, Dr Stefano Masi from the Department of Clinical and Experimental Medicine, Università di Pisa, Italy, and Dr Alberto Giannoni from the Fondazione Toscana Gabriele Monasterio, Pisa, who were not involved with the research, write that the study "provides the first solid evidence supporting the need for a radical shift in the approach to AVD. Indeed, over the last few years, the research on valvular heart disease has been focused on improving treatment rather than prevention strategies.....Thus, the findings provided by Rahimi et al might be considered the first step towards a change in the management of AVD and likely to influence future clinical trials and guidelines. Current European guidelines for the management of arterial hypertension do not consider AVDs as manifestations of heart damage related to hypertension and, consequently, do not suggest accurate assessment of aortic valve function and structure in patients with arterial hypertension. Also, they might stimulate new lines of research, particularly imaging studies, with the scope of identifying early alterations of the aortic valve in patients with hypertension that might be highly predictive of future AVD".

The proportion of people living with AS is estimated to be around 0.4% of the population in the USA, although the prevalence increases with age; in the US, 0.02% of 18-44-year-olds have AS, but 2.8% of people aged 75 and over are diagnosed with it. For AR the corresponding prevalence in these age groups is estimated to be 0.2% and 2% respectively, and the prevalence for AS and AR is similar in Europe. The number of people diagnosed with severe aortic valve disease has grown steadily in recent years and is expected to continue with the aging of populations.

Some 23 million prescriptions for opioid painkillers were written in the UK in 2014 at a cost of around £322 million. Misuse is becoming a significant public health issue, including in the US, where the death rate from opioid misuse has quadrupled over the past 15 years, they point out.

But it's not clear whether the rise in opioid use is being driven by need or inappropriate prescribing. To try and find out, the researchers drew on the responses of 5711 people to the national Health Survey for England for 2011.

In 2011, the survey included questions on chronic pain, defined as lasting three or more months, its intensity, its impact on routine activities of daily living, and whether opioids had been prescribed to treat it.

The North East, North West, and Yorkshire and the Humber regions denoted the North of England, while London, East of England, West Midlands, East Midlands, South East, and South West regions denoted the South.

The prevalence of chronic pain was higher in the North than it was in the South: just under 37 per cent compared with 35 per cent. Across the nine regions, the highest prevalence was in the North East (43%), and the lowest in London (29%).

Pain intensity was greater in the North, where nearly 12.5 per cent of respondents said their pain was moderately or severely limiting, compared with just over 9 per cent of Southerners.

Levels of anxiety and poor general health were also higher in the North than in the South.

But despite similar levels of chronic pain in the North and the South, opioid use was higher in the North: 2.5 per cent vs 1.7 per cent.

And while the use of opioids was associated with the intensity of chronic pain, after taking account of potentially influential factors, such as anxiety levels, it was also linked to educational attainment and general health.

Households in the higher income brackets were significantly more likely to use opioids than those in the lowest, as were those where respondents had reported 'bad' or 'very bad' general health compared with those who said their health was 'very good.'

This is an observational study, and as such, can't establish cause. Nor were the researchers able to differentiate between strong and weak opioids or gather information on dose. But the findings chime with those of other similar studies, they point out.

"Our results are timely, and show that, in England, the prescribing of opioid analgesics is largely driven by health need (pain)," they explain.

"Thus to develop future strategies going forward, and avoid a potential 'opioid epidemic,' as observed in the USA, it is important that consideration is given to other ways of managing chronic pain," they add.

"Given our findings, more needs to be done--at a national level--to support prescribers to manage people who have chronic pain, without the need to initiate opioid analgesics."

Your genes can determine how your heart rate and blood pressure respond to exercise - and may act as an early warning of future problems with your heart or blood vessels - according to new research published in The Journal of Physiology.

When people exercise, their heart rate and blood pressure increase. However, the magnitude of this increase is different for different people. Previous research has shown that abnormally large increases in blood pressure during exercise makes it more likely that people will suffer from future high blood pressure. Therefore understanding why people react differently to exercise is important as this can help to identify risk factors and enable early monitoring or treatment of individuals at risk.

Until now it has not been known why the response to exercise varies between different people. This new research has found that genetic differences in receptors found in skeletal muscles can contribute to this different response. Receptors are groups of specialised cells that detect changes in the environment and cause some kind of response. The scientists identified that the presence of two common genetic mutations in receptors found in skeletal muscle led to higher blood pressure during exercise compared to people who did not have them, particularly in men.

The research conducted by the University of Guelph (Canada), involved measuring heart rate and blood pressure of 200 healthy young men and women before and during a handgrip exercise, plus analysing their DNA for genetic risk factors.

While the study is limited by the sample size and the specific type of exercise used, the effect of these genetic variants in the skeletal muscle receptors was significant. Further work will be needed to look at other types of exercise and to replicate this finding.

Philip J. Millar, corresponding author of the study commented on the findings of the results 'This research suggests the presence of these receptors can contribute to larger blood pressure responses during exercise - a risk factor for future problems with the heart or blood vessels. It is important to examine why we saw this difference mainly in men, and to understand the specific mechanisms behind how these genetic variants influence their heart rate and blood pressure responses to exercise.'

Differences in the DNA within the mitochondria, the energy-producing structures within cells, can determine the severity and progression of heart disease caused by a nuclear DNA mutation. A new study found that when a nuclear DNA (nDNA) mutation was combined with different mild variants of mitochondrial (mtDNA) in mice, the severity of heart disease was markedly different. One mtDNA variant dramatically worsened heart disease, while another mtDNA variant conferred protection from heart damage.

Greater understanding of these genetic interactions may eventually permit improved diagnostics and therapies for patients with cardiomyopathy, a leading worldwide cause of heart failure.

"When people think of genetic changes, they most commonly consider mutations and variations in nuclear DNA--the familiar genes within cell nuclei," said study leader Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at Children's Hospital of Philadelphia. "But the DNA within mitochondria may have a profound effect on disease symptoms, depending on how it interacts with nuclear DNA. This research delineates some of those processes in the development of cardiomyopathy."

Wallace and colleagues, including first author Meagan J. McManus, PhD, also from CHOP, describe their work in an online paper Aug. 30, 2018 in the journal Cell Metabolism.

Like many other metabolic and degenerative diseases, cardiomyopathy, a group of diseases characterized by progressive weakening of the heart muscle, can progress slowly or become sharply severe, even across patients who share the same disease-causing mutation. One example is cardiomyopathy induced by a mutation in the nuclear gene ANT1. "Such broad phenotypic variability isn't explained by the governing principles of classic Mendelian genetics," said McManus. "Since mtDNA plays by its own rules, it could be the missing piece in this genetic puzzle."

McManus added that clues to this variability came from a 2013 study in which Wallace and colleagues showed that mtDNA variation correlated with cardiomyopathy progression in Mennonite families in Pennsylvania with heart disease caused by a recessive nDNA mutation. The scientists found a link between disease course and mtDNA haplogroups, ancient lineages that reflect ancestral human migrations, a long-standing research focus of Wallace's throughout his pioneering career in mitochondrial genetics.

However, this clinical correlation didn't provide conclusive proof that mtDNA determined nDNA expressivity--the degree to which a mutation exerts health-related effects. For this purpose, the research team developed mouse models with specific changes in the mtDNA and crossbred them to Ant1-- mice, the genetic equivalent of the human ANT1 mutation implicated in cardiomyopathy.

One mtDNA variant had a change in amino acid 25 (P to L) in the gene ND6 (ND6P25L); the other mtDNA variant had a change in amino acid 421 (V to A) in the gene COI (COIV421A). In isolation, each mitochondrial variant has only mild effects on heart function in mice, but they show strikingly different effects when they interact with the nuclear gene mutation.

Ant1-- animals with the mtDNA ND6P25L variant aged rapidly and died of heart failure, while animals with the mtDNA COIV421A variant lived longer, with better heart function. The team then investigated the basis of this relationship at the molecular level. Interestingly, the mtDNA variants shifted mitochondrial shape and size in opposing directions. When combined with nDNA Ant1-- , these changes in morphology conferred by the mtDNA were consistent with their respective functional consequences. Ant1-- mice with the ND6P25L variant had smaller, abnormal mitochondria and increased age-dependent energetic decline. Ant1-- mice with the COIV421A variant had larger mitochondria, and better health and survival.

Given that mtDNA variation determined the severity of the cardiomyopathy phenotype, the next question was whether mtDNA variation could also explain the age-related onset of the symptoms. "In normal aging, our cells lose the ability to clear out and replace defective mitochondria, which may lead to increased mtDNA damage and the accumulation of mutations," said McManus. "To determine if this was the case, we measured somatic mtDNA mutation levels across the lifespan of all the mtDNA-nDNA combination strains. The correlation was practically perfect: the somatic mutation rate predicted the severity of cardiomyopathy and mortality." Thus, the accumulation of somatic mtDNA mutations can account for the delayed-onset and progressive course of age-dependent disease.

Although follow-up studies are necessary to determine how closely the findings in animals predict similar processes in humans, the current study provides a new animal model to further investigate possible future clinical treatments. To take one example, there were some indications that abnormal physiology in the ND6P25L-Ant1-- mice may include defects in mitochondrial fusion (a way that mitochondria adapt to stress), and in autophagy, the cell's normal cleanup process. If so, future cardiomyopathy patients with a corresponding genetic risk might benefit from future treatments that boost these functions.

"This study proves that mtDNA variation can explain the seemingly aberrant behaviors of classical Mendelian disease genes. Hence, characterizing mtDNA variation should be an important adjunct to studies of nuclear DNA diseases," concluded Wallace. "This finding may offer opportunities to develop new strategies to treat heart disease, and possibly other conditions affected by interactions between nuclear and mitochondrial genes."

Continuity Between Patient and Prescribing Physician Reduces Risky Opioid Prescriptions

An ongoing relationship between patients with long-term opioid use and the doctors who prescribe the medication is associated with fewer risky opioid prescriptions and fewer opioid-related hospitalizations. A retrospective cohort study analyzed data from Oregon's Prescription Drug Monitoring Program, Vital Statistics, and hospital discharge registry for more than 78,000 patients with long-term opioid use. Patients with higher continuity with the physician prescribing opioids received fewer risky prescriptions (based on multiple prescriber metrics) compared to patients in the lowest continuity quartile, and were less likely to be hospitalized for opioid-related causes. However, on average, patients with long-term opioid use had significantly lower continuity scores than patients with long-term use of a stimulant or benzodiazepine, suggesting that efforts are still needed to improve opioid prescribing continuity. This study, which adds to the limited literature on prescriber continuity and opioids, suggests that continuity with the prescribing physician is an important factor associated with reducing opioid harms.

Opioid-Prescribing Continuity and Risky Opioid Prescriptions

Sara E. Hallvik, MPH, et al.
HealthInsight Oregon, Portland, Oregon
http://www.annfammed.org/content/16/5/440

Young Physicians Feel Unprepared to Treat Opioid Use Disorder with Buprenorphine

Few early career family physicians report being adequately trained to provide buprenorphine treatment for opioid use disorder and even fewer provide it in their practices. Analyses of data from 1,979 family physicians who completed residency in 2013 found that 10 percent (n=198) felt adequately trained during residency to provide buprenorphine, and seven percent (n=138) reported providing buprenorphine treatment in their current practice. Of those currently providing buprenorphine, 46 percent (n=63) reported they were prepared in residency to do so.
However, more than two-thirds of those residency-trained to provide buprenorphine are not doing so in practice, suggesting logistical barriers to providing buprenorphine after graduation. According to the authors, promoting residency training in buprenorphine treatment and overcoming barriers to its provision in practice could increase access to addiction services.

Buprenorphine Provision by Early Career Family Physicians

Sebastian T. Tong, MD, MPH, et al.
Virginia Commonwealth University, Richmond, Virginia
http://www.annfammed.org/content/16/5/443

Medical Homes with After-Hours Care Are Associated with Increased Emergency Department Use

Enrollment in a medical home mandated to provide after-hours care is associated with a small increase in emergency department visit rates. This finding comes from a large-scale study of all adults in Ontario, Canada, enrolled in medical homes between April 1, 2005 and March 31, 2012 (n=2,945,087). Researchers found that in the years before enrollment in a medical home, the emergency department visit rate increased by 0.8 percent per year, while after medical home transition the rate increased by 1.5 percent per year. Enrollment in a medical home was also associated with a decrease in the overall primary care visit rate but a small increase in continuity of care. The authors hypothesize that the decline in the primary care visit rate associated with medical home enrollment may help explain the counter-intuitive increase in emergency department visits. Canada's health care reforms were implemented in the context of a relatively fixed primary care workforce, and increased after-hours primary care may have been offset by a decrease in regular office hours. Another possible explanation is that introducing mandatory after-hours provision with medical homes fueled greater demand for health care. This study highlights the importance of prospectively evaluating reform efforts that aim to improve access to primary care after hours, the authors state.

Emergency Department Use and Enrollment in a Medical Home Providing After-Hours Care

Tara Kiran, MD, MSc, et al.
St. Michael's Hospital, Toronto, Ontario, Canada
http://www.annfammed.org/content/16/5/419

Social Isolation is Associated With Negative Experience in Primary Care

Among older people, social isolation is associated with a negative experience as a primary care patient. A cross-sectional study in 28 primary care practices in Japan utilized screening tools to assess social isolation and patients' experiences of key domains of primary care: first contact, in which the primary care clinician is the patient's usual entry point into the health care system; longitudinality or duration of the patient-physician relationship; coordination of care by the primary care clinician; comprehensiveness of services available and provided; and community orientation of care. Among 465 patients age 65 years or older, social isolation was negatively associated with overall primary care assessment scores and was significantly associated with longitudinality, comprehensiveness of services provided, and community orientation. Comprehensiveness of services provided had the strongest association with social isolation. These findings, the authors suggest, can contribute to our understanding of how social isolation influences health. They call for targeted interventions for socially isolated elderly patients aimed at improving their experience of primary care.

Social Isolation and Patient Experience in Older Adults

,p>Shunichi Fukuhara MD, DMSc, et al.
Kyoto University, Kyoto, Japan
http://www.annfammed.org/content/16/5/393

The Loss of Professional Connections and the Doctors' Dining Room

Historically, family physicians were part of a connected professional community sustained in large part through informal gatherings of clinicians in hospitals, clinics, and professional organizations. Family physician John Frey reflects on how, as an intern in the 1960s, the hospital dining room for doctors was his source of political and medical acculturation and socialization. The demise of doctors' dining rooms in subsequent years, he suggests, reflects the professional isolation that characterizes primary care practice today, with fewer opportunities to interact with colleagues, particularly those outside the physician's practice setting. For most medical professionals, he observes, lunch has become a solitary pursuit in front of a computer screen, rather than a shared collegial experience. Frey calls for more social interaction during medical training and more emphasis on being part of a community of professionals: "Not valuing time with other physicians or making informal conversations possible leads to a soulless efficiency and professional isolation that drains physicians of our ability to help ourselves, help each other and help patients," he writes.

Professional Loneliness and the Loss of the Doctors' Dining Room

,p>John J. Frey III, MD
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
http://www.annfammed.org/content/16/5/461

Editorial: Articles Provide New Insights into Loneliness, Social Isolation and Health

An editorial by Professor Timothy Daaleman suggests that the articles by Aoki et al (social isolation and patient experience) and Frey (loss of the doctors' dining room) provide a uniquely primary care perspective that adds new ways of thinking about loneliness, social isolation and health. By positing that factors in the medical encounter can be associated with social connectedness and that personal physicians may be a source of intimate connection for patients experiencing loneliness, the Aoki study connects directly to core tenets of primary care. "If continuity of care is associated with the improved receipt of preventive services and reduced hospitalizations, could the primary care environment and the tenor of continuity visits be mediators of health outcomes in lonely or socially isolated patients?" Daaleman asks. Frey's recollections not only raise important issues (physician loneliness and isolation) that have received insufficient attention in discussions of burnout and professional dissatisfaction; they also illustrate the physical and relational components of safe spaces that facilitate meaningful conversation and relationship-building. Taken together, these two articles provide insights for those researching social isolation and loneliness, for medical directors who can promote social connection, and for physicians experiencing professional isolation. In all of their endeavors, according to Daaleman,"it is our connectedness with others that matters."

The Long Loneliness of Primary Care

Timothy P. Daaleman, DO, MPH
University of North Carolina, Chapel Hill, North Carolina
http://www.annfammed.org/content/16/5/388

Preliminary Research Suggests Possible Link Between Added Fructose and Allergies

New research provides preliminary evidence of a possible link between beverages that are high in free (or added) fructose and allergic symptoms or allergic sensitization in children and adolescents. Analyses of 860 children and 1,142 adolescents in the 2005-2006 National Health and Nutrition Examination Survey do not yield entirely consistent findings, but lend some support to an association between allergy and high intake of beverages with excess free fructose. After controlling for potential confounders, children who consumed non-diet fruit drinks at least five times per week had 2.5 times greater odds of allergic sensitization than children who consumed such beverages one to three times per month. The association was stronger among adolescents; those who consumed beverages with excess free fructose one to four times per week or at least five times per week were five times more likely to have allergic symptoms than those who seldom drank such beverages. Adolescents consuming apple juice at least five times per week were twice as likely to have allergic sensitization than those who seldom consumed such beverages. These findings provide some evidence for the hypothesis that there may be a link between intake of beverages high in free fructose and allergic symptoms or allergic sensitization in children and adolescents. Longitudinal studies are needed to confirm the causality and to clarify underlying mechanisms.

Excess Free Fructose Beverages and Allergy in Children and Adolescents: Results From NHANES 2005-2006
,p>Xueyan Wang BS, et al
Beijing Shijitan Hospital, Beijing, China
a target="_blank" href="http://www.annfammed.org/content/16/5/408">http://www.annfammed.org/content/16/5/408

New Tool Helps Identify Patients at Risk of Substantial Impairment From Dizziness

A new tool can help primary care physicians identify older patients at risk of an unfavorable course of dizziness (i.e., six months of substantial dizziness-related impairment). The risk score, based on a validated prediction model, consists of four easily obtained predictors of dizziness: age, history of arrhythmia, score on the Dizziness Handicap Inventory (screening version), and looking up as a trigger for dizziness. The authors suggest that the tool can activate primary care physicians to target potential contributing factors for high risk of an unfavorable course of dizziness, even when the cause of dizziness is unknown.

Predicting an Unfavorable Course of Dizziness in Older Patients

Hanneke Stam, MD, et al
Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands
Predicting an Unfavorable Course of Dizziness in Older Patients

>Editorial: The Promise and Challenges of Clinical Prediction Rules

A related editorial explores both the promise and challenges of clinical prediction rules. Clinical prediction rules have gained popularity as tools to standardize and increase the accuracy and consistency of clinicians' diagnostic and prognostic assessments and management decisions. If, however, they are to meet their promise and improve quality of care, the authors argue, they must be evaluated on relevant processes of care and patient outcomes. In light of the challenges in evaluating their effectiveness, it is important to select clinical prediction rules in relevant clinical domains with proven predictive accuracy for impact analysis, anticipate barriers to the impact of clinical prediction rules, and consider how best to implement these tools to improve care processes, patient outcomes and health system efficiency.

Clinical Prediction Rules: Challenges, Barriers, and Promise

Emma Wallace MB, PhD et al
Royal College of Surgeons in Ireland, Dublin, Ireland
http://www.annfammed.org/content/16/5/390

Documenting Social Determinants of Health in EHRs is Feasible but Challenging

A growing awareness that social factors--the conditions in which people live, work and play--influence health suggests that it is crucial to document such information in patients' electronic health records. A new study has found that adopting EHR tools to systematically document social determinants of health in primary care is feasible, but substantial barriers exist. In this pilot study, researchers implemented social determinants data tools in three Pacific Northwest community health centers. Among 1,130 patients for whom social determinants data were collected, 97 to 99 percent (n=1,098) had one or more social need documented in the EHR, with 210 (19 percent) receiving an EHR-documented social determinants referral. Fifteen to 21 percent of patients with a documented social need wanted help from the clinic to address the need. Although the study identified many barriers to implementing and designing tools and workflows, participating community health centers successfully documented social determinants in the EHR and continued to do so post-study. The authors explain that, to meet the growing national emphasis on documentation of social determinants of health in EHRs, a wide range of factors and substantial gaps in knowledge must be addressed.

Adoption of Social Determinants of Health EHR Tools by Community Health Centers

Rachel Gold, PhD, MPH, et al.
Kaiser Permanente, Portland, Oregon
http://www.annfammed.org/content/16/5/399

Health Care Organizations Use Complex Interventions to Help Patients Find Employment

Employment status is a key social determinant of health. According to a new analysis, when health care organizations try to help patients find employment, they do so through innovative, complex interventions. Researchers in Toronto conducted a systematic review of 88 existing studies of interventions in a variety of health settings (e.g., primary care practices, hospitals, emergency departments, community health centers, and health centers in prisons) to help unemployed patients gain employment. Most articles (89 percent) focused on people with mental illness. The majority of studies (74 percent) succeeded in helping patients gain employment. Characteristics of successful interventions included, (1) a collaborative multidisciplinary team with regular communication, (2) a comprehensive package of services, (3) individualized components, (4) a holistic view of health and social needs, and (5) prospective engagement with employers. The authors suggest that primary care practices can begin addressing employment issues by raising awareness of employment as an important social determinant of health, training staff (e.g., social workers, community health workers and system navigators) to provide employment support, and building relationships with employment services. The authors call for research to evaluate the long-term impact of employment interventions across different health care settings and with diverse patients.

Employment Interventions in Health Settings: A Systematic Review and Synthesis

Andrew D. Pinto MD, CCFP, FRCPC, MSc, et al.
The Upstream Lab, St. Michael's Hospital, Toronto, Ontario, Canada
http://www.annfammed.org/content/16/5/447

POEMs Illustrate Breadth and Evolution of Primary Care Practice

POEMs (Patient Oriented Evidence that Matters) are studies that address a relevant clinical question, demonstrate improved patient-oriented outcomes, and have the potential to change practice. This report identifies POEMs in each of the last 20 years that were highest ranked by the originators of POEMs for having recommended a major and persistent change in practice. POEMs have recommended novel effective interventions (e.g., beta-blockers in heart failure and a longer interval between Pap smears for most women), abandoning ineffective practices (e.g., routinely recommending hormone replacement therapy for postmenopausal women), and abandoning potentially harmful practices (e.g., intensive blood sugar control for patients with type 2 diabetes mellitus and aggressive therapy for low-grade prostate cancer). These POEMs illustrate the breadth of practice change in primary care and the need for family physicians to have a systematic approach to keeping up with the medical literature.

Top 20 POEMs of the Past 20 Years: A Survey of Practice-Changing Research of Family Physicians

Mark H. Ebell MD, MS, et al.
University of Georgia, Athens, Georgia
http://www.annfammed.org/content/16/5/436

Innovations in Primary Care

Innovations in Primary Care are brief one-page articles that describe novel innovations from health care's front lines. In this issue:

Humanistic Pocket Tool for Compassionate Care - Clinicians caring for homeless veterans have developed techniques, summarized on a pocket card, to remain respectful, empathic and compassionate when interacting with patients with complex behavioral, social or psychosocial issues.
http://www.annfammed.org/content/16/5/467.full

Lessons Learned from Rapid Scaling of Integrated Behavioral Health - Rapid implementation of a system-wide integrated behavioral health program requires strong backing from leadership, buy-in from management and frontline workers, interdisciplinary coordination, a shift in workplace culture, and persistence.
http://www.annfammed.org/content/16/5/464.full

A Simple Effective Technique for Taking an Adolescent Sexual History - Using a pen and exam table paper, a physician creates a simple visual aid during adolescent visits to acquire sexual history information in a comfortable, efficient, and thorough manner.
http://www.annfammed.org/content/16/5/465.full

Mentored Training Positions For Early Career GPs - In Scotland, early career general practitioners can spend two years in a supportive primary care practice developing their skills and receiving mentored training in an additional field e.g., medical education, geriatrics or palliative care.
http://www.annfammed.org/content/16/5/466.full

A recent Finnish study conducted at the University of Jyväskylä showed that adolescents with better aerobic fitness have more compliant arteries than their lower fit peers do. The study also suggests that a higher anaerobic threshold is linked to better arterial health. The results were published in the European Journal of Applied Physiology.

Arterial stiffness is one of the first signs of cardiovascular disease, and adults with increased arterial stiffness are at higher risk of developing clinical cardiovascular disease. However, arterial stiffening may have its origin already in childhood and adolescence.

"In our study we showed for the first time that the anaerobic threshold is also related to arterial stiffness," says Dr Eero Haapala, PhD, from the University Of Jyväskylä.

Anaerobic threshold describes the exercise intensity that can be sustained for long periods of time without excess accumulation of lactic acid. The study showed that adolescents with a higher anaerobic threshold also had lower arterial stiffness than other adolescents did.

"The strength of determining anaerobic threshold is that it does not require maximal effort," Haapala explains. "The results of our study can be used to screen increased arterial stiffness in adolescents who cannot perform maximal exercise tests."

Fitness and arterial health can be improved

The results showed that both peak oxygen uptake and anaerobic threshold were related to arterial stiffness in adolescents between the ages of 16 and 19 years. Genetics may explain part of the observed associations but moderate and especially vigorous physical activity improve fitness and arterial health already in adolescence.

"Because the development of cardiovascular disease is a long process, sufficiently intense physical activity starting in childhood may be the first line in prevention of early arterial aging."

The study investigated the associations of directly measured peak oxygen uptake and anaerobic threshold with arterial stiffness among 55 Finnish adolescents between the ages of 16 and 19 years. Peak oxygen uptake and anaerobic threshold were assessed using a maximal exercise test on a cycle ergometer. Arterial stiffness was measured using pulse wave analysis based on non-invasive oscillometric tonometry. Various confounding factors, including body fat percentage and systolic blood pressure, were controlled for in the analyses.

Patients with sepsis are at increased risk of stroke or myocardial infarction (heart attack) in the first 4 weeks after hospital discharge, according to a large Taiwanese study published in CMAJ (Canadian Medical Association Journal).

Sepsis accounts for an estimated 8 million deaths worldwide, and in Canada causes more than half of all deaths from infectious diseases.

Researchers looked at data on more than 1 million people in Taiwan, of whom 42 316 patients had sepsis, matched with control patients in the hospital and the general population. All sepsis patients had at least one organ dysfunction, 35% were in the intensive care unit and 22% died within 30 days of admission. In the total group of patients with sepsis, 1012 had a cardiovascular event, 831 had a stroke and 184 had a myocardial infarction within 180 days of discharge from hospital. Risk was highest in the first 7 days after discharge, with more than one-quarter (26%) of myocardial infarction or stroke occurring in the immediate period and 51% occurring within 35 days.

"We found that within the first 4 weeks after discharge from hospital was the critical period with a markedly elevated risk of [myocardial infarction] and stroke," writes Dr. Chien-Chang Lee, Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan, with coauthors.

The authors also found that younger patients with sepsis aged 20 to 45 years were at higher risk of heart attack or stroke compared to patients over age 75.

This study extends the findings of a Danish study that reported similar trends.

"Based on our study (Han Chinese) and the study in Denmark (European) that reported similar findings for two different ethnic groups, it is likely that these results are generalizable to different populations," write the authors.

They call for further validation of their findings in different populations.

Utilizing new mobile application technology, researchers at The University of New Mexico found that medical cannabis provides immediate symptom relief across dozens of health symptoms with relatively minimal negative side effects.

In two recent studies titled, "Patient-Reported Symptom Relief Following Medical Cannabis Consumption," and "Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions" published in the journals, Frontiers in Pharmacology and Medicines, respectively, UNM Department of Psychology Associate Professor Jacob Miguel Vigil and UNM Department of Economics Assistant Professor Sarah See Stith, document that patients experienced statistically and clinically significant therapeutic benefits when they used cannabis for symptoms ranging from chronic pain to insomnia.

These studies analyzed data collected with the Releaf App, developed by co-authors Franco Brockelman, Keenan Keeling and Branden Hall and currently, the largest repository of user-entered information on the consumption and effects of cannabis use in the United States with nearly 100,000 recorded user sessions.

Since its release in 2016, the commercially developed Releaf App has been the only publicly available, incentive-free patient educational software program designed for recording how individual cannabis usage sessions correspond to immediate changes in symptom intensity levels and experienced side effects.

"If the results found in our studies can be extrapolated to the general population, cannabis could systematically replace multi-billion dollar medication industries around the world. It is likely already beginning to do so." - Jacob Vigil

This electronic assessment tool enables patients to monitor and manage their cannabis consumption decisions under naturalistic conditions while avoiding the limitations of retrospective survey collection methods (e.g., memory bias, social desirability effects) making it an ideal research tool for measuring real-world cannabis use.

In the first study, across 27 different health conditions with symptoms that ranged from seizure disorders to depression, users reported an average symptom reduction of nearly 4 points on a 1-10 scale following the consumption of cannabis in its various product forms, from concentrates to topicals.

The second study focused specifically on the use of raw natural cannabis flower, or 'buds' for treating insomnia, with similar degrees of effectiveness that varied according to characteristics of the flower and combustion methods. Both investigations were supported in part by the University of New Mexico Medical Cannabis Research Fund, which was designed to facilitate the types of biomedical cannabis-based research that historically have been difficult to fund through conventional governmental entities, such as the National Institutes of Health.

Most prescription medications carry a long list of unavoidable negative side effects and risks of serious health concerns and even death, allowing alternative forms of medication to compete for patient preferences and healthcare industry demands. Medical cannabis is rapidly gaining popularity with the largest expansions in use among older people and patients with significant health conditions.

"Observational studies are more appropriate than experimental research designs for measuring how patients choose to consume cannabis and the effects of those choices," said Vigil. "By collecting massive amounts of patient-entered information on actual cannabis used under real-life circumstances we are able to measure why patients consume cannabis, the types of products that patients use, and the immediate and longer-term effects of such use. In other words, many of the important and practical research questions that randomized controlled trials fail to address."

Cannabis has been investigated as a potential treatment for a wide range of medical conditions from post-traumatic stress disorder to cancer, with the most consistent support for the treatment of chronic pain, epilepsy and spasticity. These studies hint at just how wide cannabis' therapeutic potential may be and are among the first to measure how characteristics of cannabis consumed by millions of people in the U.S. every day are likely to affect different types of health disturbances, both in symptom severity levels and experienced positive and negative side effects.

One of the most striking patterns in the current results was the breadth of symptoms that appeared to improve following cannabis consumption. More than 94 percent of cannabis users reported symptom intensity reductions following self-administered cannabis use across the various health conditions measured with the Releaf App. This may reflect the ability of the plant's phytocannabinoids to influence the human endocannabinoid system, which regulates both mental and physical health and behavioral systems.

According to the endocannabinoid deficiency theory, many mental and physical health disturbances result from the dysregulation of the body's innate endocannabinoid system (ECS), often described as a master network of chemical signals that promote physical and psychological homeostasis, or biological state-efficiency. The ECS consists of natural ligands (e.g., anandamide and 2-AG) and receptors (CB1 and CB2) that appear to play a major role in efficient regulation of a basic bodily systems including sleep, feeding (e.g., gut permeability and adipogenesis), libido and fertility, pain perception, motivation, happiness, anxiety, learning and memory, social functioning, autoimmune responses, cellular redox, and cancer pathophysiology.

"In other words and unlike conventional pharmaceutical approaches, which largely target specific neurotransmitter sites, cannabis may act to improve a broad spectrum of symptoms by regulating homeostatic functioning, perhaps best described as a system-modulating rather than symptom-modulating form of therapy," said Vigil. "The medicinal potential of this concept and practical application for treating so many and seemingly diverse health conditions is unlike that of any other single medication currently known to exist."

In addition to therapeutic benefits, these studies also showed that cannabis use is associated with frequent and numerous, yet generally non-serious side effects. Positive and context-specific side effects were far more commonly reported than negative side effects by the Releaf App users, with the most frequent reported side effects being positive (relaxed, peaceful, comfy) and the least frequent side effects being negative (paranoid, confused, headache).

Ultimately, cannabis could find a permanent place among our modern repertoire of medication options if it can treat users' health conditions more effectively and more safely than conventional pharmaceutical remedies. As in the case of insomnia, prescription sleep aids such as antidepressants (e.g., trazodone, amitriptyline, and doxepin), benzodiazepines (e.g., diazepam and lorazepam), gamma-aminobutyric acid (GABA) medications (zolpidem and eszopiclone), and anti-psychotics (aripiprazole, olanzapine, quetiapine and risperidone) are associated with significant clinical drawbacks and heightened risk of morbidity.

The widespread apparent use of cannabis as a sleep aid and for treating myriad other health symptoms underscores the importance of further medical research regarding its risk-benefit profile and the effectiveness of cannabis as a substitute for other substances, including alcohol, over-the-counter and prescription sleep aids, and scheduled medications (e.g., opioids and sedatives).

According to Stith, "The economic impact of cannabis treatment should also be considered given the current burden of opioid and other high-risk prescriptions on healthcare systems, which have been forced to implement costly modifications to general patient care practices, including prescription monitoring programs, drug screening, and more frequent doctor-patient interactions.

"In addition, if the short-term risk-benefit profile of cannabis found in our studies reflects its longer-term therapeutic potential, substitution of cannabis for traditional pharmaceuticals could reduce the risk of dangerous drug interactions and the costs associated with taking multiple medications by allowing patients to treat a constellation of comorbidities with a single treatment modality. "

"If the results found in our studies can be extrapolated to the general population, cannabis could systematically replace multi-billion dollar medication industries around the world. It is likely already beginning to do so," Vigil added.