Body

ROSEMONT, Ill. (May 1, 2018)--An estimated 45 percent of people are at risk of developing knee osteoarthritis (OA) in their lifetime. According to a network meta-analysis research article published in the May 1, 2018 issue of the Journal of the American Academy of Orthopaedic Surgeons (JAAOS), the nonsteroidal anti-inflammatory drug (NSAID) naproxen was ranked most effective in individual knee OA treatment for improving both pain and function, and is considered a relatively safe and low-cost treatment method.

Nonsurgical treatments for knee OA supported by previous research evidence include strength training, low-impact aerobic exercises, NSAIDs, and weight loss in individuals with a body mass index over 25. This new research analyzed data from multiple trials to determine the relative effectiveness of various nonsurgical treatments for knee OA. The treatments that were compared and ranked included acetaminophen; ibuprofen; intra-articular (IA) or joint injections of cortisone; platelet-rich plasma (PRP); hyaluronic acid (HA); several NSAIDs, such as naproxen, celecoxib, and diclofenac; and both oral and IA placebo.

"This is the first comprehensive mixed-comparison analysis comparing best-evidence scientific research and excluding lower quality studies that can bias the outcomes," said lead author and orthopaedic surgeon David Jevsevar, MD, MBA. "Using a statistical ranking technique, we worked to provide evidence regarding which of the most common NSAIDs are most likely to decrease pain and improve function, and we attempted to fill in the gaps in evidence for more inconclusive treatments such as HA, PRP, and corticosteroids."

Authors analyzed 53 randomized controlled trials that examined knee OA treatments for at least 28 days and included a minimum of 30 participants per study group. Knee OA treatments were ranked on a scale of one to five, with one being the most effective. They found the following:

For pain reduction, cortisone injections provided the greatest short-term (4 to 6 weeks) pain relief, followed by ibuprofen, PRP injections, naproxen, and celecoxib.

Naproxen ranked the highest for probability for improving function, followed by diclofenac, celecoxib, ibuprofen, and PRP injections.

Naproxen was ranked the most effective individual knee OA treatment for improving both pain and function followed by cortisone injections, PRP injections, ibuprofen and celecoxib.

HA injections did not achieve a rank in the top five treatments for pain, function, or combined pain and function. An analysis of 12 articles also found that results with HA are not significantly different from those with IA placebo for treatment of knee OA.

"Because knee OA has both a high disease burden and high treatment costs, additional prospective studies using similar outcomes, timelines, and measures of clinically important changes are needed," explained Dr. Jevsevar. "While the information in this analysis is helpful to physicians, patients also can benefit from these findings and use it with their doctors to weigh all possible treatment options."

Although the use of NSAIDs for arthritic conditions such as knee OA has potential risks, including heart attack and stroke, existing evidence indicates that naproxen has less potential for adverse cardiovascular events.

AUGUSTA, Ga. (May 1, 2018) - New research published in Cancer Immunology Research by Drs. Esteban Celis and Hussein Sultan of the Georgia Cancer Center at Augusta University could serve as the stepping-stone in constructing vaccines with a greater likelihood of finding and attacking tumors in the human body.

According to Celis and Sultan, the key in this vaccine strategy is increasing the amount of time a cytokine called interleukin 2 (IL2) stays in the body. IL2 is a molecule in the immune system responsible for regulating the activity of some white blood cells known as killer T cells.

"After administering peptide-based vaccines in mouse models of cancer, we saw that sustained IL2 signaling dramatically increased the number of tumor-specific cancer-killing T cells (CD8+)," said Dr. Hussein Sultan, a postdoctoral fellow in the laboratory of Celis, leader of the Center's Cancer Immunology, Inflammation and Tolerance Program.

During their experiments, Celis and Sultan noticed there was also an increase in the T cells' ability to resist cancer immune evasion caused by a protein called programmed death-ligand 1 (PD-L1). It is well known that the PD-L1 protein can be produced by tumor cells, allowing them to evade destruction by the killer T cells.

"Together, these results substantially improved the antitumor efficacy of peptide-based vaccines in tumor-bearing mice," Sultan said.

Celis added, "In order to be effective, IL2 needed to be administered either as a complex of IL2 and anti-IL2 antibody, or in the form of polyethylene glycol-modified IL2 (PEG-IL-2). These formulations prolonged the half-life of IL2, allowing sustained activation of the IL2 receptor on vaccine-generated T cells, allowing them to survive longer in the body and attack the tumor."

According to Celis, it is difficult for vaccines to induce antibodies against tumors because most of the tumor antigens are not foreign proteins, as is the case with viruses. On the other hand, T cells have the capacity to recognize other types of antigens.

"As we know, cancer cells are created when normal cells undergo certain mutations," Celis said. "So, they don't always look foreign to our immune system."

Both Celis and Sultan hope their observations in mouse models of cancer can find their way into clinical studies with human cancer patients.

"Working on this research project was very rewarding and exciting," Sultan said. "I want to help the scientific community discover insights on how to use the body's immune system to fight this devastating disease."

New Haven, Conn. -- Despite steady declines in death rates in recent years, lung cancer remains the leading cause of cancer deaths in wealthy countries. In a new study, Yale researchers collaborated with investigators in Europe to examine lung cancer care and survival rates for patients with one of the most common forms of the disease.

Led by professor of medicine and of epidemiology Cary Gross, M.D., the global research team analyzed data on more than 170,000 older patients diagnosed with non-small cell lung cancer in England and the United States between 2008 and 2012. They compared several aspects of lung cancer care and outcomes, including patient characteristics, stage of cancer at diagnosis, treatment, and overall survival.

The research team found significant disparities in lung cancer care and survival between the two countries. In the United States, 25% of patients were diagnosed at the earliest stage of cancer compared with 15% of patients in England. Forty-five percent of U.S. patients were diagnosed late, at stage 4, versus 52% of their English counterparts.

Differences also emerged in treatment. Of U.S. patients diagnosed at stage 1, 60% had surgical treatment compared with only 55% of stage-1 patients in England.

These disparities from diagnosis through treatment appear to contribute to a substantial gap in overall survival rates, said the researchers. Two years after being diagnosed, 31% of U.S. lung cancer patients were still alive, while only 19% of English patients were, the researchers said.

"These findings -- the first using age- and stage-specific, population-based data -- show that lung cancer patients receive more active treatments and have better survival in the United States compared to England. Further work needs to be done to fully explain the reasons for this," said first author Anita Andreano of the University of Milan-Cicocco.

While the poorer lung cancer care outcomes in England are cause for concern, there's room for improvement on both sides of the Atlantic, said Gross, who is also a member of Yale Cancer Center. "This should be a call to action in both countries to learn how we could improve care and learn from each other's systems," he noted. "We need to share ideas and best practices, so we can continue to reduce tobacco use, implement effective lung cancer screening programs, and ensure access to high-quality care."

New Rochelle, NY, May 1, 2018--Mayo Clinic researchers, reporting results of the SMART study, have shown that abnormal results on a stress electrocardiogram are an independent predictor of cardiovascular events such as heart attack, heart failure, hospitalization for chest pain, and death in perimenopausal or menopausal women. The study, which also demonstrated the predictive value of the blood biomarker brain natriuretic peptide (BNP), is published in Journal of Women's Health, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Women's Health website.

The article "Prognostic Utility of Stress Testing and Cardiac Biomarkers in Menopausal Women at Low to Intermediate Risk for Coronary ARTery Disease (SMART Study): 5-Year Outcomes" is coauthored by Sharon Mulvagh, MD, Mayo Clinic (Rochester, MN) and Dalhousie University (Halifax, Canada) and colleagues from Mayo Clinic (MN and Phoenix, AZ), Memorial Hospital (Jacksonville, FL), Assiut University (Egypt), and Arcispedale Santa Maria Nuova (Reggio Emilia, Italy). This prospective study evaluated the predictive value of stress testing and cardiac biomarkers over a 5-year follow-up period in women who were at low-to-intermediate risk of a cardiovascular event.

"Clinicians need effective and proven noninvasive tools to assess women of low-to-moderate risk of a cardiovascular event who present with chest pain and related symptoms," says Susan G. Kornstein, MD, Editor-in-Chief of Journal of Women's Health, Executive Director of the Virginia Commonwealth University Institute for Women's Health, Richmond, VA, and President of the Academy of Women's Health. "In this study, Mulvagh et al. established the predictive value of stress ECG and resting BNP and emphasize the importance of future research to discover cardiac biomarkers of myocardial ischemia at earlier stages in women."

A questionnaire of older men and women suffering from chronic pain who were given medical marijuana found that the drug significantly reduced pain and their need for opioid painkillers, Northwell Health researchers report.

The results of the study, "Older Adults' Use of Medical Marijuana for Chronic Pain: A Multisite Community-Based Survey," are scheduled to be presented May 3, 2018 at the annual meeting of the American Geriatrics Society in Orlando, FL.

To gauge how effective medical marijuana was at managing chronic pain and reducing opioid use, researchers surveyed 138 medical marijuana users with an anonymous 20-question survey focusing on how often they used the marijuana, in what form they took it, how much it reduced pain and whether or not they were able to cut back their use of other painkillers.

When patients were asked if they were able to curb their use of other painkillers after starting medical marijuana, 18 percent reported decreasing their use "moderately," 20 percent "extremely" and 27 percent "completely." An overwhelming number of subjects (91 percent) would recommend medical marijuana to others.

Comments from patients tell the tale:

"My quality of life has increased considerably since starting medical marijuana," one patient said. "I was on opiates for 15 years, and 6 months on marijuana, and off both completely."

Another patient said: "It [medical marijuana] is extremely effective and has allowed me to function in my work and life again. It has not completely taken away the pain, but allows me to manage it."

"I was on Percocet and replaced it with medical marijuana. Thank you, thank you, thank you," said another.

These patients had been living with chronic pain from osteoarthritis, spinal stenosis, hips and knees that could not be replaced, and pain not relieved by steroid injections, said Diana Martins-Welch, MD, a co-author of the study and physician in the Division of Geriatric and Palliative Medicine, Department of Medicine at Northwell Health.

Based on these results, she believes that medical marijuana could be effective in curbing the opioid epidemic now ravaging the United States. "What I'm seeing in my practice, and what I'm hearing from other providers who are participating in medical marijuana programs, is that their patients are using less opioids," said Martins-Welch. "I've even gotten some patients completely off opioids."

As effective as medical marijuana can be, it's not widely available or prescribed, Martins-Welch said. Plus, people have to jump through many hoops just to get certified to receive it, she said.

Martins-Welch believes medical marijuana should be more widely available and easier to get. Medical marijuana is legal in only 30 states, she said. In addition, because marijuana is federally illegal, it's expensive and not covered by insurance, putting it beyond the reach of many patients who could benefit from it, she said.

Medical marijuana can cost on average $300 for a one-month supply, Martins-Welch said. "And it's a cash-only business."

"Even the process you have to go through to get certified is expensive," she said.

Martins-Welch and colleagues surveyed men and women between the ages 61 to 70 about their use of medical marijuana. Patients responded to 20 questions about their marijuana use. The researchers found that most patients, 45 percent, used vaporized oil, while 28 percent used pills and 17 percent used marijuana-laced oil. Twenty-one percent used marijuana once a day, 23 percent used it twice daily, and 39 percent used marijuana more than twice a day.

Using marijuana in these forms dramatically reduces its mind-altering effect, Martins-Welch said.

In most cases, a doctor recommended medical marijuana (46 percent) followed by a family member or friend (24 percent) or another health care provider (6 percent), while others did not specify who recommended it (24 percent).

When asked how pain levels changed before and one month after starting marijuana, most patients reported that average pain scores dropped from 9.0 on a scale of 0-10 to a more moderate pain threshold of 5.6.

However, older patients reported a reduction in the use of other painkillers less often than younger patients (64 percent versus 93 percent), the researchers found. Older patients also recommended medical marijuana less often than younger ones (86 percent versus 100 percent respectively).

When patients were quizzed about whether side effects of medications impacted their daily activities, the average score went from 6.9 before starting medical marijuana to 3.5 a month after using the drug.

Patients who received home care visits from nurses were more likely to visit the emergency department during the evening on the same day, particularly for non-urgent issues, according to new research in CMAJ (Canadian Medical Association Journal).

"An emergency department visit is not necessarily a negative outcome, but may be if a frail patient could more appropriately be treated by their usual community-based providers who know them best," says Dr. Andrew Costa, McMaster University, Hamilton, Ontario, who led the study.

Compared with younger people, frail older adults visit the emergency department more often, have longer stays, more misdiagnoses, and are more likely to be admitted to hospital.

"There have been concerns that -- while striving for more efficiency -- home care has evolved to be task-focused without the kind of full-scope, comprehensive practice that could be integrated with responsive primary care," says Dr. Costa.

The study was conducted in Ontario's Hamilton-Niagara-Haldimand-Brant region, which has the largest number of adults older than age 65 in the province. Researchers used home care billing records for 2015 to determine which home care services a patient received, then linked those data to emergency department records to determine if a patient visited the same day after 5 pm. They found that patients who received home care visits from a nurse were more likely to visit the emergency department. The likelihood was greater among people who were not admitted to hospital or who had non-urgent scores for severity of illness that brought them to hospital.

"It's difficult to determine the appropriateness of an emergency department visit, but we found stronger associations with less acute emergency visits. This suggests that some patients likely could have received care in less acute settings if it was available," says Aaron Jones, a study author and PhD student at McMaster under Dr. Costa.

In a related commentary, Dr. Allan Detsky, Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, and coauthors write, "These findings are disappointing but not unexpected, and serve to remind us that patients who require home-based care are complex. When community-based nurses are neither integrated into primary care teams nor equipped with resources to manage patients' problems effectively -- perhaps by a limited scope of practice -- patients have nowhere else to go but the emergency department."

Sometimes this is due to a "failure to cope" (called "the social admission" in the United States) and can lead to poor care from health care providers because of negative attitudes.

"We must all remember that social problems are real problems and that those with "failure to cope" require compassionate and thoughtful care just as every other patient does; they are not impositions on our professional lives," urge the commentary authors."

"The association between home care visits and same-day emergency department use: a case-crossover study" is published April 30, 2018.

Healthy older people who exercise regularly are less inclined to struggle to find words to express themselves, research led by the University of Birmingham has discovered.

Researchers found that older adults' aerobic fitness levels are directly related to the incidence of age-related language failures such as 'tip-of-the-tongue' states.

The research, published today in Scientific Reports, is the first of its kind to investigate the relationship between aerobic fitness levels and temporary cognitive lapses, such as not having a word come to mind when speaking - known as a 'tip-of-the-tongue' state.

People in a tip-of-the-tongue state have a strong conviction that they know a word, but are unable to produce it, and this phenomena occurs more frequently as we grow older.

The University of Birmingham study - carried out in collaboration with the University of Agder in Norway, the University of Leuven in Belgium and King's College London - measured the occurrence of tip-of-the-tongue states in a psycholinguistic experiment.

The study saw a group of 28 healthy adults (20 women with the average age of 70 and 8 men with the average age of 67), being compared in a 'tip-of-the-tongue' language test to 27 young people (19 women with the average age of 23 and 8 men with the average age of 22).

The test involved a 'definition filling task', done on a computer. They were asked to name famous people in the UK, such as authors, politicians and actors, based on 20 questions about them. They were also given the definitions of 20 'low frequency' and 20 'easy' words and asked whether they knew the word relating to the definition.

The participants' underwent a static bike cycling test - a gold standard test which quantified their ability to use oxygen during exercise and their resulting individual aerobic fitness levels.

Lead author Dr Katrien Segaert, of the University of Birmingham's School of Psychology, said: "Older adults free from medical diseases still experience age-related cognitive decline.

"Significantly, what we found was that the degree of decline is related to one's aerobic fitness.

"In our study, the higher the older adults' aerobic fitness level, the lower the probability of experiencing a tip-of-the-tongue state.

"Importantly, our results also showed that the relationship between the frequency of tip-of-the-tongue occurrences and aerobic fitness levels exists over and above the influence of a person's age and vocabulary size."

Dr Segaert said that tip-of-the-tongue states are uniquely a problem with language functioning.

"Older adults sometimes worry that tip-of-the-tongue states indicate serious memory problems but this is a misconception: tip-of-the-tongue states are not associated with memory loss," she added. "In fact, older adults usually have a much larger vocabulary than young adults. Instead, tip-of-the-tongue states occur when the meaning of a word is available in our memory, but the sound form of the word can temporarily not be accessed."

"Accessing the sound forms of words is essential for successful and fluent language production, and its disruption has very noticeable negative consequences for older adults."

She said she hoped the study would add gravitas to the public health message that regular exercise is important to ensure healthy ageing.

She added: "There are a lot of findings already on the benefits of aerobic fitness and regular exercise, and our research demonstrates another side of the benefits, namely a relationship between fitness and language skills. We were able to show, for the first time, that the benefits of aerobic fitness extend to the domain of language."

"Maintaining good language skills is extremely important for older adults. Older adults frequently have word finding difficulties and they experience these as particularly irritating and embarrassing."

"Speaking is a skill we all rely on every day. Communication with others helps us maintain social relationships and independence into old age."

In future research, the University of Birmingham plans to undertake exercise intervention studies to determine whether regular exercise can successfully increase language abilities.

In a study of adults with rheumatoid arthritis, those who were severely obese experienced more rapidly progressing disability than patients who were overweight. This was not explained by features of their arthritis, including the amount of inflammation in their joints. In the Arthritis Care & Research study, weight loss after enrollment was also associated with worsening disability, possibly as a sign of frailty.

To examine the effects of obesity in patients with rheumatoid arthritis over time, Joshua Baker, MD, MSCE, of the Perelman School of Medicine at the University of Pennsylvania, and his colleagues examined information on 23,323 patients with rheumatoid arthritis from the National Data Bank of the Rheumatic Diseases and 1697 from the Veterans Affairs RA registry.

Severe obesity was associated with more rapid progression of disability. The study also found that patients who lost weight tended to become disabled more quickly, especially in those who were already thin. "We believe that this is because when people get older and acquire illnesses, they tend to lose weight. Therefore, the important weight loss in this study is unintentional," said Dr. Baker. "So, this study suggests that patients with rheumatoid arthritis and obesity would benefit from intentional weight loss through a comprehensive management strategy; however, when we see that someone is losing weight without trying, it's probably a poor prognostic sign, especially if they are already thin."

The findings are especially relevant when considering the rising rates of obesity in recent years. "While patients and rheumatologists may be focused mostly on disease activity, we should also consider this common condition, which can contribute to problems that are usually attributed to the arthritis itself," said Dr. Baker. "In addition, unintentional weight loss should alert us that the patient may be becoming frail and is at risk for developing new disability."

As new therapies and approaches to weight loss become available, these results will help promote their use in patients with arthritis, to help prevent disability over the long-term. The findings may also encourage health providers to recognize unintentional weight loss as a poor prognostic sign and refer patients for strength training, physical therapy, and other interventions to prevent disability.

Boston, MA - Maintaining five healthy habits--eating a healthy diet, exercising regularly, keeping a healthy body weight, not drinking too much alcohol, and not smoking--during adulthood may add more than a decade to life expectancy, according to a new study led by Harvard T.H. Chan School of Public Health.

Researchers also found that U.S. women and men who maintained the healthiest lifestyles were 82% less likely to die from cardiovascular disease and 65% less likely to die from cancer when compared with those with the least healthy lifestyles over the course of the roughly 30-year study period.

The study is the first comprehensive analysis of the impact of adopting low-risk lifestyle factors on life expectancy in the U.S. It will be published online April 30, 2018 in Circulation.

Americans have a shorter average life expectancy--79.3 years--than almost all other high-income countries. The U.S. ranked 31st in the world for life expectancy in 2015. The new study aimed to quantify how much healthy lifestyle factors might be able to boost longevity in the U.S.

Harvard Chan researchers and colleagues looked at 34 years of data from 78,865 women and 27 years of data from 44,354 men participating in, respectively, the Nurses' Health Study and the Health Professionals Follow-up Study. The researchers looked at how five low-risk lifestyle factors--not smoking, low body mass index (18.5-24.9 kg/m2), at least 30 minutes or more per day of moderate to vigorous physical activity, moderate alcohol intake (for example, up to about one 5-ounce glass of wine per day for women, or up to two glasses for men), and a healthy diet--might impact mortality.

For study participants who didn't adopt any of the low-risk lifestyle factors, the researchers estimated that life expectancy at age 50 was 29 years for women and 25.5 years for men. But for those who adopted all five low-risk factors, life expectancy at age 50 was projected to be 43.1 years for women and 37.6 years for men. In other words, women who maintained all five healthy habits gained, on average, 14 years of life, and men who did so gained 12 years, compared with those who didn't maintain healthy habits.

Compared with those who didn't follow any of the healthy lifestyle habits, those who followed all five were 74% less likely to die during the study period. The researchers also found that there was a dose-response relationship between each individual healthy lifestyle behavior and a reduced risk of early death, and that the combination of all five healthy behaviors was linked with the most additional years of life.

"This study underscores the importance of following healthy lifestyle habits for improving longevity in the U.S. population," said Frank Hu, chair of the Department of Nutrition at Harvard Chan School and senior author of the study. "However, adherence to healthy lifestyle habits is very low. Therefore, public policies should put more emphasis on creating healthy food, built, and social environments to support and promote healthy diet and lifestyles."

CHICAGO --- From presidents to retirees, more than 17 million people over the age of 50 golf regularly. Knee osteoarthritis, which causes swelling, pain and difficulty moving the joint, is one of the leading causes of disability in this age group.

It may seem intuitive that golfers with knee osteoarthritis should stay off their feet and ride in a golf cart. But new research from the Shirley Ryan AbilityLab and Northwestern Medicine has found, for the first time, that walking the course provides significantly higher health benefits and is not associated with increased pain, cartilage breakdown or inflammation.

This study is the first comparing the health benefits of walking the golf course versus using a cart, as well as the first to use a blood-based biomarker analysis in knee osteoarthritis during a prolonged sporting event. The findings will be presented April 28 at the Osteoarthritis Research Society International Annual Meeting in Liverpool, England.

The health benefits of golf have decreased as the number of people who ride the course has increased over the past 20 years. In the late 1980s, 45 percent of all rounds of golf were played with a golf cart. By 2006, 69 percent of rounds were played with a cart. During this same time period, activity has decreased among Americans, while obesity has increased.

"Individuals with knee osteoarthritis are often concerned about pain and may be more likely to use a golf cart," said lead study author Dr. Prakash Jayabalan, a physician scientist at the Shirley Ryan AbilityLab and an assistant professor of physical medicine and rehabilitation at Northwestern University Feinberg School of Medicine.

"However, through sophisticated blood-based biomarker analysis, this study has shown that golfers with knee osteoarthritis do not need to be concerned about worsening their disease through walking the course. In fact, walking provides the best health benefit," Jayabalan said.

The study, completed in partnership with the Glenview Park District Golf Course in Glenview, Illinois, involved 15 participants -- 10 who had knee osteoarthritis and five who were of similar age but did not have the disease. Participants played 18 holes (one round of golf) walking the course and, on a separate day, the same individuals played a round riding a golf cart. The research team compared their heart rates to determine the intensity of exercise performed and took blood samples during each round to measure markers of cartilage stress and inflammation.

The researchers found that, prior to starting either round, the golfers with knee osteoarthritis had an average pain score of 1.3 (on a scale of 0-10). When they played the round walking the course, they had an average 2.1-point increase in pain score. When they played the round using the golf cart, they experienced on average a 1.5-point increase, a difference that is not clinically significant.

The research team also measured blood-based biomarkers of cartilage stress and inflammation. Although both methods of transportation caused an increase in these markers (as would be expected with regular walking), there was no difference between the rounds.

When walking the course, golfers with knee osteoarthritis spent more than 60 percent of the round with heart rates in the moderate intensity heart rate zone. When driving on a cart, golfers spent 30 percent of the round in this range. While this figure is lower, it still fulfills daily exercise recommendations.

Although walking the course offers the most significant health benefits, the study found that riding the course with a golf cart during a round -- and the requisite moderate walking that comes with it -- still offers cardiovascular benefits and helps fulfill daily exercise guidelines.

"Bottom line: walking the course is significantly better than using a golf cart, but using a golf cart is still better than not exercising at all," said Jayabalan.

Bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of multiple myeloma, but these procedures are far too invasive to perform at every patient visit. Scientists from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, however, have shown that two ways to measure multiple myeloma DNA in blood samples provide highly detailed sets of genetic information that agree well not just with each other but with results from bone marrow tests.

"Until now, we haven't had a good way to measure how multiple myeloma cell populations evolve from precursor stages to diagnosed disease, and then respond to treatments, says Irene Ghobrial, MD, a Dana-Farber medical oncologist. "This is where blood biopsies can make a huge difference--extending our understanding of multiple myeloma, and really giving us a timeline of how the disease progresses and responds to therapy."

The collaborative research examined blood biopsies that gathered multiple myeloma tumor DNA from two sources. One is circulating free DNA (cfDNA), scraps of DNA released into the bloodstream by dying cells. The other is circulating tumor cells (CTCs)--myeloma cells themselves.

"Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding, because this means that routine genetic profiling of patient tumors from blood would be feasible," says Ghobrial, co-senior author on a paper reporting the work in Nature Communications.

The blood biopsy analyses followed a two-step sequencing approach, says Viktor Adalsteinsson, PhD, group leader of the Blood Biopsy Team at the Broad Institute and co-senior author on the paper. The first step, developed by his team and called "ultra-low pass" whole genome sequencing, was a cost-effective method to identify blood samples with tumor DNA fraction of at least 5-10%, allowing more comprehensive genetic analysis. In the second step, the researchers performed whole exome sequencing (analyzing the protein-coding regions of the genome) on those samples.

The investigators examined cfDNA from 107 patients and CTCs from 56 patients. The scientists then matched up cfDNA with bone marrow data from nine patients, and compared all three forms of biopsy in four additional patients. Overall, the gene profiles overlapped closely--demonstrating about 99% agreement between liquid and bone marrow biopsies for tumor gene mutations, for instance.

Such high levels of agreement suggest that the two forms of liquid biopsy might be used interchangeably to track patients with multiple myeloma, the researchers say, and employing both techniques might further increase the chances of understanding the disease in each patient.

It's also possible that blood biopsies will offer more comprehensive genetic information than bone marrow tests, says Salomon Manier, MD, PhD, co-first author on the paper and a former graduate student in the Ghobrial lab.

Knowing the entire genetic spectrum of disease is crucial to individualize treatment, especially given the growing number of therapeutic options for multiple myeloma, Manier points out. But bone marrow biopsies collect cells from just one location, so those tests can miss nearby cells with quite different characteristics.

"We can't do personalized medicine with a single bone marrow biopsy," he says. "We need these blood biopsies to help guide treatment, because patients' tumors change over time."

The investigators emphasize that results of their study must be confirmed in larger patient cohorts, now ongoing, before blood biopsies can be brought into clinical use.

Among their next steps, the scientists aim to develop methods that provide more detailed and clinically appropriate genetic information, and to hone techniques that work in blood samples with lower fractions of cancer DNA. "Our ultimate goal is to eventually use all the samples to monitor disease progression," says Jihye Park, PhD, researcher in the Ghobrial lab and co-first author on the paper.

"The technology is basically there, says Ghobrial. "Our patients are so excited to see these tests, and now we need to develop clinical tools that become part of routine testing."

"These noninvasive techniques can really open the door for longitudinal study of cancer evolution and progression," says Adalsteinsson, whose group pursues many projects to comprehensively sequence solid tumors as well as blood cancers. "We believe it's important to look broadly at a patient's cancer genome and how it changes over time--to identify not only the known actionable mutations of today but also to discover new ones that will inform better and more effective treatments of tomorrow."

Since its clinical description in 1881, Tay-Sachs disease has had almost totemic significance as a cruel and relentless genetic condition that destroys the developing brain of babies and young children. Formerly considered to be restricted to Ashkenazy Jews, it can occur at almost any age and in any ethnic group. Moreover, with its close relatives, Sandhoff disease and the exceptionally rare GM2 activator deficiency, Tay-Sachs often masquerades as other neurological illnesses. There is no treatment beyond palliative care, and with a pressing medical need so typical of countless other nervous diseases, there is a pressing need and a formidable challenge in contemporary research.

This article considers the history, social context and scientific complexities of Tay-Sachs disease: not only does it represent a metabolic defect of glycosphingolipids but it is, par excellence, a lysosomal disease and so a tantalising target for treatment by functional complementation. Lysosomes were discovered by Christian de Duve; but even though he had had training as a physician, the founding father of Cell Biology had little time for studying the pathogenesis of inborn lysosomal diseases. However, de Duve realised that lysosomes could be readily accessed from outside the cell and, at the end of his life, stated that his research had been motivated by his wish to cure diseases such as Tay-Sachs disease, which progressively destroys nerve cells. In considering Tay-Sachs and related lysosomal diseases, after a prolonged period of therapeutic research, gene therapy at last offers a highly promising and tractable stratagem. This sanguine conclusion emphasises the accuracy of de Duve's insights and the striking boldness of his vision.

The GM2 gangliosidoses comprise Tay-Sachs and Sandhoff disease as well as the ultra-rare GM2 activator protein deficiency, intimately linked biochemically, pathologically and clinically. Their manifestations result from defects in one of three genes: HEXA, HEXB and GM2A, which code for the α- and β-subunits of β-hexosaminidase and GM2 activator protein, respectively. The integrity of this triad, which cooperate to hydrolyse ganglioside GM2 in the lysosome, is an absolute requirement; and when one or other of the genes is dysfunctional, GM2 ganglioside accumulates progressively in tissues rich in this sphingolipid such as the brain. Disease onset correlates roughly with residual enzymatic activity. Typically, in the acute infantile form arrest of neurodevelopment followed by regression of attained milestones progress inexorably, with death occurring at around 3 years of age, whereas in late-onset forms variable presentations occur that often resemble better-known neurodegenerative conditions.

Since first descriptions of GM2 gangliosidosis in the late nineteenth century as unique and devastating disease entities principally of young children, attempts to eradicate the disease through prevention in at-risk populations has been rapid and highly successful, once the biochemical defects were understood. A testament of this success is demonstrated by the fact that disease prevalence is currently higher in the general population, largely due to a lack of widespread screening programmes.

In common with other lysosomal enzymes, those responsible for the most frequent forms of GM2 gangliosidosis, β-hexosaminidase A and B, are made in the endoplasmic reticulum and travel to the lysosome where they execute their function. However, it was discovered that a significant proportion of these enzymes is secreted into the extracellular space; remarkably, they can be re-captured by neighbouring cells and transported to the lysosome where they function normally - a property that can be exploited in therapeutic applications. Purified enzyme has been injected intravenously and into the cerebrospinal fluid of patients with disappointing results. Substrate reduction therapies to ameliorate the burden of the stored material and pharmacological chaperones have also failed to rescue the disease. This has been attributed principally to the low penetrance of these substances into the brain parenchyma due to the blood-brain-barrier.

The discovery of naturally occurring animal models of disease - several breeds of cat and sheep - together with the creation of mouse strains by genetic manipulation allows systematic evaluation of potential treatments. Gene therapy currently rates as number one stratagem to definitively impact the course of the disease. Impressive outcomes in the mouse model have now been replicated in the larger and more complex cat and sheep brains. Encouraged by these results a few centres around the world have embarked in the design of clinical trials using recombinant Adeno-associated viruses for gene transfer.

Cocaine and other drugs of abuse hijack the natural reward circuits in the brain. In part, that's why it's so hard to quit using these substances. Moreover, relapse rates hover between 40 and 60 percent, similar to rates for other chronic conditions like hypertension and Type 1 diabetes.

University of Pennsylvania behavioral pharmacologist and neuroscientist Heath Schmidt studies how long-term exposure to drugs such as cocaine, nicotine, and prescription opioids affects the brain and how these changes promote relapse in someone who has kicked the habit. A recent paper, published in the Nature journal Neuropsychopharmacology, investigated a novel treatment for cocaine addiction, something that touches 900,000 people in the United States annually.

"As a basic scientist I'm interested in how the brain functions during periods of abstinence from cocaine and other drugs and how neuro-adaptations in the brain promote relapse back to chronic drug taking," he explains. "From the clinicians' perspective, they're looking for medications to try to prevent relapse. Our goal as basic scientists is to use animal models of relapse to identify novel medications to treat cocaine addiction."

Schmidt and colleagues from Penn Nursing and Penn Medicine had hypothesized that the neural mechanisms and neural circuits in the brain that play a role in food-seeking might overlap with those key to drug-taking. Through several experiments, they discovered that drugs that activate receptors for glucagon-like peptide 1 (GLP-1), a hormone that reduces food intake and blood glucose levels, could actually decrease the desire to seek out cocaine. What's more, there are several FDA-approved medications used to treat diabetes and obesity that already target GLP-1 receptors.

"One of the first questions we had--and we were really just kind of curious--was, does cocaine at all affect circulating levels of metabolic factors like leptin, insulin, GLP-1 that have been shown to regulate food intake?" says Schmidt, whose primary appointment is in Penn's School of Nursing.

The research team got its answer from a simple experiment with a rat animal model: Blood drawn after 21 days of cocaine intake revealed decreased levels of the GLP-1 hormone. Though the primary cells that synthesize and release this hormone are found in the small intestine, there's also a source in the brain called the nucleus tractus solitarius.

"Knowing all of this got us interested in GLP-1," Schmidt says. "Does it actually play a role in modulating cocaine-mediated behaviors?"

From there, the research team homed in on GLP-1 receptors and the drugs that activate them, what are known as receptor agonists. To test the efficacy of the medications in question, Schmidt and colleagues used an animal model of relapse with rats. For a three-week period, the rats could press a lever for intravenous infusions of cocaine as frequently as they desired. On average, the animals self-administered 28 infusions of cocaine each day.

The scientists then swapped out the cocaine for saline, leading to a period of withdrawal. Lever-pressing rates dropped significantly.

"At that point, we considered drug-taking to be extinguished," Schmidt says. "We then reinstated drug-seeking by re-exposing the rats to the drug itself or to cues paired with the drug during the self-administration phase, like a light that comes on when the lever gets pressed."

Once again rats depressed the lever at high rates, an indication that they were seeking the drug--akin to relapse in a human who is addicted.

The researchers next pretreated the animals with one of the FDA-approved drugs intended for diabetes and obesity treatment, Exendin-4, to determine whether it might reduce or altogether block cocaine-seeking. Results showed a significant decrease in drug-craving and -seeking, both after an acute injection of cocaine and from re-exposure to environmental cues during withdrawal.

"This tells us Exendin-4 can block the effects of cocaine itself but also condition stimuli previously paired with cocaine," Schmidt notes. "This was really exciting because it's the first demonstration that the GLP-1 system, and the drugs that target this system, could potentially play an important role in cocaine seeking and relapse. The other really interesting aspect of these studies are the doses."

GLP-1 receptor agonists are known to cause nausea and vomiting at pretty high rates in diabetic and obese patients who use them, so Schmidt and colleagues wanted to ensure that the reason for a decrease in cocaine-seeking wasn't from animals being sick. They identified doses that both reduced cocaine-seeking and did not produce adverse effects. A follow-up experiment that infused the GLP-1 agonist directly into the brain replicated the findings. Taken together, these findings indicate that low doses of a GLP-1 receptor agonist can selectively reduce cocaine-seeking without causing nausea.

As a final step, the researchers isolated the brain pathway able to boost GLP-1 signaling, by using a fluorescent dye to track where the drugs actually went in the body after they were administered.

"We've shown for the first time that central GLP-1 signaling plays an important role in cocaine-seeking," Schmidt explains. "We've identified systematic and intra-cranial doses of GLP-1 receptor agonists that reduce cocaine-seeking and don't produce adverse effects, and we think that if you increase GLP-1 signaling in the brain in general, you can reduce cocaine-seeking in rats and, potentially, craving-induced relapse in humans." To begin testing this, Schmidt's team is collaborating with researchers at Yale University to screen the efficacy of these drugs in a population of humans addicted to cocaine.

Beyond that, Schmidt says he's hopeful these results have potential for drugs of abuse beyond cocaine, too. However, he adds, much more research is needed before this can be stated conclusively. "There is a lot we don't know about the GLP-1 system in the brain," he says. "What is the exact circuitry in the brain? Is this signaling the same as what mediates food intake or is it slightly different? Does cocaine change it in any way? We're working on that." 

SAN DIEGO, April 26, 2018 - A new study looked at the effectiveness of novel risk tool to predict 30-day readmission rates in patients undergoing transcatheter aortic valve replacement (TAVR). This first ever tool calculates a score to help clinicians and medical professionals predict risk of 30-day readmission for TAVR patients and can be easily incorporated in patient electronic medical records (EMR). The study was presented today at the Society for Cardiovascular Angiography and Interventions (SCAI) 2018 Scientific Sessions.

More than five million Americans are diagnosed with heart valve disease each year (AHA). TAVR is a procedure used for intermediate and higher open surgical-risk patients with severe narrowing of the aortic valve. In TAVR, a prosthetic valve is implanted percutaneously in the place of the diseased native valve. Patients who undergo TAVR are typically older with higher prohibitive risks and greater number of clinical comorbidities. Nearly 15-20 percent of patients who undergo TAVR - a less invasive procedure to replace the heart's aortic valve - are readmitted within 30 days. Readmissions are costly to patient outcomes and are also associated with more than $40 billion in hospital costs annually.

The study analyzed patients in the Nationwide Readmissions Database (NRD) who underwent TAVR from January 2013 to September 2015. Complex survey methods, hierarchical regression and the 'rms' library were implemented to create a prediction ruler to determine probability for 30-day readmission. The study's researchers performed an internal calibration with bootstrapping.

During the study period, a total of 39,305 patients underwent endovascular TAVR, and 6,380 (16.2 percent) were readmitted within 30 days. The final risk tool included the following variables: chronic kidney disease, end stage renal disease on dialysis, anemia, chronic lung disease, chronic liver disease, atrial fibrillation, length of stay >5 days, acute kidney injury and discharge disposition. The c-statistic of the model was 0.63. A score of 212 was associated with a more than 30 percent readmission rate.

"The creation of this tool and the results of the study are very assuring because it allows for better understanding how patients should be managed peri-TAVR. By recognizing patients at higher risk of readmission, we can guide post discharge care coordination and improve transitions of care to decrease readmission, improve quality of life, reduce healthcare costs and ultimately impact mortality rates," said lead author Sahil Khera, MD, Massachusetts General Hospital.

"Use of the simple risk tool will allow the entire care team to quantify readmission risk and enhance our ability to provide personalized transitional care to hopefully mitigate this risk," said co-author Sammy Elmariah, MD, also from the Massachusetts General Hospital.

The authors are looking to start using this tool and incorporating into EMRs in hospital systems across the country in the near future.

Session Details:
"Late-Breaking Clinical Science II: Derivation of a Simple Risk Tool to Predict 30-day Readmission after Transcatheter Aortic Valve Replacement" [April 27, 2018, 11:00 a.m. - 12:00 p.m. PDT, Seaport DE]

SAN DIEGO, April 26, 2018 - A contemporary, real-world analysis shows lower mortality rates when culprit-only intervention is used for patients with multivessel disease (MVD) and acute myocardial infarction (AMI) with cardiogenic shock (CS). The authors compared culprit vessel intervention (CVI) to multivessel intervention (MVI) and presented the results today as late-breaking clinical science at the Society for Cardiovascular Angiography and Interventions (SCAI) 2018 Scientific Sessions.

In patients with AMI and CS, percutaneous coronary intervention (PCI) of the culprit vessel is associated with improved outcomes. However, a large majority of these patients have multivessel disease (MVD). Whether or not PCI of non-culprit disease in the acute setting improves outcomes is unclear. The results of this new study come on the heels of the recent randomized CULPRIT-SHOCK trial that was the first to find revascularization of all significant non-culprit lesions worsens outcomes. The late-breaking clinical science study is the most recent study to compare the two PCI strategies in this patient population.

The study assessed CVI versus MVI in 649 patients with AMI, CS and MVD that were enrolled in the British Columbia Cardiac Registry (2008-2014). All-cause mortality was evaluated at 30 days and one-year.

Compared with MVI, CVI was associated with lower mortality at 30 days (23.7 percent vs. 34.5 percent) and one-year (32.6 percent vs. 44.3 percent). CVI was an independent predictor for survival at 30 days (HR=0.78, 95 percent Cl: 0.64-0.97, p=0.023) and one-year (HR=0.78, 95 percent Cl: 0.64-0.97, p=0.023). The findings were confirmed in propensity-matched cohorts. Overall, in patients with AMI and CS, a CVI approach was associated with lower mortality.

"The comparison between culprit-only and multivessel intervention is a hot topic of conversation and debate in our field, and the results of our study add to the recent CULPRIT-SHOCK trial and help us better understand the positive outcomes of a culprit-only approach," said lead author Bilal Iqbal, Victoria Heart Institute Foundation, Canada. "The CULPRIT-SHOCK trial is the largest body of randomized evidence in the CS population. The recent Korean registry has shown that MVI may be better, but there are differences in the definition of MVI, making comparison difficult. Importantly, in CULPRIT-SHOCK and our study, MVI was defined as non-culprit PCI at the time of index intervention, and CVI was defined as PCI of culprit vessel only at the time of index intervention. Whereas in the Korean registry, MVI included non-culprit PCI, even if it were performed as an in-hospital staged procedure. Thus, it is conceivable that by adopting the definition of CVI used in our study and CULPRIT-SHOCK, the Korean study may have yielded different results."

The authors call for more randomized studies to further evaluate the two PCI strategies for this patient population in order to gain a better understanding of the safety and feasibility of culprit-only lesion approach.

Session Details:
"Late-Breaking Clinical Science I: The prognostic impact of revascularization strategy in acute myocardial infarction and cardiogenic shock: insights from the British Columbia Cardiac Registry" [April 26, 2018, 11:00 a.m. - 12:00 p.m. PDT, Seaport DE]

About SCAI
The Society for Cardiovascular Angiography and Interventions is a 4,200-member professional organization representing invasive and interventional cardiologists in approximately 75 nations. SCAI's mission is to promote excellence in invasive/interventional cardiovascular medicine through physician education and representation, and advancement of quality standards to enhance patient care.

For more information about the SCAI 2018 Scientific Sessions, visit SAN DIEGO, April 26, 2018 - A contemporary, real-world analysis shows lower mortality rates when culprit-only intervention is used for patients with multivessel disease (MVD) and acute myocardial infarction (AMI) with cardiogenic shock (CS). The authors compared culprit vessel intervention (CVI) to multivessel intervention (MVI) and presented the results today as late-breaking clinical science at the Society for Cardiovascular Angiography and Interventions (SCAI) 2018 Scientific Sessions.

In patients with AMI and CS, percutaneous coronary intervention (PCI) of the culprit vessel is associated with improved outcomes. However, a large majority of these patients have multivessel disease (MVD). Whether or not PCI of non-culprit disease in the acute setting improves outcomes is unclear. The results of this new study come on the heels of the recent randomized CULPRIT-SHOCK trial that was the first to find revascularization of all significant non-culprit lesions worsens outcomes. The late-breaking clinical science study is the most recent study to compare the two PCI strategies in this patient population.

The study assessed CVI versus MVI in 649 patients with AMI, CS and MVD that were enrolled in the British Columbia Cardiac Registry (2008-2014). All-cause mortality was evaluated at 30 days and one-year.

Compared with MVI, CVI was associated with lower mortality at 30 days (23.7 percent vs. 34.5 percent) and one-year (32.6 percent vs. 44.3 percent). CVI was an independent predictor for survival at 30 days (HR=0.78, 95 percent Cl: 0.64-0.97, p=0.023) and one-year (HR=0.78, 95 percent Cl: 0.64-0.97, p=0.023). The findings were confirmed in propensity-matched cohorts. Overall, in patients with AMI and CS, a CVI approach was associated with lower mortality.

"The comparison between culprit-only and multivessel intervention is a hot topic of conversation and debate in our field, and the results of our study add to the recent CULPRIT-SHOCK trial and help us better understand the positive outcomes of a culprit-only approach," said lead author Bilal Iqbal, Victoria Heart Institute Foundation, Canada. "The CULPRIT-SHOCK trial is the largest body of randomized evidence in the CS population. The recent Korean registry has shown that MVI may be better, but there are differences in the definition of MVI, making comparison difficult. Importantly, in CULPRIT-SHOCK and our study, MVI was defined as non-culprit PCI at the time of index intervention, and CVI was defined as PCI of culprit vessel only at the time of index intervention. Whereas in the Korean registry, MVI included non-culprit PCI, even if it were performed as an in-hospital staged procedure. Thus, it is conceivable that by adopting the definition of CVI used in our study and CULPRIT-SHOCK, the Korean study may have yielded different results."

The authors call for more randomized studies to further evaluate the two PCI strategies for this patient population in order to gain a better understanding of the safety and feasibility of culprit-only lesion approach.

Session Details:
"Late-Breaking Clinical Science I: The prognostic impact of revascularization strategy in acute myocardial infarction and cardiogenic shock: insights from the British Columbia Cardiac Registry" [April 26, 2018, 11:00 a.m. - 12:00 p.m. PDT, Seaport DE]