Body

WHAT:

A more intensive biomedical research approach is necessary to control and ultimately eliminate tuberculosis (TB), according to a perspective published in the March 2018 issue of The American Journal of Tropical Medicine and Hygiene. In the article, authors Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and Robert W. Eisinger, Ph.D., special assistant for scientific projects at NIAID, discuss the need to modernize TB research by applying new diagnostic, therapeutic, and vaccine approaches. The perspective is based on a lecture delivered by Dr. Fauci on Nov. 17, 2017 in Moscow at the first World Health Organization Global Ministerial Conference, "Ending TB in the Sustainable Development Era: A Multisectoral Response."

TB, a bacterial infection that typically infects the lungs, is one of the oldest known human diseases and the leading infectious cause of death worldwide. The authors recall the significant HIV/AIDS research advances made in the nearly 37 years since AIDS was first recognized, and encourage the scientific community to strive for comparable TB milestones.

Specifically, the authors call for systems biology approaches (using large data sets and modeling to understand complex biological systems) to fill critical knowledge gaps in understanding how Mycobacterium tuberculosis (Mtb) infection causes disease. Such research could help explain why some people infected with Mtb have latent infections and show no signs of disease while others, especially those co-infected with HIV, become sick. The perspective also underscores the need for improved diagnostic tests, including those that can detect Mtb in various specimens as well as rapid, inexpensive tests that can detect drug-resistant TB.

Lengthy and complex treatment regimens and an increasing number of multi-drug-resistant TB infections make the disease increasingly difficult to cure. The authors note that the ultimate treatment goal should be drug combinations administered for shorter time periods that can cure people infected with any strain of Mtb. Another research goal is a safe and more broadly effective vaccine, which remains one of the most difficult challenges, according to Drs. Fauci and Eisinger. However, they explain, a vaccine and other significant advances are possible with an innovative and aggressive biomedical research program and rapid translation of results into global control strategies.

DALLAS - March 9, 2018 - Mandatory flu vaccines for health care workers improve participation by as much as 30 percent and reduce absenteeism during critical periods of patient surges by about 6 percent, findings from a multi-institutional study show.

Previous work focused on the impact of health care worker vaccination on improving patient outcomes. The findings expand the potential benefits of an institutional policy and help settle previous conflicting data on whether the mandatory policies reduce health care worker absenteeism. As seen this year, health care institutions can struggle to care for surging numbers of patients with influenza when the number of workers available is declining due to illness.

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If you get the flu:

The key is to see your doctor early during the illness because anti-viral therapy is most effective if used within 48 hours of the onset of symptoms.

Always see a physician immediately if you're having chest pains or trouble breathing - both of these symptoms may be an indication of pneumonia.

Beware of potential build-up of acetaminophen and over-the-counter medicines.

Most common symptoms:

Sudden onset of fever

Headaches

Nausea

Body aches

Coughing and sneezing

Strategies to reduce infection risk:

Practice good hand hygiene - wash your hands often and be mindful of what you touch, including your keyboard, cell phone, handshakes and doorknobs. Both washing your hands or using hand sanitizers can help, although the alcohol-based gels may be easier on sensitive skin.

Cover your nose and mouth when you cough or sneeze. Use your sleeve if you don't have a tissue handy. Avoid touching nose of coughing into hands.

Protect your household - all those who are eligible to get the flu vaccine should. Doing this also helps protect anyone in your household (newborns and those with other medical conditions) who may not be eligible to get one.

If your child contracts the flu, try to keep him or her home from school.

If you contract the flu, don't try to be a champion - stay home until you're healthy.

"Studies suggest that higher vaccination rates among health care workers decrease patient mortality and health care associated in?uenza in certain settings," said Dr. Trish Perl, Chief of Infectious Diseases at UT Southwestern Medical Center, and one of the study corresponding authors and overall Principal Investigator. "In addition, absenteeism can pose a serious threat to how effectively a hospital is able to manage the surge of patients during an outbreak. Our study shows that mandatory vaccination policies help maintain better staffing levels and staffing options during those critical surges."

Researchers studied the effects over three separate flu seasons at three institutions with mandatory vaccination policies and four institutions that offered optional vaccination. For all individuals studied (4,000-plus health care workers), vaccination was offered free and on-site.

Researchers found that:

At mandatory sites, 97 percent, 96 percent and 92 percent of health care workers received vaccinations in the three years studied.

At nonmandatory sites, 67 percent, 63 percent, and 60 percent of workers were vaccinated over the same period.

Absenteeism among health care workers was about 6 percent lower at mandatory sites than nonmandatory sites, and the number of days absent also was lower.

Males, older workers, and those at nonmandatory vaccination sites had longer durations of sick leave.

Vaccinated health care workers had a 30 percent reduction in absenteeism compared with nonvaccinated health care workers.

"This was a large study across a variety of types of institutions, including pediatric and adult acute care hospitals and VA facilities, which asked whether policies that require employees to get a flu vaccine protected both the employee as well as the institutions," said Dr. Perl, Professor of Internal Medicine who holds the Jay P. Sanford Professorship in Infectious Diseases.

The study, which appears in the journal Infection Control and Hospital Epidemiology, didn't look specifically at whether higher rates of vaccination of health care workers reduced infections among patients, but previous studies have shown that this is true, especially among the most vulnerable patient populations.

The Healthy People collaborative in the U.S. has a goal of 90 percent vaccination rates among health care workers by 2020. The study suggests that goal will be difficult to achieve with only voluntary policies, said Dr. Perl.

Children with mitochondrial diseases who suffered acute metabolic strokes benefited from rapid intravenous treatment with the amino acid arginine, experiencing no side effects from the treatment. The diseases were caused by a range of different genetic disorders. In half of the stroke episodes, patients showed clinical improvements in symptoms such as seizures and partial paralysis.

Mitochondrial disease results from malfunctions in mitochondria, the energy-generating "batteries" dwelling within our cells. Caused by mutations in roughly 300 different genes, there are a broad variety of mitochondrial disorders, most of which currently have no effective treatment.

Two mitochondrial medicine experts from Children's Hospital of Philadelphia (CHOP) reported on eight years of clinical experience in providing intravenous (IV) arginine when new-onset neurologic problems concerning for acute stroke-like episode developed in nine pediatric mitochondrial disease patients. Their retrospective study appeared online Feb. 2 in Molecular Genetics and Metabolism.

"In half of our patients we saw at least partial reversal of their metabolic stroke symptoms," said study leader Marni J. Falk, MD, executive director of CHOP's Mitochondrial Medicine Frontier Program. "This is a single-center retrospective study of clinical practice outcomes, but one with promising results. While we need more research, conducted prospectively in larger groups of patients, this analysis expands the evidence base of potentially promising treatments for a wide range of otherwise very severe and progressive mitochondrial diseases." Falk's co-author was Rebecca D. Ganetzky, MD, a clinical geneticist and attending physician who specializes in metabolic diseases.

Metabolic strokes occur in a broad range of mitochondrial disorders. Arginine is already used to acutely treat these complex strokes in adult patients who have a well-known mitochondrial disease syndrome called MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes). Unlike classic strokes caused by blood clots blocking major arteries in the brain, metabolic strokes result from energy deficiency at the cellular level in brain regions with a particularly high energy demand. Recent clinical practice guidelines from the Mitochondrial Medicine Society recommended using IV arginine in patients having stroke-like episodes from MELAS, and considering its use at the time of stroke-like episodes in other mitochondrial diseases. However, no previous systematic studies were performed to objectively evaluate benefits and risks of IV arginine in other mitochondrial diseases beyond MELAS.

The current study reported on nine unrelated patients treated at CHOP between 2009 and 2016 once or more for acute stroke-like events in which they developed new neurological problems. The team evaluated outcomes from a total of 17 different stroke-like episodes. Patients ranged in age from under 19 months to 23 years, with a median age of 8 years at the time of their metabolic stroke. All had non-MELAS mitochondrial disorders, resulting from diverse genetic causes.

Like many patients with mitochondrial disease, nearly all patients in this cohort were already taking oral "mitochondrial cocktails" of vitamins and cofactor supplements, commonly including oral arginine, at the time of their stroke-like episode. Despite their frequent use, nearly all such nutritional supplements are unstandardized and untested. Ganetzky pointed out that intravenous arginine is much more potent than oral arginine, adding "This study was an opportunity to more systematically analyze a therapy that is clinically used on an empiric basis in the course of acute clinical care." Arginine is not used to treat classic, non-metabolic vascular strokes.

In eight (47 percent) of the 17 stroke-like episodes, positive clinical responses occurred, including stopped seizures, normalized strength, and resolved atonia (low muscle tone). Greater improvements occurred in children with acute hemiplegic stroke (weakness or paralysis on one side of the body). Magnetic resonance imaging (MRI) performed in some patients showed that brain changes caused by the stroke returned to normal after patients received IV arginine. Two patients who did not respond to IV arginine treatment for stroke-like episodes that developed during acute infections died of progressive, multi-system problems. No adverse effects were seen from the IV arginine treatment.

Overall, the best results from IV arginine occurred when patients received treatment immediately upon clinical recognition of a new neurologic problem that was concerning for an acute metabolic stroke. Previous research has suggested that arginine acts by improving the flow of nitric oxide, which relaxes blood vessels to improve circulation.

"Given these observed clinical benefits with low overall risks, our retrospective study data support the current use of IV arginine at the onset of acute metabolic strokes in children with many forms of mitochondrial disease," said Falk, who added that prospective, larger studies should be performed. "As we move forward in mitochondrial medicine, we strongly encourage the objective evaluation of all current practices and potential therapies as rigorously as possible, both in preclinical models and in robust clinical trials."

An educational session on opioid abuse and new prescription guidelines led to a 45 percent decrease in opioids prescribed after hand surgery, according to a study at Hospital for Special Surgery (HSS). The educational session was mandatory for all HSS staff involved in prescribing controlled substances. The hospital also conducted extensive research to develop guidelines for opioid prescription.

The study, "Opioid Prescriber Education and Guidelines Decrease Opioids Prescribed after Ambulatory Hand Surgery," was presented today at the American Academy of Orthopaedic Surgeons Annual Meeting in New Orleans.

"Prescription opioid misuse is an epidemic in the United States with almost 2 million Americans having abused prescription opioid medication. It's now the leading cause of death in adults under 50," said Daniel Osei, MD, a hand surgeon at HSS and senior investigator. "Recent studies demonstrate a consistent over-prescription of opioid medications nationwide. As physicians, we always strive to provide adequate pain control for our patients. But we are also increasingly aware that when there are excess amounts of unused medication, it can be diverted to uses other than treating pain."

Currently, there is no national standardized prescriber education course or postoperative opioid guidelines for ambulatory hand surgery. However, prescriber education previously has been shown to decrease over-prescription on a small scale.

The HSS researchers set out to evaluate the effect of the education session and the hospital's new opioid guidelines on physician prescribing practices after ambulatory hand surgery.

HSS mandated a one- to two-hour education program in November 2016 for all employees qualified to prescribe controlled substances. The hospital also formulated prescribing guidelines after an extensive review of the medical literature on the amount of pain medication commonly needed after hand surgery. The new guidelines, which recommended a specific number of pills based on the type of hand surgery performed, were disseminated to staff in February 2017.

To see if there was a change in prescribing practices, investigators reviewed postoperative opioid prescriptions for patients who underwent ambulatory hand surgery in the two months prior to the mandatory education session; in the two months following physician education; and during the two-month period that followed the dissemination of prescribing guidelines.

A total of 731 ambulatory hand surgeries with postoperative opioid prescriptions for patients were included in the study. All three time periods had a similar ratio of surgery types. Researchers found a 45 percent reduction in opioids prescribed after the education session and distribution of guidelines.

"It would be difficult to overstate the importance of this study. A 45 percent reduction is a huge amount and demonstrates the success of the program in reducing the amount of prescribed narcotics," said Dr. Osei. "Our results suggest that similar standardized education and prescribing guidelines on a national level could reduce the amount of opioids prescribed after ambulatory hand surgery nationwide."

The next step for Dr. Osei and his colleagues at HSS will be an analysis of how well the prescribing practices worked in terms of pain control and patient satisfaction for those in the study. He noted that among his own patients, he did not notice an increase in requests for more pain medication.

WHAT:

Monoclonal antibodies (mAbs)--preparations of a specific type of antibody designed to bind to a single target--have shown promise in the fight against cancer and autoimmune diseases. They also may play a critical role in future battles against emerging infectious disease outbreaks, according to a new article by scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The article is published online this week by The New England Journal of Medicine and outlines the potential uses for mAbs as treatments for infectious diseases and as a prevention tool for protecting individuals at risk of infection and slowing disease outbreaks.

The article, written by NIAID Director Anthony S. Fauci, M.D., and colleagues Hilary D. Marston, M.D., M.P.H., and Catharine I. Paules, M.D., highlights the research advances that could allow for rapid, strategic deployment of mAbs to prevent and treat emerging infectious diseases and, potentially, alter the course of epidemics.

Although mAbs were originally described in the 1970s, their value has become more widely recognized as scientists have developed more direct and improved approaches to identifying, selecting, optimizing and manufacturing them. These advances have allowed for improved safety and efficacy, and substantial efficiencies in identifying promising candidates. For example, mAbs now can be identified directly from individuals previously infected by or vaccinated against a specific pathogen. Moreover, modifications can be made to extend the life of a mAb and further improve its safety.

Because mAbs with optimized targeting and other characteristics can be developed, their activity can be precisely tailored to serve specific treatment and prevention purposes. For example, during the 2014-2016 Ebola outbreak, a small clinical trial of the drug ZMapp, which contains three different mAbs, appeared to show a drop in mortality among infected volunteers who received the experimental therapeutic. Additionally, research in laboratory animals suggests that mAbs may play a role in protecting pregnant women in Zika-endemic areas and their fetuses from infection. Further, promising preclinical studies suggest that mAbs aimed at specific targets on the influenza virus could treat influenza disease and interrupt influenza transmission when used prophylactically in uninfected individuals.

The authors caution that mAb-based therapies may be costly to develop and deploy at first and should be used judiciously. However, prices will likely fall in the future, as target optimization may offer effectiveness with smaller amounts of antibody, or novel approaches such as delivering antibodies through DNA or mRNA constructs, may be further developed. By prioritizing research for mAbs against infectious diseases, the authors assert, global health leaders can improve preparedness for treating and preventing emerging and re-emerging infectious diseases.

ARTICLE:

HD Marston et al. Monoclonal Antibodies for Emerging Infectious Diseases--Borrowing from History. The New England Journal of Medicine DOI: 10.1056/NEJMp1802256 (2018).

WHO:

NIAID Director Anthony S. Fauci, M.D., is available for comment.

AUGUSTA, Ga. (March 8, 2018) - Analysis of the inflammation-promoting proteins in the blood of patients with type 1 diabetes and related kidney disease indicates that the promoters of inflammation are diverse even in the same medical condition and that patients likely would benefit from an anti-inflammatory treatment that directly targets theirs, scientists report.

"We all think that prevention of inflammation will help prevent or delay diabetic kidney disease and probably other consequences of type 1 diabetes," says Dr. Jin-Xiong She, director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Augusta University and Georgia Research Alliance Eminent Scholar in Genomic Medicine.

"But not all inflammation is the same and not all patients have the same inflammation, even patients with the same condition like type 1 diabetes," says She, corresponding author of the study in the journal Frontiers in Immunology.

"From a prevention or therapeutic point of view, you really have to know what are the primary inflammatory mediators that are increased in a given patient so you can target those. That is really predictive, preventive personalized medicine and that is exactly what we are trying to enable," She says.

Chronically high levels of glucose in type 1 diabetes appear to get the attention of the immune system, resulting in chronic inflammation that can destroy organs, nerves and blood vessels.

So the MCG scientists looked at blood levels of a dozen mediators of inflammation in 89 patients with diabetes-related kidney disease as well as 483 patients without the kidney problems. The mediators' presence in the bloodstream indicate they might be having an impact body-wide. Previous studies in similar patients have assessed one or only a handful of these mediators.

The new, more comprehensive assessment of a dozen mediators, found 10 were elevated in patients who had related kidney damage. But it was these proteins in the TNF-alpha family and IL-6 that were significantly elevated in 40 percent of these patients, compared to those with well-functioning kidneys.

Another 40 percent of patients had moderately elevated levels of these mediators, indicating that they might not be the strongest treatment target for that second group, She says.

Blood levels of these inflammatory mediators may also provide biomarkers for predicting who has or who will likely get diabetes-related kidney disease, says Dr. Sharad Purohit, biochemist in the MCG Center for Biotechnology and Genomic Medicine and the study's first author. They also could help assess the effectiveness of treatment or prevention strategies.

Two classic inflammatory markers regularly measured in hospitals, C-reactive protein, or CRP, and serum amyloid A, or SAA, did not appear to be significant players in these patients, Purohit notes.

The MCG scientists are already doing a similar mediator analysis in a larger number of type 1 patients and are working with the MCG Department of Family Medicine to also start looking in the blood of patients with type 2 diabetes. The extensive analyses being done by the scientists are not yet available to physicians.

The scientists also are pursuing how to best target these mediators, including several nutritional supplements already known for their anti-inflammatory effects. While many anti-inflammatory agents exist, it is largely unknown what specific mediators they target.

Diabetes and high blood pressure are the leading causes of kidney failure in the United States, according to the National Kidney Foundation. Type 1 diabetes is an autoimmune disease where the insulin-producing cells of the pancreas are targeted by the patient's immune system. In type 2 diabetes, patients become less sensitive to the insulin they produce so they cannot properly use and store glucose.

(Boston)--Researchers have identified a protein in saliva (histatin-5) that protects the body from traveler's diarrhea.

The findings, available online in the Journal of Infectious Diseases, may lead to the development of new preventive therapies for the disease.

Traveler's diarrhea is an inconvenience to many in the U.S., but worldwide it can be deadly. It produces a watery diarrhea, which can cause life-threatening dehydration in infants or other vulnerable populations in endemic countries. With more than one billion cases each year, hundreds of thousands of deaths can be attributed to this bacterial disease which is caused by enterotoxigenic Escherichia coli (ETEC), invading the small intestine using arm-like structures called "pili."

Researchers from Boston University School of Medicine (BUSM) and collaborators exposed miniature human small intestines that they were able to grow in a dish (organoids) to the bacteria ETEC in the presence and absence of the protein histatin-5. When examined under the microscope, significantly fewer bacteria were able to attach to the tissue in the presence of histatin-5.

"We found that the protein histatin-5 present in human saliva stiffens the pili of ETEC, preventing the bacteria from effectively adhering to the small intestine," explained corresponding author Esther Bullitt, PhD, associate professor of physiology and biophysics at BUSM. "If they can't attach, they simply can't cause disease."

Prior to this study, it was not known that saliva could play such a large role in protecting the body from gut infections. According to the researchers, this initial line of defense in the mouth likely explains why it takes such a large number of ETEC to infect a human. They also suggest that histatin-5 might be manufactured as a dissolvable powder and used to prevent traveler's diarrhea in the future.

This new finding opens up the possibility that other salivary proteins might exist which protect against many other diseases, including infectious gastritis, food poisoning or even pneumonia. "We believe that our data represent the first example of a new paradigm in innate immunity: the contributions of salivary components to preventing infection. This research opens an untapped avenue for prevention of enteric infectious diseases through the targeted use of naturally occurring components of saliva."

Scientists with the Greehey Children's Cancer Research Institute at UT Health San Antonio have discovered a surprising connection between a breast cancer protein, BRCA1, and a pediatric cancer called Ewing sarcoma.

Their findings, reported March 7 in the journal Nature, reveal a completely new mechanism by which BRCA1 can be rendered dysfunctional. "The observations raise many new questions about both Ewing sarcoma and BRCA1 biology," said the study's senior author, Alexander J.R. Bishop, D.Phil., of UT Health San Antonio.

Ewing sarcoma is a pediatric bone and soft tissue cancer. The median age of Ewing sarcoma patients is 15 years, and more than half of patients are adolescents. "Our team worked to identify why Ewing sarcoma is usually sensitive to standard cancer drugs, with the hope of finding new targets for therapy and revealing new ways to treat the disease if it returns or does not respond to standard therapies," Dr. Bishop said.

Fused genes

Almost all Ewing sarcomas are caused by a rearrangement of two genes that are fused together. The resulting combination of the Ewing sarcoma protein, EWSR1, and another protein, usually FLI1, is called a "fusion oncogene." This bad actor promotes cancer.

The researchers reported in Nature that:

The mutant protein produced by the fusion oncogene interferes with normal EWSR1 protein function. Because of this, the cancer's normal cell functions run unchecked.

BRCA1, which repairs damaged DNA (genetic material) when those same cell functions shut off, cannot do this repair because the machinery keeps running.

"EWSR1 is like a train conductor who sees damage on the tracks ahead and stops the train," Dr. Bishop said. "BRCA1 is the repair crew who are passengers on the train and go fix the damage when the train stops. But now you've got this mutant bully, this fusion oncogene, who prevents the conductor from being able to stop the train and prevents the repair crew from getting off to work on the tracks."

HOUSTON-(March 7, 2018) - One of the nation's leading cardiologists is challenging the new hypertension guidelines, perhaps sparing up to 10 million people from unnecessarily aggressive blood pressure treatments.

Robert A. Phillips, M.D., Ph.D., Houston Methodist's chief medical officer, and his colleagues investigated the impact of new guidelines issued in November that redefine high blood pressure. Phillips, who is an expert in hypertension and cardiovascular disease, says while patients at higher risk for cardiovascular disease benefited from the stricter guidelines, those with lower risk had more harm than benefit from the intensive treatment recommendations.

The findings are described in a paper titled "Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension," appearing online March 7 and in print April 17 in the Journal of the American College of Cardiology, a leading medical journal in the field of cardiovascular disease.

"While it's estimated that 107,500 deaths could be averted annually in the U.S. by implementing more aggressive treatments, it may be accompanied by other serious, adverse events," Phillips said. "This presents clinicians and patients with a dilemma, potentially trading one clinically significant condition for another."

The new rules were written by a panel of 21 scientists and health experts who reviewed more than 900 published studies. Issued by the American Heart Association, American College of Cardiology and nine other professional health organizations, the new guidelines classify hypertension as a reading of 130 over 80, rather than 140 over 90. Under these new tightened rules, 46 percent of U.S. adults are now considered hypertensive, up from 32 percent.

This call for more aggressive treatment is based largely on data from the Systolic Blood Pressure Intervention Trial, or SPRINT, which was a large-scale study of more than 9,000 people, sponsored by the NIH's National Heart, Lung and Blood Institute.

"Classifying patients by degree of future risk might be the best way to identify who could benefit most from intensive treatment," Phillips said. "We developed a model using the 10-year cardiovascular disease risk and found that aggressive treatment of patients with a risk greater than or equal to 18.2 percent would result in more benefit than harm, while those with a risk of less than that would fare better under a standard blood pressure management approach."

These numbers are at odds with the new guidelines, which suggest treating patients with a greater than 10 percent risk.

One in four deaths in the United States each year are due to heart disease, according to the Centers for Disease Control and Prevention. It's the leading killer of both men and women, but the disease's genetic complexity makes it difficult to treat.

In a recently-published paper in npj Systems Biology and Applications, Northeastern physics professor Alain Karma and his colleagues describe their discovery of 36 previously unknown genes implicated in heart failure. The team confirmed that one of those genes plays a causal role in cardiac hypertrophy--abnormal thickening of the heart muscle--which can lead to heart failure.

"This is an exciting direction for personalized medicine, and also for identifying genes and therapeutic targets for complex diseases that involve many genes," Karma said.

The ultimate goal is to create personalized therapeutic drugs to reverse heart disease. Researchers are probably still a decade away from achieving that sort of tailored therapy, Karma said. But companies interested in developing such drugs can use the method he and his colleagues developed and the genes they identified to get a step closer.

The framework described in the paper can also be used to predict whether individuals suffering from a particular disease will respond to a given drug treatment, said lead author Marc Santolini, a postdoctoral research associate at Northeastern's Center for Complex Network Research.

"The method can predict beforehand whether a patient should be prescribed a different drug using just a simple blood test. This would save time and accelerate the therapy," Santolini said. "In general, this research highlights the importance of personalized approaches to uncover novel disease genes and better understand disease processes."

The traditional approach to finding genes related to heart disease works like this: Researchers take donated hearts from people who died unexpectedly but were previously healthy. They analyze the gene expression--that is, the amount of messenger RNA and proteins--produced by the genes of healthy hearts and compare it with the gene expression of sick hearts explanted from end-stage heart failure patients undergoing heart transplant.

"You see a different gene expression profile," Karma said. For example, if a gene found in the sick hearts expresses twice the amount of RNA as it did in the healthy hearts, it might be relevant to the disease. But so far, Karma said this method hasn't been very successful in finding important genes.

His team took an entirely different approach--using the Hybrid Mouse Diversity Panel, a collection of 100 genetically different strains of mice that can be used to analyze the genetic and environmental factors underlying complex traits. Within each strain, the mice are inbred, making them all identical twins on a genetic level.

Researchers took two mice from the same strain and gave one of them a stressor drug that induces heart failure. They then compared the stressed mouse's gene expression with its non-stressed twin. Since the mice have the same genome, they were able to pinpoint individual genes that changed expression as a direct result of the heart stressor. The researchers identified 36 such genes.

Many of these genes were previously unknown to be implicated in heart failure. Karma said one of them is known as a transcription factor, meaning it controls the expression of many other genes. The researchers confirmed the gene's role by using molecular biology techniques to silence it and observe the resulting changes of expression. They found the transcription factor gene was directly connected to a whole network of proteins known to play a role in cardiac hypertrophy.

One of the genes Karma found, called RFFL, was previously known to researchers to be implicated in other cardiac processes. However, it was not known to be related to hypertrophy, said Gideon Koren, a physician and director of the Cardiovascular Research Center at Rhode Island Hospital & the Cardiovascular Institute. Koren has been studying RFFL in his lab for the past two years.

"All of the sudden, this study reveals the gene is important for the hypertrophic trait," Koren said. "We now think that RFFL is an important node that can cross-talk with cardiac hypertrophy failure and cardiac excitation." Cardiac excitation is the process that enables the chambers of the heart to contract and relax. "That was something that we wouldn't have explored, given what we knew about RFFL," Koren added.

As a next step, Karma said the new method could be tested on human stem cells, which have the same genetic code as the person they came from and can be induced to have similar gene expression patterns as heart cells.

"When you are comparing two populations of cells from the same person--one that has been controlled and one that has been under the effect of a drug or stressor--you can compare the change of gene expression in a personalized way," Karma said.

Mortality rates were increased for patients with rheumatoid arthritis relative to the general population across all causes of death in a recent Arthritis Care & Research analysis.

The study included 87,114 rheumatoid arthritis patients in Ontario and 348,456 age/sex/area-matched general population comparators from 2000 to 2013. During follow-up, 14% of rheumatoid arthritis patients and 9% of individuals in the general population died.

While the causes of death were similar in the two groups--most frequently being circulatory system diseases, cancer, and respiratory conditions (including respiratory infections), patients with rheumatoid arthritis were dying at a younger age. The potential life years lost before the age of 75 years among rheumatoid arthritis patients was approximately double that among those in the general population.

"Our findings offer new insights into the importance of cardiovascular and respiratory contributions--including pneumonia--to shortening patient lives," said lead author Dr. Jessica Widdifield, of Sunnybrook Research Institute, in Toronto, adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and Assistant Professor at the Institute of Health Policy, Management & Evaluation, University of Toronto. She noted that deaths in patients with rheumatoid arthritis are largely attributed to complications of the disease and its treatment as well as to other comorbid conditions. "One in three deaths was attributed to heart disease. This finding underscores the importance of increased efforts to prevent heart disease and its progression, and patients and physicians should be thinking about this early in the disease course, and earlier in the patient's life. The heightened risk associated with respiratory diseases and respiratory infections should also be emphasized."

CLEVELAND, Ohio (March 7, 2018)--Anxiety is one of the most common mental health disorders, and it's more likely to affect women, especially middle-aged women. Although anxiety can be caused by many factors, a new study suggests that the amount of abdominal fat a woman has could increase her chances of developing anxiety. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Everyone is familiar with the term "stress eating" that, among other things, can lead to a thicker waistline. In this study that analyzed data from more than 5,580 middle-aged Latin American women (mean age, 49.7 years), the cause-and-effect relationship was flipped to determine whether greater abdominal fat (defined as waist-to-height ratio in this instance) could increase a woman's chances of developing anxiety. Although this is not the first time this relationship has been examined, this study is the first of its kind known to use waist-to-height ratio as the specific link to anxiety. Waist-to-height ratio has been shown to be the indicator that best assesses cardiometabolic risk. A general guideline is that a woman is considered obese if her waist measures more than half of her height.

The article "Association between waist-to-height ratio and anxiety in middle-aged women: a secondary analysis of a cross-sectional multicenter Latin American study" reports that 58% of the study population were postmenopausal, and 61.3% reported experiencing anxiety. The study found that those women in the middle and upper thirds of waist-to-height ratios were significantly more likely to have anxiety, and those in the upper third were more likely to actually display signs of anxiety compared with women in the lower two-thirds.

Anxiety is a concern because it is linked to heart disease, diabetes, thyroid problems, respiratory disorders, and drug abuse, among other documented medical problems. Research has shown an increase in the frequency of anxiety in women during midlife, likely as a result of decreased levels of estrogen, which has a neuroprotective role.

"Hormone changes may be involved in the development of both anxiety and abdominal obesity because of their roles in the brain as well as in fat distribution. This study provides valuable insights for healthcare providers treating middle-aged women, because it implies that waist-to-height ratio could be a good marker for evaluating patients for anxiety," says Dr. JoAnn Pinkerton, NAMS executive director.

A new Journal of Internal Medicine study describes an innovative program to eliminate hepatitis C virus (HCV) as a public health threat in Iceland.

In the TraP Hep C program, which started in January 2016, an emphasis is placed on finding early cases and treating patients at high risk for transmitting HCV: people who inject drugs. All patients with national health insurance are offered treatment regardless of fibrosis stage and comorbid conditions.

The program includes a multidisciplinary public health model of care and cooperation between government, health services, the penitentiary system, and community organizations. The results of the Icelandic project will provide important data and inform others globally trying to achieve the World Health Organization's goal of HCV elimination by 2030.

"So far this project has been extremely well received by patients, and we are aiming to complete the active treatment phase, encompassing all known cases in the country, by the end of 2018," said senior author Dr. Magnus Gottfredsson, of the University of Iceland.

Recent findings suggest a novel positron emission tomography (PET) imaging approach determining epidermal growth factor receptor (EGFR) mutation status for improved lung cancer patient management. The findings are published in the Mar. 7 issue of Science Translational Medicine.

This study was performed in the lab of Baozhong Shen, the TOF-PET/CT/MR Center of The Fourth Hospital of Harbin Medical University and the Molecular Imaging Research Center (MIRC) of Harbin Medical University. The senior authors are Dr. Baozhong Shen, Harbin Medical University Professor of Radiology, Dr. Sanjiv Sam Gambhir, Professor & Chair of Radiology, Stanford University, School of Medicine and Dr. Zhen Cheng, Associate Professor of Radiology, Stanford University, School of Medicine. Dr. Xilin Sun, Harbin Medical University Professor of Radiology, is the lead author. Drs. Baozhong Shen and Xilin Sun are scientists at the Molecular Imaging Research Center (MIRC) of Harbin Medical University.

The estimation of EGFR mutation status is essential for the identification of non-small cell lung carcinoma (NSCLC) patients who may benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs), and hence for improving therapeutic efficacy. While several techniques are currently available to assess EGFR mutation status, these methods require tumor biopsies and can often fail or have poor reproducibility due to insufficient material for mutation analysis. Additionally, intra- and inter-tumor heterogeneity over space and time makes it even more challenging to assess EGFR mutation status in real time. Plasma samples of patients with NSCLC is a less invasive method and has been used as surrogate tumor tissues for detecting genetic alterations. However, many studies have found the inconsistency of EGFR mutation status in plasma DNA samples as compared to tumor tissue DNA samples. Plasma samples also cannot address the issue of expression heterogeneity (primary tumor vs. metastatic site(s)).

"How can we overcome the limitations of tumor tissue biopsy and plasma samples for detecting genetic alterations, and obtain comprehensive tumor EGFR profiling in real-time?" asked Dr. Baozhong Shen. "Can this technique provide both EGFR mutation status information at the molecular level and precise anatomical information such as size, shape, NSCLC tumor location(s), and their relationship with adjacent structures?".

"Molecular imaging with PET shows the potential for non-invasively detecting cancer biomarkers in primary or metastatic tumors, and therefore for identifying patients who are likely to respond to specific treatments." Shen said. "We wanted to develop a novel strategy with PET imaging for non-invasively determining EGFR mutation status in real-time, predict NSCLC patients who may benefit from EGFR-TKI therapy, and monitor EGFR-TKI treatment outcome".

The researchers designed and synthesized a novel small molecule PET tracer, 18F-MPG, with high specificity to activating EGFR mutant kinase. The preclinical studies showed that the newly developed 18F-MPG allows one to noninvasive and repeatedly detect activating EGFR mutational status in mouse models of NSCLC with high sensitivity and specificity. More importantly, the researchers then translated this strategy to NSCLC patients. The first-in-human PET/CT imaging of 75 patients with 18F-MPG was performed to show that this tracer can be used as a companion diagnostic to identify NSCLC patients with EGFR activating mutant tumors (primary tumor or metastatic) with 84.3% accuracy. Good patient outcomes were observed after EGFR-TKI therapy in the subpopulation with very high pretreatment 18F-MPG uptake, which demonstrates the potential of using 18F-MPG PET/CT to predict treatment response. These results demonstrate that noninvasive imaging of EGFR activating mutation status in primary and metastatic tumors with 18F-MPG PET/CT is a valid strategy for stratifying NSCLC patients for EGFR-TKI treatment. This strategy achieves: (i) differentiating of tumor EGFR-activating mutation status with non-invasive, whole-body PET imaging; (ii) prediction of EGFR-TKIs sensitivity/resistance and patient survival; and (iii) monitoring of the dynamic changes in EGFR mutation status during therapy and guidance of precise treatment.

"There currently are no methods to predict EGFR-TKI therapy response in patients and design effective EGFR-TKIs therapies when a genetic test is not feasible or ambiguous." Shen said. "With 18F-MPG PET/CT imaging, we were able to quantitate EGFR-activating mutation status in NSCLC patients (primary tumor or metastatic) and directly determine/visualize the location(s) and morphology of the NSCLCs."

This new study is believed to be the first reported to analyze the association between EGFR mutation status in tumor tissue and 18F labeled EGFR-TKI tracer uptake in NSCLC patients.

DALLAS, March 7, 2018 - When heart failure patients receive a heart pumping device known as a left ventricular assist device (LVAD), their caregivers seem to suffer, too - at least initially, according to research in Journal of the American Heart Association (JAHA), the Open Access Journal of the American Heart Association/American Stroke Association.

In a study of 50 pairs of heart failure patients and their caregivers, researchers noted that patients reported dramatically improved quality of life in the first month after receiving an LVAD, however at the same time, caregivers reported significantly increased strain - a subjective measure of stress related to caregiving.

The American Heart Associations' scientific statement on LVAD patient selection notes that adequate social support is crucial for the success of LVAD therapy, and many centers require patients to have a designated primary caregiver (i.e., unpaid family member or friend) to help them manage their condition.

Researchers found caregiver strain worsens immediately after implant and then returns to pre-implant levels over six months, but does not further improve. The quality of the patient-caregiver relationship was associated with better outcomes for both, and may be a target for future interventions.

The greatest sources of strain for LVAD caregivers in this sample were time constraints (no time for self-care or other obligations) and compromised social life, followed by physical strain.

The study is one of the first to examine how the patient-caregiver relationship may influence both patient and caregiver outcomes.

"As cardiologists using heart pumps to support this extremely sick group of heart failure patients, we sometimes neglect the impact of our therapies on caregivers and families. This clearly shows how these advanced therapies affect caregivers, and that the relationship of the patients to their caregivers can alter outcomes," said JAHA Editor in chief Barry London, M.D., Ph.D., who is also Director of Cardiovascular Medicine at the University of Iowa Carver College of Medicine.

Researchers say interdisciplinary clinical approaches that consider both the patient and the

caregiver as individuals as well as the characteristics and health of their relationship to one another may be more effective than solely patient-focused approaches.