Body

(Boston)--In an effort to address the opioid epidemic in new, safe and effective ways, increasing access to buprenorphine, without a prescription, could prove helpful for treating persons with opioid use disorder (OUD), according to a Viewpoint in this week's JAMA.

It is estimated that two million people in the U.S. struggle with OUD (approximately 130 die daily from an overdose) while only 20 to 40 percent receive medications such as buprenorphine, methadone and naltrexone to treat this disorder.

The Drug Addiction Treatment Act of 2000 allows physicians to prescribe buprenorphine, a schedule III medication for outpatient treatment of OUD. However, according to the authors, the steps required for patients to initiate buprenorphine treatment and for prescribers to provide buprenorphine are onerous.

"It is not surprising that many patients who require buprenorphine are unable to access this medication. Throughout the process patients can lose motivation and never start the treatment they need. Even after taking the necessary steps, most prescribers who receive a Drug Enforcement Agency waiver do not prescribe buprenorphine to allowable limits," explained corresponding author Payel Roy, MD, instructor of medicine at Boston University School of Medicine.

The authors believe buprenorphine could be offered without a prescription, available behind the counter in a model similar to that used for other medications, while limiting unrestricted access by setting age and quantity limitations. "Limiting quantities to a three-day supply could encourage patients to seek long-term treatment from a clinician for their medical and psychosocial needs. But having the choice to walk into a pharmacy, any time day or night and buy a dose of buprenorphine rather than inject a dose of fentanyl that can kill you, seems a good option," said co-author Michael Stein, MD, professor and chair, Health Law, Policy & Management at Boston University School of Public Health.

The authors concede there are several challenges and concerns for providing buprenorphine without a prescription that need to be considered, including the risk associated with taking the drug in combination with other drugs and/or alcohol, the possibility that it may become a gateway drug, the chance that it may be shared or sold, and the lost benefit of long-term physician monitoring.

"However, given the enormous burden of OUD, increased buprenorphine access could lead to reduced health costs, less drug-related criminal activity and lower transmission rates for infectious disease in addition to saving lives," said Roy, a second-year addiction medicine fellow at Boston Medical Center.

Patients with bowel cancer who have stopped responding to a widely used targeted drug could benefit from immunotherapy, a major new study reveals.

Scientists found that bowel tumours which had initially responded to cetuximab before developing resistance became more visible to the immune system - potentially leaving them vulnerable to immunotherapies.

A phase II clinical trial has already begun to test the possible benefit of immunotherapy in patients who have stopped responding to cetuximab.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust teased out the various complex mechanisms by which bowel cancers became resistant to cetuximab. Their study could not only lead to new approaches to treatment but also to tests to assess which patients are likely to develop resistance to cetuximab most rapidly.

The research is published in the prestigious journal Cancer Cell today (Monday) and was largely funded by Cancer Research UK, with additional support from the NIHR Biomedical Research Centre at The Institute of Cancer Research (ICR) and The Royal Marsden.

The researchers studied tumour samples from 35 people with advanced bowel cancer who were treated as part of a clinical trial of cetuximab led by the ICR and The Royal Marsden.

Cetuximab is effective for some people with advanced bowel cancer - but the treatment only works in around half of patients, and most will eventually stop responding as their cancer becomes drug resistant. Once bowel tumours evolve to become resistant to cetuximab, patients have very limited treatment options, and new therapies are desperately needed.

The new study offers a detailed picture of the many different ways in which bowel cancers can evade treatment with cetuximab either from the outset or through acquired drug resistance.

Surprisingly, the researchers were only able to find genetic changes that could explain the development of drug resistance in 36 per cent of the tumours they studied.

But in five out of seven patients who had stopped responding to cetuximab, tumours had become heavily infiltrated by non-cancerous cells from supportive tissue around the tumour, which nurtured the cancer cells and helped them to grow during treatment.

This finding adds to our understanding of the complex nature of cancer evolution, in which tumours often adopt genetic strategies to evade treatment or change their environment as a non-genetic approach to developing drug resistance.

The research team then studied the different types of immune cells in tumour samples before and after treatment with cetuximab, in an effort to find new ways to tackle drug-resistant cancers.

The researchers found that on average, cancer-killing immune cells were six times more active in tumours that had become resistant to cetuximab than those that had not responded to the drug from the outset.

The researchers believe that cetuximab kills cancer cells in a way that sends signals that attract immune cells to the tumour - and their findings suggest that immunotherapies designed to take the brakes off the immune system could be effective in these cancers.

Researchers at the ICR and The Royal Marsden have now begun a phase II clinical trial of a combination of two immunotherapy drugs, nivolumab and relatlimab, in patients with advanced bowel cancer whose tumours have stopped responding to a combination of cetuximab and chemotherapy.

The new study also identified six new genetic mechanisms that can cause cetuximab resistance in patients. These findings could lead to the development of better tests to pick out patients who will either not respond to cetuximab from the outset or will rapidly stop responding - so they can be identified early and where possible switched to alternative treatments.

The new research forms part of the ICR's ambitious strategy to understand and overcome cancer evolution and drug resistance through the world's first 'Darwinian' drug discovery programme.

The ICR - a charity and research institute - is raising the final £15 million of a £75 million investment in a new Centre for Cancer Drug Discovery to house the research programme, which aims to create a new generation of 'anti-evolution' treatments.

Dr Marco Gerlinger, Team Leader in Translational Oncogenomics at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"In our new study, we have shone a light on the complex biology that lies behind the ability of bowel cancers to evade treatment with the targeted drug, cetuximab.

"Most bowel cancers are 'immune deserts' - so it's enormously exciting to see that cetuximab attracts immune cells into these tumours. At the ICR and The Royal Marsden, we have already started a clinical trial of immunotherapy in people whose bowel tumours have become resistant to cetuximab and chemotherapy. I'm eager to see if immunotherapy can unleash the immune cells and shrink these tumours.

"Our findings could also lead to better tests so that people with changes in their tumours that mean they're unlikely to respond to cetuximab - or likely to stop responding - could be spared unnecessary treatment."

Professor David Cunningham, Director of the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, said:

"This research underlines the importance of understanding how cancer evolves, especially when it occurs as a direct effect of treatment. In this study the antibody cetuximab made colorectal cancer tumours potentially susceptible to immunotherapy. This finding could have implications for the treatments we provide to patients with this disease."

Rachel Shaw, Research Information Manager at Cancer Research UK, said:

"Bowel cancer is the fourth most common cancer in the UK, and it's the second biggest cancer killer. Treatment resistance remains a huge part of the challenge, so it's vital that we find new ways to treat this disease.

"While cetuximab works well for lots of people, most will eventually stop responding to their treatment. Delving into the mechanics of how cetuximab changes the biology of bowel tumours has given us valuable insight into what the next best treatment step could be, and we look forward to seeing the results of the trial."

Professor Sir Mel Greaves, who will be Director of Cancer Evolution within the ICR's new Centre for Cancer Drug Discovery, said:
"Cancers are a moving target, constantly adapting and evolving within their environment so that they can survive, progress and evade treatment. As this intriguing study shows, cancers don't always need to accumulate genetic changes to become drug resistant - they can also modify their behaviour and their immediate environment in complex and subtle ways to render treatments ineffective.

"By unravelling the mechanisms underpinning cancer evolution and adaptation in response to drugs, our research aims to open up new treatment strategies - in this case through use of immunotherapy in bowel cancers that have become more visible to the immune system. It's an approach which lies at the heart of the ICR's pioneering plans to create a new generation of anti-evolution treatments, once we have raised the final £15 million to complete our Centre for Cancer Drug Discovery."

It's an unforeseen side effect of the nation's opioid epidemic: Adolescent heroin users.

A USC study in the July 8 issue of JAMA Pediatrics shows that teens who use prescription opioids to get high are more likely to start using heroin by high school graduation.

"Prescription opioids and heroin activate the brain's pleasure circuit in similar ways," said senior author Adam Leventhal, a professor of preventive medicine and psychology and director of the USC Institute for Addiction Science at the Keck School of Medicine of USC. "Teens who enjoy the 'high' from prescription opioids could be more inclined to seek out other drugs that produce euphoria, including heroin."

Leventhal said the study, conducted from 2013-2017, is the first to track prescription opioid and heroin use in a group of teens over time. In 2017, 9% of the nation's 47,600 opioid overdose deaths occurred in people under the age of 25, according to data from the Centers for Disease Control and Prevention. In addition to overdose, health risks of heroin use are devastating and include severe addiction, hepatitis C, HIV and other infections.

Using twice-yearly surveys to track high schoolers' use of various drugs, researchers followed 3,298 freshmen from 10 Los Angeles-area high schools through their senior year. Participants were asked about their previous and current use of prescription painkillers -- such as Vicodin, Oxycontin and Percocet -- to get high.

The researchers also asked the students if they used heroin or other substances like marijuana, alcohol, cigarettes, methamphetamine and inhalants. They made statistical adjustments to account for differences in family environment, psychological disposition, family history of substance use and other factors associated with nonmedical prescription opioid use.

Of the nearly 3,300 students in the study, 596 reported using prescription opioids to get high during the first 3.5 years of high school. The researchers found that prescription painkiller use made a big difference in who later used heroin: 13.1% of current prescription opioid users and 10.7% of previous prescription opioid users went on to use heroin by the end of high school. Only 1.7% of youth who did not use prescription opioids to get high had later tried heroin by the end of high school.

"Adolescents are sometimes overlooked in the opioid epidemic discussion," said first author Lorraine Kelley-Quon, a pediatric surgeon and assistant professor of surgery and preventive medicine at Children's Hospital Los Angeles and the Keck School of Medicine. "The association between nonmedical opioid use and later heroin use in youth is concerning and warrants further research and health policy interventions."

To further confirm their results, the researchers also evaluated whether marijuana, alcohol, and methamphetamine use were linked to later heroin use. But the association between prescription opioids and heroin use was stronger than the associations for heroin use with other substances.

"While we can't definitively conclude that there is a cause-and-effect relation, there may be something unique about opioid drugs that makes youths vulnerable to trying heroin," Leventhal said. "The results do not appear to be driven by the tendency of some teens to act out, rebel, or experiment with many types of drugs."

In addition to Leventhal and Kelley-Quon, the study's authors are Junhan Cho, Jessica Barrington-Trimis and Afton Kechter of Keck School of Medicine; David Strong of University of California, San Diego; and Richard Miech of the University of Michigan.

PITTSBURGH, July 8, 2019 - New research from the University of Pittsburgh and the U.S. Department of Veterans Affairs (VA) shows that dispensing a year's supply of birth control pills up front would support women's reproductive autonomy while also being cost effective.

The paper, published today in JAMA Internal Medicine, used a mathematical model to demonstrate that reducing birth control refills would better allow female veterans to prevent undesired pregnancies, and the money saved on health care costs would more than outweigh the expense of providing birth control in larger quantities.

"Medication dispensing limits are thought to be cost-saving because you're not wasting pills and medicines that people aren't going to use," said lead author Colleen Judge-Golden, an M.D., Ph.D. student at Pitt's School of Medicine. "Our analysis shows that concerns about wastage of contraceptive pills are overshadowed by the potential consequences of missed refills, and especially of unintended pregnancies."

VA data shows that 43% of women receiving three-month increments of birth control pills experience at least one gap between refills over the course of a year of use. Outside the VA, women who get a year's worth of birth control pills up front experience fewer gaps, and ultimately, fewer unintended pregnancies.

Since the VA doesn't yet offer the option of dispensing a 12-month supply, Judge-Golden analyzed how expensive such a program would be, together with senior author Sonya Borrero, M.D., M.S., director of Pitt's Center for Women's Health Research and Innovation and associate director of the VA's Center for Health Equity Research and Promotion.

The researchers estimate that among the approximately 24,000 women receiving oral contraceptives from the VA, offering a year's supply of pills would prevent 583 unintended pregnancies and save the VA about $2 million a year in prenatal, birth and newborn care costs.

"We see extended contraceptive dispensing as a win-win," said Judge-Golden, "promoting women's health and women's autonomy to use birth control as they decide, while also being economically sustainable for the VA."

To date, 17 states and the District of Columbia have passed laws requiring insurers to cover a year's supply of contraceptives. As the largest integrated American health system, the VA has an opportunity to deploy this evidence-based policy on a national scale.

"This is a great opportunity for the VA to roll out this policy change on a national level and continue to be a leader and set an elevated standard for women's health care," Borrero said.

PHILADELPHIA - For patients with prostate cancer, treating the disease with androgen deprivation therapy (ADT) is linked to a higher likelihood of being diagnosed with Alzheimer's disease or dementia, compared to patients who do not receive the therapy, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania. The results were published this week in JAMA.

Of the 154,089 men sampled in the study, 62,330 received ADT within two years of their prostate cancer diagnosis and 91,759 did not. Of the patients with prostate cancer who received the hormone therapy, 13 percent were later diagnosed with Alzheimer's disease, compared to 9 percent who did not receive ADT. For dementia, those numbers widened: 22 percent of prostate cancer patients who received ADT were diagnosed with dementia, compared to 16 percent who did not receive the therapy. This research builds on previous, smaller studies which showed similar correlations between hormone therapy and cognitive risks in patients with prostate cancer. The lifetime risk for Alzheimer's dementia for men overall is 12 percent, according to data from the Framingham Heart Study.

"To our knowledge, this is one of the largest studies to date examining this association, and it followed patients for an average of eight years after their prostate cancer diagnosis. Our results suggest that clinicians need to raise their awareness about potential long-term cognitive effects of hormone therapy and discuss these risks with their patients," said the study's principal investigator Ravishankar Jayadevappa, PhD, a research associate professor of Geriatrics and senior fellow in the Leonard Davis Institute of Health Economics.

Prostate cancer is the most commonly diagnosed non-skin cancer in the United States and the second leading cause of cancer death in American men. ADT, or hormone therapy, has been shown to dramatically reduce the spread and progression of the disease. The treatment works by reducing levels of male hormones in the body, called androgens, to stop them from stimulating prostate cancer cells to grow. It is typically used in patients who have an advanced state of the disease, when the cancer has metastasized, or in those with a high risk of recurrence after their initial treatment.

Despite the benefits of ADT, its use has faced controversy, as some evidence suggests that decreasing androgen levels may increase risk factors for Alzheimer's and dementia, including loss of lean body mass, diabetes, cardiovascular disease, and depression. Hormone therapy may also affect cognitive function by impairing neuron growth and the regeneration of axons.

After controlling for several factors, such as other medical conditions, disease severity and sociodemographic characteristics -- like age and marital status -- the Penn researchers determined the hazard ratio for prostate cancer patients who receive hormone therapy. A hazard ratio measures the effect of an intervention over time. With all other factors remaining equal, the research team determined that patients with prostate cancer who receive hormone therapy face a hazard ratio that translate to a 14 percent increased risk of developing Alzheimer's and a 20 percent increased risk of dementia, when compared to other prostate cancer patients who are not exposed to ADT.

The Penn study contrasts with results from several recent papers that have examined the association -- or lack thereof -- between ADT and dementia. These past studies relied on data from a single institution, while others fail to adjust for cancer stage, ADT dose, and duration. Many examined a small cohort of patients and only for a short amount of time following their treatment.

By contrast, Jayadevappa's team used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database of the National Cancer Institute, which brings together Medicare administrative claims data and clinical tumor registry data from 18 different sites, encompassing 28 percent of the U.S. population. For their retrospective study, the Penn researchers collected data from a sample of men ages 66 years and older with localized or advanced prostate cancer who were diagnosed between 1996 and 2003.

The team noted more research is necessary to understand the possible biological mechanisms that underlie the link between dementia and ADT. As to whether physicians should advise their patients regarding the risk of hormone therapy, it may depend on the patient and the severity of his or her disease, cautioned study co-author Thomas Guzzo, MD, MPH, chief of Urology.

"I think we need to look at these patients on an individual level. Certainly there are patients who need hormonal therapy and benefit from it greatly," Guzzo said. "There are others where the evidence is less clear, and in these patients, we should strongly consider the risk of hormonal therapy versus the benefit in treating their prostate cancer. This should be a shared decision-making process with the patient."

Osaka, Japan - Long-term dialysis treatment is tough on the body in many ways, but one of the most serious complications is dialysis-related amyloidosis, a disease characterized by abnormal buildup of protein aggregates--called amyloid fibrils--in joints, tissues and organs.

Although there is no cure, recent research by Osaka University researchers sheds light on how amyloid fibrils form and aggregate, thereby allowing the identification of new therapeutic and preventive avenues to further improve the lives of sufferers.

In a study published in Proceedings of the National Academy of Sciences of the United States of America, Osaka University researchers have identified that polyphosphate (polyP), which is a naturally occurring polymer in the body and a food and drink additive, induces the formation of amyloid fibrils from β2 microglobulin proteins.

PolyPs play an important role in life as storage of phosphorous. When kidney function is normal, β2 microglobulin serum blood levels remain low. However, β2 microglobulin are not efficiently removed from the body in advanced stages of kidney disease. The implementation of dialysis further accentuates this problem, because β2 microglobulin is inable to pass through the dialysis membrane to be filtered.

"Because blood concentration of β2 microglobulin is higher when dialysis is used, the increased level of β2 microglobulin is the most important risk factor. However, the detailed mechanism triggering amyloid formation remains unclear. We wanted to investigate the effects of polyPs, compounds recently reported to be effective for other amyloid proteins, on the formation of amyloid fibrils from β2 microglobulin in an effort to learn how we may prevent it," says Dr. Yuji Goto.

To do this, the researchers monitored the effect of polyP on the formation of amyloid fibrils from β2 microglobulin under acid and neutral conditions. Under acidic conditions, low polyP concentrations resulted in protein aggregates with an amyiloid-fibril structure but high polyP concentrations induced unstructured (or amorphous) aggregates.

"The results observed under acidic conditions were characteristic of a competitive mechanism," explains Chun-ming Zhang, previous graduate student of the Institute for Protein Research at Osaka University. "Based on this, we hypothesized that the tendency to form amyloid fibrils or amorphous aggregates is dependent upon the chemical environment."

However, under normal pH conditions, the results were quite different. The amyloid fibrils that formed were thicker; polyPs promoted amyloid fibril formation through protein aggregation by salting-out effects.

This is the first evidence resolving how polyPs affect amyloid formation at different pH. These findings have clinical application potential because monitoring polyP levels in people receiving long-term hemodialysis could provide information regarding an individual's risk of dialysis-related amyloidosis.

Medicinal cannabis oil containing both cannabidiol (CBD) and a small amount of THC can reduce or end seizures in children with severe, drug-resistant epilepsy, a study by the University of Saskatchewan (USask), Canada has found.

Children with severe epilepsy also experienced improvements in their quality of life after taking low doses of the medicinal cannabis oil, according to research published in Frontiers in Neurology.

The study tested the effects of medicinal cannabis oil with 95 per cent CBD, a chemical which does not create a high, and 5 percent THC, a substance which can be intoxicating in large enough doses.

Studying an evidence-based scientifically guided dosage regimen, the research team found no evidence of THC intoxication when using CBD-enriched whole plant extracts.

"What makes these results really exciting is it opens up as a treatment option for kids who have failed to respond to traditional medications," said Dr. Richard Huntsman (M.D), a paediatric neurologist who led the study.

Three of the seven children in the USask study--mainly funded by Saskatchewan's Jim Pattison Children's Hospital Foundation--stopped having seizures altogether.

"Some of the improvements in quality of life were really dramatic with some of the children having huge improvements in their ability to communicate with their families. Some of these children started to talk or crawl for the first time. They became more interactive with their families and loved ones," said Dr. Huntsman.

Several studies have shown that cannabis products containing CBD can be effective in helping to control seizures in children with epileptic encephalopathy, a severe form of epilepsy which begins in childhood. Despite this, many children cannot access these products because there is very little guidance for physicians on which doses to use and some health-care providers are concerned about possible intoxication from THC.

This research found that most of the children had a reduction in seizures with a twice daily dose of CBD totaling 5-6 milligrams of cannabis extract per kilogram of weight (mg/kg) per day. By the time a CBD dose of 10-12 mg/kg per day was achieved, all children experienced a reduction in their seizures, most by more than 50 per cent.

"What is really important is that we have been able to dispel in a scientific manner some of the concerns about how to dose these products and the possibility of them causing a 'high' in these children. We did this by slowly increasing the dose of cannabis extract in a very tightly regulated manner. We watched the children very closely for side effects and measured blood levels of CBD and THC," said Dr. Huntsman,

The children had drug-resistant epilepsy, failing to respond to at least two forms of anti-convulsant medication. They had been prescribed several anti-convulsant medications yet continued to have seizures, with one child experiencing 1,223 in the month leading up to the study.

"We are very proud to support this important pediatric research, which is making such a difference in the lives of children who have severe epilepsy," said Brynn Boback-Lane, President and CEO of Jim Pattison Children's Hospital Foundation. "This groundbreaking study is giving hope and improved health outcomes. It is heartening to have donors that see the value of such important work."

Allyssa Sanderson's eight-year-old son Ben from Prince Albert, Sask. was one of the participants in the study. Ben was born without complications, but later developed infantile spasms. When Ben was two, he was diagnosed with Lennox-Gastaut syndrome, a severe form of epilepsy.

Despite trying multiple medications and treatments, Ben's seizures were unpredictable. He was seizure-free on some days, but on others had 150 seizures a day.

"Ben was very lethargic and would just lay there and have seizures all day. He wasn't active and didn't even want to eat. His eyes looked dull, and he didn't focus on anything. He really looked lifeless," Allyssa explained. "I knew this trial was a last resort for my son."

Once Ben started taking CBD, he began showing improvements in his seizure frequency and then became seizure-free during the study.

"I was seeing the change in Ben every single day. I was thankful as I watched his little personality come out. He was back to his silly self that I hadn't seen in years. He was stronger. I believe this research is one of the greatest things to happen for kids with epilepsy," Allyssa said.

The Developmental Origins of Health and Disease (DOHaD) hypothesis is supported by multiple human epidemiological studies and animal studies. It states that the nutritional environment in early life makes people susceptible to lifestyle-related diseases, such as obesity, diabetes and heart attack, as adults. Many of those diseases exhibit reduced mitochondrial metabolism in the tissues of the body. Now, researchers from Kumamoto University in Japan reveal that two metabolic pathways involved in energy metabolism may play a role in the DOHaD hypothesis.

All cells regulate gene expression related to metabolic pathways, and adapt to environmental changes such as fluctuations in nutrition, oxygen supply, exercise, and temperature. Cells in the human body use two types of cellular metabolism, mitochondrial respiration and glycolysis. Mitochondrial respiration produces energy for the cell when oxygen is supplied (aerobic), and glycolysis is used when oxygen is scarce (anaerobic). The activity of metabolic genes changes significantly as the method of energy production shifts between these two mechanisms. Some of the most critical changes are due to histone acetylation and methylation (the addition/removal of acetyl and methyl groups) of lysine amino acids. The enzymes deacetylase SIRT1 and demethylase LSD1 are especially important in the regulation of metabolic genes because they remove the acetyl and methyl groups, respectively, of target proteins.

Two metabolic pathways, NAD+ –SIRT1 and FAD–LSD1, regulate the function of specific gene sets, and transmit nutrient signals. Recently, Kumamoto University researchers revealed that these two pathways are controlled by dietary vitamins and nutritional hormones, induce metabolic activity, and develop tissue-specific properties in fat and skeletal muscle cells. They found that FAD–LSD1 pathway represses mitochondrial metabolism and induces fat accumulation under obese condition.

DOHaD theorizes that people affected by malnutrition during early development may have a low birth weight and an increased risk of lifestyle-related diseases as adults. Although the mechanisms behind this have not been clarified, the researchers think that at least two responses work at different times. The immediate response consumes stored energy and prioritizes maintaining life, and the adaptive response "programs" the body to store energy in anticipation of future bouts of starvation. This is considered a natural survival strategy for nascent undernutrition. An adaptive response can easily adjust to undernutrition, but it makes a person more susceptible to lifestyle-related diseases, such as obesity and diabetes, under an excess of nutrition.

The NAD+–SIRT1 pathway burns energy and the FAD–LSD1 pathway stores energy, and together they can remodel metabolic tissues. In muscle development, the SIRT and LSD1 pathways selectively promote slow and fast twitch fiber formation respectively, which increases susceptibility to lifestyle-related diseases. Thus, the researchers believe that these enzymes are involved in DOHaD mechanisms. Specifically, that SIRT1 can play a role in the immediate response and that LSD1 can be involved in the adaptive response.

Speaking about future activities, research leader Professor Mitsuyoshi Nakao said, "We hope our work will help lead to new disease control and prevention strategies by improving the understanding of lifestyle-related diseases, and the nutrition of young parents and babies during perinatal periods."

A window film with a specially designed molecule could be capable of taking the edge off the worst midday heat and instead distributing it evenly from morning to evening. The molecule has the unique ability to capture energy from the sun's rays and release it later as heat. This is shown by researchers at Chalmers University of Technology, Sweden, in the scientific journal Advanced Science.

On sunny summer days it can be little short of unbearable to stay indoors or in cars. The heat radiates in and creates an unpleasantly high temperature for people, animals and plants. Using energy-intensive systems such as air conditioning and fans means combating the thermal energy with other forms of energy. Researchers at Chalmers University of Technology are proposing a method that utilises the heat and distributes it evenly over a longer period instead.

When their specially designed molecule is struck by the sun's rays it captures photons and simultaneously changes form - it is isomerised. When the sun stops shining on the window film the molecules release heat for up to eight hours after the sun has set.

"The aim is to create a pleasant indoor environment even when the sun is at its hottest, without consuming any energy or having to shut ourselves behind blinds. Why not make the most of the energy that we get free of charge instead of trying to fight it," says chemist Kasper Moth-Poulsen, who is leading the research.

At dawn when the film has not absorbed any solar energy it is yellow or orange, since these colours are the opposite of blue and green, which is the light spectrum that the researchers have chosen to capture from the sun. When the molecule captures solar energy and is isomerised, it loses its colour and then becomes entirely transparent. As long as the sun is shining on the film it captures energy, which means that not as much heat penetrates through the film and into the room. At dusk, when there is less sunlight, heat starts to be released from the film and it gradually returns to its yellow shade and is ready to capture sunlight again the following day.

"For example, airports and office complexes should be able to reduce their energy consumption while also creating a more pleasant climate with our film, since the current heating and cooling systems often do not keep up with rapid temperature fluctuations," says Moth-Poulsen.

The molecule is part of a concept the research team calls MOST, which stands for 'Molecular Solar Thermal Storage'. Previously the team presented an energy system for houses based on the same molecule. In that case - after the solar energy had been captured by the molecule - it could be stored for an extended period, such as from summer to winter, and then used to heat an entire house. The researchers realised that they could shorten the step to application by optimising the molecule for a window film as well, which would also create better conditions for the slightly more complex energy system for houses.

What the researchers still have to do is to increase the concentration of the molecule in the film whilst also retaining the film's properties, and bring down the price of the molecule. But according to Moth-Poulsen they are very close to this innovation.

"The step to applying our film is so short that it could happen very soon. We are at a very exciting stage with MOST," he says.

A new study published early online in CANCER, a peer-reviewed journal of the American Cancer Society, shows that women of color and young women may face elevated risks of developing triple-negative breast cancers, which are often aggressive and do not respond to hormone therapy or targeted therapy.

Previous U.S. studies have found racial disparities in triple-negative breast cancer diagnoses, but few have looked beyond the scope of one state. To conduct a larger study, Lia Scott, PhD, MPH, of the Georgia State University School of Public Health, and her colleagues analyzed all breast cancer cases diagnosed during 2010-2014 from the United States Cancer Statistics database, a population-based surveillance system of cancer registries with data representing 99 percent of the U.S. population.

The team identified 1,151,724 cases of breast cancer from 2010-2014, with triple-negative cases accounting for approximately 8.4 percent of all cases. The researchers uncovered a significant burden of triple-negative breast cancer for women of color, specifically non-Hispanic black women, and for younger women.

Compared with non-Hispanic white women, non-Hispanic black women and Hispanic women had 2.3-times and 1.2-times higher odds of being diagnosed with triple-negative breast cancer, respectively. More than 21 percent of non-Hispanic black women were diagnosed with triple-negative breast cancer, compared with less than 11 percent for all other types of breast cancer. Women younger than 40 years of age had twice the odds of being diagnosed with triple-negative breast cancer than women aged 50-64 years. Also, among women who were diagnosed with breast cancer, those diagnosed at late stages were 69 percent more likely to have triple-negative cancer than other types.

The authors noted that due to the aggressive nature of triple-negative breast cancer and the lack of therapeutic options, it is important to know which individuals face a higher risk and what factors may influence this risk.

"With the advent and availability of more comprehensive cancer data, such as the United States Cancer Statistics database, it is important that we continue to explore disparities in order to better inform practice and policy around screenable cancers like breast cancer," said Dr. Scott. "We hope that this update on the epidemiology of triple-negative breast cancer can provide a basis to further explore contributing factors in future research."

DALLAS, July 8, 2019 -- Microvascular disease is independently associated with a higher risk of leg amputation compared to people without the disease, according to new research in the American Heart Association's journal Circulation.

The study, funded by the American Heart Association Strategically Focused Research Network in Vascular Disease and the U.S. Department of Veterans Affairs, examined amputation risk among people with microvascular disease or peripheral artery disease (PAD) or those who had both microvascular disease and PAD. Researchers used data from the Veterans Aging Cohort Study, which included more than 125,000 veterans who initially did not have amputations when the study began. Over an average of nine years, participants with:

microvascular disease had a 3.7-fold increased risk of lower limb amputation, and experienced 18% of all amputations during the study;

PAD had a 13.9-fold increased risk of lower limb amputation and suffered 22% of all amputations;
microvascular disease and PAD had a 23-fold increase in the risk of lower limb amputation which accounted for 45% of all amputations.

PAD is a narrowing of the arteries away from the heart and is typically found in the legs. It causes cramping, pain or fatigue in the leg muscles while walking or climbing stairs. If left untreated, PAD can lead to gangrene and the need for amputation.

In microvascular disease, tiny vessels that carry blood to muscles and other tissues throughout the body no longer function properly. While the disease is commonly diagnosed in the eyes (retinopathy) or in the kidney (nephropathy), the authors believe those are markers of microvascular dysfunction throughout the body.

"This study advances the idea that microvascular disease is a system-wide disorder rather than only affecting one part of the body," said Joshua A. Beckman, M.D., lead author of the study and professor of medicine and director of Vascular Medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

"PAD (in the legs) has long been considered a sign that a patient likely also has narrowed arteries leading to the heart or brain. If a patient has PAD, they have a higher risk of other cardiovascular diseases, such as heart attacks and strokes," Beckman said. "Our study suggests that microvascular disease in any part of the body, such as the eyes, kidneys or feet (neuropathy) may be linked to decreased blood vessel function in other parts of the body, putting patients at risk for potential lower-limb amputations."

Based on the findings, Beckman suggests patients with microvascular disease require close observation and care of their feet to detect sores or injuries early to promote healing and reduce amputations. "Patients with both microvascular disease and PAD have the highest risk of lower-limb amputation and need maximal medical therapies to reduce their risk," Beckman said.

Barcelona, Spain, 6 July 2019 - Medical oncologists administer anticancer drug regorafenib to try to improve overall survival in patients with metastatic colorectal cancer who have ceased to respond to standard therapy (known as refractory mCRC). However, some of the adverse events related to the use of this drug often limits its use in clinical practice. A study reported at the ESMO World Congress on Gastrointestinal Cancer 2019 suggests the usefulness of a more flexible dosing, which improves patients' quality of life without jeopardising efficacy. (1,2)

This international trial, led by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD), included 299 patients from over a dozen hospitals in Spain, Italy and France. The average age of the participants was 64 and they had received an average of four treatment lines prior to inclusion in the trial with regorafenib between July 2016 and September 2017.

"Regorafenib has been approved since 2013 for patients with metastatic colorectal cancer (mCRC) who have progressed to standard treatments," said study author, Dr. Guillem Argiles, medical oncologist and clinical investigator, Gastrointestinal & Endocrine Tumors Group, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

"Its adverse toxicity profile often limits its use in routine clinical practice. This clinical trial attempted to show the usefulness of different dose strategies in order to improve its tolerability and quality of life in patients who can benefit from the medicine in the context of advanced disease."

In the trial, patients were randomised 1:1:1: standard dose 160 mg/day for three weeks followed by a week off; reduced dose of 120 mg/day for three weeks followed by a week off (reduced dose group); or intermittent dose of 160 mg/day a week, followed by a week off (intermittent dose group). The patients in the latter two groups (reduced or intermittent dose) were escalated to the standard of care dose if, after a first treatment cycle, no limiting toxicities that prevented to continuing to stay in the trial occurred. "We reduced the dose in the first cycle and then escalated because it has been shown that the toxicity is higher in the first and second months of treatment", explained Argiles.

The investigators observed that flexible dosing showed numerical improvement on several parameters that improved tolerance, such as fatigue, hypertension or hand-foot syndrome (reaction due to redness, swelling and pain caused in the palms), although REARRANGE did not meet its primary endpoint of improving regorafenib global tolerability in the reduced and intermittent dose groups. The average treatment duration was 3.2 months in the standard group; 3.7 in the reduced dose group; and 3.8 in that with alternating weeks. Median progression-free survival was not different across groups (approximately 2 months).

"Although statistical significance was not achieved, we did observe a numerical reduction in some side-effects that can be very troublesome for the patients", explained Argiles. "These results, interpreted in the context of other trials, like the American study ReDOS (3), tell us that the more flexible doses of regorafenib are an effective alternative in order to improve quality of life in patients with metastatic refractory colorectal cancer".

Commenting on the results, Prof. Eric Van Cutsem, from the University Leuven, Belgium, said: "This study will change clinical practice with regard to the use of regorafenib in patients with metastatic colorectal cancer, because it demonstrates and supports something that many clinicians have already observed and were carrying out in regular clinical practice". In his opinion, the trial shows that this reduction in regorafenib initial dose limits the drug toxicity while maintaining its efficacy.

What The Study Did: This study used measures of implicit and explicit biases to assess how health care professionals associated men and women with career and family, and how surgeons associated men and women with surgery and family medicine.

Authors: Arghavan Salles, M.D., Ph.D., of Washington University in St. Louis, is the corresponding author.

(doi:10.1001/jamanetworkopen.2019.6545)

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

People with a genetic predisposition to obesity are not only at greater risk of excess weight, their genes interact with an increasingly "obesogenic" environment, resulting in higher body mass index (BMI) in recent decades, finds a study from Norway published by The BMJ today.

But the findings also show that BMI has increased for both genetically predisposed and non-predisposed people since the 1960s, implying that the environment remains the main contributor to the obesity epidemic.

Obesity has almost tripled worldwide since 1975, but the origins of the epidemic are still unclear. Previous studies have suggested an interplay between genes and the environment, but are limited by a narrow age span, short follow-up, and self-reported weight.

How the effect of genetic predisposition on obesity differs as environments are becoming more obesogenic is also unknown.

So researchers in Norway set out to study changes in body mass index (BMI) over five decades, and to assess the effect of the environment on BMI according to genetic predisposition.

Their findings are based on data from 118,959 people aged 13-80 years in the Nord - Trøndelag Health Study who had repeated height and weight measurements recorded between 1963 and 2008. Of these, 67,305 were included in analyses of the association between genetic predisposition and BMI.

After taking account of potentially influential factors, the data show a noticeable increase in BMI in Norway starting between the mid-1980s and mid-1990s. What's more, compared with older birth cohorts, those born after 1970 had a substantially higher BMI already in young adulthood.

When participants were divided into five equal groups (the top fifth being the most genetically susceptible to higher BMI and the bottom fifth being the least), BMI differed substantially between the highest and lowest fifths for all ages at each decade, and the difference increased gradually from the 1960s to the 2000s.

For example, for 35 year old men, the most genetically predisposed had 1.20 kg/m2 higher BMI than those who were least genetically predisposed in the 1960s, compared with 2.09 kg/m2 in the 2000s. For women of the same age, the corresponding differences in BMI were 1.77 kg/m2 and 2.58 kg/m2.

"Hence, the increased difference in BMI of 0.89 kg/m2 and 0.81 kg/m2 for men and women, respectively, in the 2000s, could be attributed to the gene-obesogenic environment interaction," say the researchers.

This is an observational study so can't establish cause. However, the results were largely unchanged after several additional analyses, suggesting that the findings withstand scrutiny.

The researchers therefore conclude that in the Norwegian population, BMI increased substantially from the 1960s to 2000s for both men and women, and the increase was more evident in people with a genetic predisposition to higher BMI.

"Our study suggests that genetic predisposition interacts with the obesogenic environment and this has resulted in higher BMI in recent decades," they write. And they call for population-wide strategies to reduce overall BMI.

A greater understanding of the variation between people is key, say US researchers in a linked editorial.

For instance, BMI seems to vary across population groups and within a given population over time - and most of this variation remains unexplained. As such, they suggest that an exclusive focus on population-wide preventive strategies "is unlikely to make a noticeable difference in reversing the obesity epidemic."

Future research, "should aim to identify more clearly the sources of within population variation to inform better strategies for improving the health of both populations and individuals," they write. "Further, it is necessary to consider both mean BMI and the variation in BMI when deciding where best to target these strategies."

Using advanced technology, scientists at Chan Zuckerberg (CZ) Biohub, Mayo Clinic and University of California, San Francisco (UCSF), have discovered an autoimmune disease that appears to affect men with testicular cancer.

Called "testicular cancer-associated paraneoplastic encephalitis," the disease causes severe neurological symptoms in men. They progressively lose control of their limbs, eye movements, and, in some cases, speech. The disease begins with a testicular tumor, which appears to cause the immune system to attack the brain. Affected men often find themselves misdiagnosed or undiagnosed and appropriate treatment is delayed.

In a study published in The New England Journal of Medicine, the scientists identified a highly specific and unique biomarker for the disease by using a variation of "programmable phage display" technology. Their refined version of this technology simultaneously screens more than 700,000 autoantibody targets across all human proteins.

Using this powerful tool, the UCSF researchers evaluated cerebrospinal fluid from a 37-year-old man who had a history of testicular cancer and debilitating neurological symptoms, including vertigo, imbalance and slurred speech. The enhanced phage technology identified autoantibodies targeting Kelch-like protein 11 (KLHL11), which is found in the testes and parts of the brain.

These results were correlated and validated with additional patient samples from the Mayo Clinic. In addition to identifying the cause of this mysterious neurological disease, the results point the way to using this protein biomarker as a diagnostic test for men with testicular cancer-associated paraneoplastic encephalitis.

"Mayo Clinic's Neuroimmunology Laboratory has a long history of biomarker discovery, and this continues that tradition, bringing together Mayo Clinic's biobank, the largest repository of biospecimens in the world, with advanced technologies being devised and implemented at UCSF and CZ Biohub," says Sean Pittock, M.D., a Mayo Clinic neurologist and corresponding author of the study. "By working together, our organizations have the potential to make biomarker discoveries much more rapidly."

Dr. Pittock is director of Mayo Clinic's Neuroimmunology Laboratory and the Marilyn A. Park and Moon S. Park, M.D., Director of the Center for Multiple Sclerosis and Autoimmune Neurology.

From darkroom to discovery

Mayo Clinic's Neuroimmunology Laboratory annually screens about 150,000 patients for autoimmune neurological diseases by applying patients' biospecimen samples -- serum or cerebrospinal ?uid -- to thin slices of brain tissue from mice. Some patients with autoimmune neurological diseases harbor antibodies that bind to tissue with a specific pattern of staining.

About 20 years ago, Mayo scientists first identified a staining pattern that researchers dubbed "sparkles" because, in a darkroom under a microscope, the patient's sample looked like stars shining dimly in the night sky, Dr. Pittock says. The male patient had ataxia -- poor coordination, involuntary eye movements, change in speech -- and turned out to have testicular cancer.

Over the years, the Mayo lab occasionally identified the sparkles pattern, and the patients' clinical stories were the same: ataxia and testicular cancer. But the pattern was faint and easy to miss, and an autoantibody target remained elusive.

A UCSF team led by Joe DeRisi, Ph.D., a biochemist and co-president of Chan Zuckerberg Biohub, and Michael Wilson, M.D., neurologist and member of the UCSF Weill Institute for Neurosciences, developed a customized version of phage technology that identified KLHL11 as the target for testicular cancer-associated paraneoplastic encephalitis based on a patient's sample. The enhanced phage technology builds on work pioneered in the laboratory of Stephen Elledge, Ph.D., at Harvard Medical School.

The collaborative effort reported in the new paper was spearheaded by co-first authors Caleigh Mandel-Brehm, Ph.D., a UCSF postdoctoral researcher, and Divyanshu Dubey, M.B.B.S., a Mayo Clinic neurologist and lab medicine physician. Analyses were conducted on biospecimens of 12 additional men with similar medical histories. All were positive for autoantibodies targeting KLHL11.

Using this biomarker signature, 37 patients now have been diagnosed with this paraneoplastic disease, and the scientists believe many more will be diagnosed.

"This study is the tip of the iceberg," Dr. DeRisi says. "We know there are more paraneoplastic autoimmune diseases waiting to be discovered and more people to help."

"For roughly half the patients with paraneoplastic or autoimmune causes of encephalitis, the protein being targeted has yet to be identified," Dr. Wilson says. "Building on the Elledge lab's work, we hope to tackle that problem head-on with this technology for finding antibodies, so we can potentially add to the number of diseases that are known, and help patients and families get diagnoses more quickly."

Study implications

Physicians who suspect a patient may have this form of paraneoplastic encephalitis currently can work with Mayo Clinic to screen for KLHL11. "Early diagnosis is extremely important," Dr. Dubey says. "If we diagnose patients early, we can start them on immunosuppressive medications. The sooner we can prevent this damage from happening, the sooner we can stop the disease progression and the better chance we have for clinical improvement in the patient's life."

In an epidemiological assessment included in the study, the prevalence of KLHL11 encephalitis in Olmsted County, Minnesota, home to Mayo Clinic's Rochester campus, was nearly 3 per 100,000 men. Thus, KLHL11 is one of the more common autoimmune encephalitis biomarkers found in Olmsted County, and likely elsewhere in the U.S. and beyond.