Body

ARLINGTON, Virginia, April 6, 2019 -- Heart failure patients who could possibly benefit from a newer class of drug to lower their heart rate were more likely to take the medication if it was prescribed before hospital discharge rather than in a follow-up doctor's visit, according to preliminary research presented at the American Heart Association's Quailty of Care and Outcomes Research Scientific Sessions 2019, a premier global exchange of the latest advances in quality of care and outcomes research in cardiovascular disease and stroke for researchers, healthcare professionals and policymakers.

"The hospitalization rate in heart failure patients is quite high despite a number of good therapies, yet we have ivabradine, a relatively new therapy that can reduce hospitalization, and we still aren't using it to the extent possible," said Robert Mentz, M.D., lead author of the study and an associate professor of cardiology at Duke University Medical Center in Durham, N.C.

When people have heart failure and less than 35 percent of the blood in the heart is pumped out with each contraction (a reduced ejection fraction), having a lower heart rate (less than 70 beats per minute) is associated with better outcomes. Current standard care for heart failure with reduced ejection fraction is to use beta-blocker medications in most patients. Beta-blockers can lower heart rate and have many other beneficial effects that improve outcomes for patients with reduction ejection fraction. Research has shown that adding ivabradine, which works in a different way to lower heart rate, may also be helpful in those patients who have a faster heart rate despite being on the highest dose of beta-blockers they can tolerate.

In 2016, the American Heart Association and the American College of Cardiology issued a focused update to heart failure guidelines to reflect newer medication options, including ivabradine, more recently proven successful in helping improve outcomes for heart failure patients, including reduced re-hospitalization.

The current study, called PRIME-HF, evaluated 104 patients (average age 57.5 years, 36 percent women, 64 percent African American) who had been hospitalized at one of 23 U.S. hospitals with worsening heart failure and were appropriate candidates to receive ivabradine. In the randomized, open-label study, researchers compared rates of medication use six months later between those whose hospital physicians were asked to initiate ivabradine prior to discharge and those whose physicians were instructed to provide usual care with consideration of starting the medication during follow-up visits.

Six months after hospitalization, the researchers found that patients whose physicians were asked to initiate ivabradine prior to discharge:

Were far more likely to be using ivabradine (40.4 percent vs. 11.5 percent);

Had a greater reduction in heart rate (10 bpm vs. 0.7 bpm, average heart rate 77 bpm vs 86 bpm);

Had not reduced their dose of beta-blockers; and

Did not develop abnormally low blood pressure or heart rate.

"This was a small study, but it provides important evidence of the safety and efficacy of starting this medication in the hospital period," Mentz said. "There's often a tendency to just say, 'Let's wait until we see the patient back in the clinic in a couple of weeks after hospital discharge.' But the reality is that so often things are incredibly busy in the outpatient setting and many patients never get started on the right medications if we delay. Our message is to act now and help patients get the greatest benefits as early as possible."

Patients in both groups encountered barriers to obtaining ivabradine, with 30.6 percent having trouble getting their initial prescription and 58.1 percent having trouble getting ivabradine at some point during the six-month study. Frequent barriers were high price, insurers declining to pay, and physicians deciding to stop the drug.

"When we designed the trial, we thought that more people would be using this medication in routine practice. The reality has been that adoption of the therapy has been very slow and only a fraction of potential patients are receiving it." Mentz said. "Some of this is related to cost while some is also related to providers' lack of familiarity with the medication and how best to use it. We are looking into how we can better support the early adoption of novel therapies in patients with heart failure to improve their outcomes."

Because of slow recruitment, the study was terminated early, so the sample is too small to assess outcomes such as survival and re-hospitalization.

Orlando, Fla. (April 6, 2019) - Findings from a new study show that the compound responsible for chili peppers' heat could help slow the spread of lung cancer, the leading cause of cancer death for both men and women. Most cancer-related deaths occur when cancer spreads to distant sites, a process called metastasis.

"Lung cancer and other cancers commonly metastasize to secondary locations like the brain, liver or bone, making them difficult to treat," said Jamie Friedman, a doctoral candidate who performed the research in the laboratory of Piyali Dasgupta, PhD, at Marshall University Joan C. Edwards School of Medicine. "Our study suggests that the natural compound capsaicin from chili peppers could represent a novel therapy to combat metastasis in lung cancer patients."

Friedman will present the research at the American Society for Investigative Pathology annual meeting during the 2019 Experimental Biology meeting to be held April 6-9 in Orlando, Fla.

In experiments involving three lines of cultured human non-small cell lung cancer cells, the researchers observed that capsaicin inhibited invasion, the first step of the metastatic process. They also found that mice with metastatic cancer that consumed capsaicin showed smaller areas of metastatic cancer cells in the lung compared to mice not receiving the treatment.

Additional experiments revealed that capsaicin suppresses lung cancer metastasis by inhibiting activation of the protein Src. This protein plays a role in the signaling that controls cellular processes such as proliferation, differentiation, motility and adhesion.

"We hope that one day capsaicin can be used in combination with other chemotherapeutics to treat a variety of lung cancers," said Friedman. "However, using capsaicin clinically will require overcoming its unpleasant side effects, which include gastrointestinal irritation, stomach cramps and a burning sensation."

The researchers are working to identify capsaicin analogs that will be non-pungent while retaining the anti-tumor activity of capsaicin. They are also trying to identify natural non-pungent capsaicin-like compounds with anti-cancer activity.

Jamie Friedman will present this research on Saturday, April 6 at 7 p.m. during the Experimental Biology Welcome Reception in Valencia Ballroom ABCD, Orange County Convention Center and on Tuesday, April 9 at 8:30 p.m. in Room W108 B (poster 368.1) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

Orlando, Fla. (April 6, 2019) - People with diabetes who use insulin to control their blood sugar can experience a dangerous condition called hypoglycemia when blood sugar levels fall too low. New insights into a recently discovered protein called neuronostatin could lead to new ways to treat and prevent hypoglycemia, which is sometimes deadly for people with diabetes.

Stephen Grote, a doctoral student working with Gina Yosten, PhD, at Saint Louis University School of Medicine, will present the research at the American Physiological Society's annual meeting during the 2019 Experimental Biology meeting to be held April 6-9 in Orlando, Fla.

For people with diabetes, taking too much insulin can lead to low blood sugar, causing dizziness and sleepiness. Symptoms may progress to confusion, seizures and loss of consciousness if blood sugar levels continue to fall. Severe hypoglycemia can also increase the risk of more hypoglycemic episodes in the following days and leads to a decreased awareness of the symptoms that typically allow a person to sense falling blood sugar levels.

"There are very few options for preventing hypoglycemia or treating hypoglycemia unawareness other than avoiding low blood sugar as much as possible," Grote said. "Understanding what neuronostatin does and how it works will provide valuable information for preventing hypoglycemia and provide more complete knowledge into how the pancreas manages blood sugar normally."

In previous work, Yosten's research group discovered neuronostatin. Their work has shown that the protein protects against hypoglycemia by causing the pancreas to release less insulin and make more glucagon, a hormone that helps regulate blood sugar levels.

In a new rat study, the researchers observed that neuronostatin injections caused an increase in blood sugar. They also examined human pancreas tissue and found that it released more neuronostatin when blood sugar levels were low and that neuronostatin increased even more with glucagon treatment. The new research points to neuronostatin as a potential therapeutic target for the treatment and prevention of hypoglycemia in people with diabetes.

"Neuronostatin is a truly novel factor, and everything we find about it pushes our knowledge of its therapeutic potential just a bit further," said Grote. "We believe that studying neuronostatin could ultimately reveal a way to use it to help prevent and reverse vicious cycles of hypoglycemia by helping the body respond appropriately to the low blood sugar with more glucagon."

The researchers are now working to better understand how neuronostatin affects glucagon and insulin release from human islets and how the body regulates neuronostatin secretion. They are also using experimental approaches that disrupt the body's response to low blood sugar to investigate how this affects neuronostatin levels and to determine if neuronostatin can be used to better manage low blood sugar.

Stephen Grote will present this research during the Experimental Biology Welcome Reception on Saturday, April 6 at 7 p.m. in the Valencia Ballroom ABCD, Orange County Convention Center and on Monday, April 8, from 10:15 a.m.-12:15 p.m. in Exhibit Hall-West Hall B (poster E621 756.1) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

Orlando, Fla. (April 7, 2019) - The buildup of fat in the liver known as fatty liver disease sometimes leads to hard-to-treat liver cancer. Scientists don't understand why the cancer risk is higher for fatty liver disease caused by excessive alcohol consumption than for non-alcoholic fatty liver disease, which is associated with obesity and type 2 diabetes.

New research has uncovered important differences in the biological pathways that lead to cancer for alcoholic fatty liver disease compared to non-alcoholic fatty liver disease. The findings could benefit the more than 3 million people diagnosed with fatty liver disease each year.

"We want to find out the key factors and pathways that lead to liver cancer in fatty liver patients so we can slow or even prevent the liver cancer," said Yue Jia, MD, PhD, a pathology resident at the Harbor-UCLA Medical Center who conducted the study. "It is estimated that this type of liver cancer is responsible for 250,000 to 1 million deaths each year."

Jia will present the research at the American Society for Investigative Pathology annual meeting during the 2019 Experimental Biology meeting to be held April 6-9 in Orlando, Fla.

In the new study, the researchers examined expression levels of proteins in liver biopsies from a group of patients with alcoholic fatty liver disease and a group with non-alcoholic fatty liver disease. The proteins studied are involved in epigenetic regulation, which controls gene expression, and inflammation, which plays an important role in the disease.

The researchers observed that the two groups of patients showed significant differences in the expression of proteins involved in epigenetic regulators and inflammation. Importantly, these differences matched the ratio of liver cancer development seen for the two groups.

"If, through additional studies, we can prove that the molecules and pathways we identified modulate liver cancer development in the alcoholic fatty liver disease or non-alcoholic fatty liver disease patients, it may help identify new targets for preventing or reducing the risk of liver cancer that arises from other liver disease," said Jia.

The researchers plan to perform additional experiments in animal models of fatty liver disease to learn more about how epigenetic regulation and inflammation pathways lead to liver cancer.

Yue Jia will present this research on Saturday, April 6 at 7 p.m. during the Experimental Biology Welcome Reception in Valencia Ballroom ABCD, Orange County Convention Center and on Monday, April 8, from 11:45 a.m.-12:45 p.m. in Exhibit Hall-West Hall B (poster A67 662.67) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

Orlando, Fla. (April 6, 2019) - According to a new study, breast cancer patients who don't respond to targeted therapy have different patterns of epigenetic modifications than patients who do respond. Epigenetic modifications change gene expression without altering the DNA's genetic code.

"Our study could contribute to new ways to predict who might not respond to targeted therapy," said Daniela Furrer, PhD, a postdoctoral fellow at Laval University in Canada, who performed the study. "It could also lead to ways to identify patients who need a closer clinical follow-up because they are more prone to experience breast cancer recurrence."

Furrer will present the research at the American Society for Investigative Pathology annual meeting during the 2019 Experimental Biology meeting to be held April 6-9 in Orlando, Fla.

Targeted cancer therapies use drugs to block molecules in cells that cause them to grow out of control. The therapy specifically targets cancer cells, unlike chemotherapy, which kills all quickly growing cells whether they are cancerous or not. Although the development of targeted therapies has increased breast cancer survival, treatment failure is still an important problem.

"This is one of the first studies to evaluate the impact of epigenetic modifications on treatment response to targeted therapy in a subgroup of breast cancer patients," said Furrer. "Importantly, we measured these changes directly in breast cancer tissues and looked at epigenetic modifications throughout the entire breast cancer cell."

For the new study, the researchers examined a type of epigenetic change known as DNA methylation in breast cancer tissue from patients with HER2-positive breast cancer who received the targeted drug trastuzumab (Herceptin). Trastuzumab targets human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells.

The researchers compared DNA methylation patterns in six patients who responded to the therapy and six who did not. Breast cancer tissue from patients resistant to the therapy exhibited 879 genes with higher levels of methylation and 293 genes with lower methylation than patients who responded to the treatment. Many of the genes affected were involved in cellular movement as well as cell death and survival, processes that play an important role in cancer.

The next step for this research is to validate the findings in a bigger group of breast cancer patients receiving the targeted treatment. If the results are confirmed, the researchers plan to develop new drugs that target the molecular pathways and cellular processes that lead to targeted treatment failure through DNA methylation.

Daniela Furrer will present this research on Saturday, April 6 at 7 p.m. during the Experimental Biology Welcome Reception in Valencia Ballroom ABCD, Orange County Convention Center and on Monday, April 8 at 9:45 a.m. in Room W108 B (poster 250.6 )(abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

ARLINGTON, Virginia, April 6, 2019 -- Patients who are African-American or Hispanic, uninsured or covered by Medicaid insurance and living in low-income ZIP codes are less likely to receive a heart-pumping device known as a left ventricular assist device (LVAD), according to preliminary research presented at the American Heart Association's Quality of Care and Outcomes Research Scientific Sessions 2019, a premier global exchange of the latest advances in quality of care and outcomes research in cardiovascular disease and stroke for researchers, healthcare professionals and policymakers.

Research has shown that there are disparities based on socioeconomic status associated with the types of care patients receive for heart disease and how well they do after treatment. The new study examined the relationship between socioeconomic status and implantation of LVADs, which are typically used to maintain patients waiting for a heart transplant or as the final therapy for patients with heart failure. Additionally, researchers set out to determine if Medicaid expansion through the Affordable Care Act, intended to improve access to insurance and healthcare for more people, has had any impact on LVAD implantation.

"There is a clear disparity in terms of access to advanced therapies like LVAD," said Xiaowen Wang, M.D., lead researcher and an instructor in medicine at Washington University in St. Louis. "Healthcare providers need to be mindful of this disparity as they make decisions about patient care."

The researchers used the federal government's State Inpatient Database, which contains all inpatient care records in participating states. They looked at data for all patients less than 85 years of age admitted with heart failure or cardiogenic shock in Alaska, Arizona, Colorado, Florida, Iowa, Maryland, Massachusetts, Michigan, Nebraska, Nevada, New Jersey, New York, Vermont, Washington and Wisconsin between January 1, 2012 and September 30, 2015.

Among 889,377 patients, 64.6 percent were more than 65 years old, 43.3 percent were women, and 64.2 percent were Caucasian. Overall, about 3,700 patients received LVADs. The researchers found that:

African Americans were 28 percent less likely and Hispanics were 38 percent less likely to receive LVADs compared to Caucasians;

Patients with Medicare were 28 percent less likely, those with Medicaid were 57 percent less likely and those without insurance were 90 percent less likely to receive LVADs compared to patients with private insurance; and

Patients residing in the lowest-income ZIP codes were 26 percent less likely to receive LVADs than those in higher-income areas.

Among patients who received LVADS, African-Americans and Hispanics were less likely to die in the hospital compared to Caucasians. Privately insured patients who received LVADs had similar rates of death as those on Medicare, higher death rates than patients on Medicaid and lower death rates than those who were uninsured.

The researchers also compared rates of LVAD implantation for patients likely to be poor in states that expanded Medicaid with states that did not expand Medicaid during the 21-month study period. They found that the rate of LVAD implantation in Medicaid expansion states increased slightly from 0.35 percent before to 0.40 percent after expansion. In non-expansion states, the LVAD implantation rate remained at 0.23 percent during the study period. The differences between these changes were not statistically significant.

Not all states participate in the State Inpatient Database, which limited the study, particularly for the analysis of LVAD implantation rates in Medicaid- and non-Medicaid-expansion states. Another limitation was the absence of data after 2015.

"As LVADs become more common with technological advances that lower complication rates and make the devices more portable, healthcare providers will need to better understand the underlying causes of these disparities in who gets these potentially lifesaving therapies and who doesn't," Wang said.

Orlando, Fla. (April 6, 2019) - An estimated six to 15 million people in the U.S. are children born of a pregnancy complicated by preeclampsia. New research performed in rats reveals that treating preeclampsia with sildenafil citrate (Viagra) may help protect the cardiovascular health of the offspring.

Preeclampsia occurs when women with otherwise normal blood pressure experience elevated blood pressure during pregnancy. Children of women with preeclampsia during pregnancy have higher blood pressure during childhood and almost double the risk of stroke later in life.

"The ultimate goal of our work is to improve the long-term health of women and children affected by preeclampsia," said Hannah Turbeville, a doctoral student at the University of Mississippi Medical Center, who conducted the new study. "There are limited guidelines for addressing the health risks to these groups, and we hope not only to bring attention to these risks but also to propel research forward that will inform preventative interventions."

Turbeville will present the new research at the American Physiological Society's annual meeting during the 2019 Experimental Biology meeting to be held April 6-9 in Orlando, Fla.

In previous work, the researchers found that sildenafil citrate, which lowers blood pressure by acting on the nitric oxide pathway, can treat preeclampsia in a rat model of the condition while also decreasing blood pressure in offspring. In the new work, they wanted to determine how sildenafil citrate affects the offspring's response to stressors that normally increase blood pressure.

To mimic human preeclampsia as much as possible, the researchers used a rat model that develops the condition without a procedure or drug. They then exposed the offspring to a stressor that increases blood pressure. The researchers observed smaller increases in blood pressure for male offspring of rats treated with sildenafil citrate compared to those that did not no receive treatment or received a more commonly used blood pressure medication. The protective effect was not apparent in female offspring.

"Our studies demonstrate the potential for targeted therapy of the nitric oxide pathway to improve the body's response to stressors in the later lives of children of women who experienced preeclampsia," said Turbeville. "This pathway plays an important role in improving blood flow and lowering blood pressure."

The researchers are working to better understand the gender-specific response to sildenafil citrate. They are also exploring whether the improved response to stressors leads to decreased risk of chronic diseases such as high blood pressure and chronic kidney disease when these offspring become adults.

Hannah Turbeville will present this research on Saturday, April 6, at 2:30 p.m. in the Plaza International Ballroom G, the Hyatt, and on Sunday, April 7, from 10:15 a.m. -12:15 p.m. in Exhibit Hall-West Hall B, Orange County Convention Center (poster E569 574.10) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

This week, publication of a special issue on tuberculosis (TB) begins in PLOS Medicine, advised by guest editors Richard Chaisson of Johns Hopkins University, Claudia Denkinger of the University of Heidelberg, and Mark Hatherill of the South African Tuberculosis Vaccine Institute.

An estimated 10 million people developed tuberculosis (TB) and 1.6 million died of TB globally in 2017, making it the number one cause of death from a single infectious agent. Last year the United Nations held a High Level Meeting on TB, where heads of state pledged to eliminate the disease by 2030.

The Special Issue opens with publication of two original research articles:

In the first article, Radojka M. Savic, of the University of California, San Francisco, and colleagues, develop a model for estimating the distribution of TB drugs in patients' lung lesions. They used data on 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types obtained from 15 patients (10 men, 5 women) undergoing lung resection surgery, to develop and evaluate a site-of-action mechanistic pharmacokinetic model for 7 major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine[CFZ], pyrazinamide [PZA], and kanamycin [KAN]). The researchers found that patients receiving standard doses of RIF and INH, who are at the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the patient population. The investigators also found that the majority of TB drugs showed poor penetration into the cavitary lesions, leading to inadequate drug levels at the site of disease and increased risk of developing drug resistance. The authors note that this was a small group of patients from a unique population of TB patients who failed treatment and underwent lung resection surgery. Still, the authors note that the finding that TB drugs do not penetrate equally in different tissues suggests that a patient-focused approach to optimize drug regimen to the disease extent, lesion type, and individual drug-susceptibility profiles may eventually be useful to guide selection of tailored drug regimens with improved outcomes. They provide a web-based tool to further explore this model and results at http:// saviclab.org/tb-lesion/.

In the second article, Ankur Gupta-Wright, of London School of Hygiene & Tropical Medicine, and colleagues develop a clinical risk score for identifying HIV-positive patients diagnosed with TB with an increased chance of dying within 2 months. The risk score includes 6 factors that can be measured upon hospital admission, including a urine TB diagnostic test to detect the protein lipoarabinomannan [LAM], age, sex, previous experience on antiretroviral treatment, anaemia, and ability to walk unaided. The score was derived in a cohort of 315 patients from the STAMP TB screening trial in Malawi and South Africa, and externally validated in 644 patients from 2 other studies done in South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. For patients identified by the score as high-risk, the odds of dying within 2 months were about 5 times greater (odds ratio 5.3, 95% confidence interval 2.2-9.5) compared to patients classified as low-risk in the validation cohort. The authors note that this risk score depends on access to urine LAM testing, does not measure all potential predictors of mortality (e.g., TB drug resistance), and further validation in larger and diverse cohorts is necessary. However, this risk score may be able to identify patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions.

In addition to the research articles this week, the Special Issue includes a blog on Speaking of Medicine featuring the stories of six survivors of TB, discussing their experiences with different aspects of the TB care cascade, and how it led them to advocate at a local and global level to improve TB care.

The Special Issue will continue with further research and discussion articles appearing over the next several weeks.

ARLINGTON, Virginia, April 5, 2019 -- Despite improvements in heart attack and heart disease care for older women, black women still experience significantly lower rates of treatment when compared with whites or Hispanics, according to preliminary research presented at the American Heart Association's Quality of Care and Outcomes Research Scientific Sessions 2019, a premier global exchange of the latest advances in quality of care and outcomes research in cardiovascular disease and stroke for researchers, healthcare professionals and policymakers.

A two-decade study showed an overall increase in heart attack and heart disease treatments after the 2005 publication of standard treatment guidelines, but racial disparities persisted. Specifically, postmenopausal black women were 50 percent less likely and Hispanic women were 16 percent less likely to be treated when they arrived at a hospital with heart attack or coronary artery disease symptoms when compared to white women. This gap persisted after accounting for education, income, insurance status and other heart health complications such as diabetes and high blood pressure.

Cardiovascular disease is a leading cause of death causing one death every 80 seconds among women. Rapid treatment is critical and while treatment rates appear to be improving, they do not appear to be improving equally for all groups.

Using data from the Women's Health Initiative, researchers looked at treatment rates for 20,262 postmenopausal women before and after 2005, including 17,509 whites; 2,181 blacks, and 572 Hispanics. Among their other key findings:

Black women who had a ST-elevation myocardial infarction (STEMI), the most serious type of heart attack where an artery is completely blocked, had lower rates of treatment pre-2005 (15 percent lower) and post-2005 (39 percent lower) compared with whites.

Restoring blood flow to the blocked artery within 12 hours of an acute ischemia or a heart attack is the gold standard of treatment, however, black women had a 33 percent lower rate of receiving this therapy regardless of timing, and a 23 percent lower rate of receiving it within 12 hours of heart attack symptoms.

Hispanic women with acute coronary syndrome or coronary heart disease also faced lower rates of treatment before 2005 (23 percent lower), but the gap narrowed slightly after 2005 (7 percent lower).

Researchers did not find any difference in treatment rates when looking at socioeconomic status.

"Our study shows that black women still receive less recommended therapy for heart attacks and coronary heart disease than white women and that improving these racial disparities is still needed," said Tarryn Tertulien, B.S., lead study author and a fourth-year medical student at The Warren Alpert Medical School at Brown University in Providence, R.I. "Increasing public campaigns targeted at racial minorities regarding patient education and developing a trusting relationship with the healthcare system should be instituted to improve this disparity in care."

Tertulien said while her study did not focus on the factors explaining these racial disparities, she said it's possible blacks and Hispanics may lack awareness about heart attack symptoms or be less likely to use emergency services, they may be hesitant about invasive procedures to open blocked arteries and there may be provider biases. She said additional research is needed to understand the origin of these disparities and to work with patients, communities, hospitals and healthcare providers to develop timely interventions for all.

A team of biologists and computer scientists has mapped out a network of interactions for how plant genes coordinate their response to nitrogen, a crucial nutrient and the main component of fertilizer. The work, published in the journal Nature Communications, offers a potential framework and more efficient methods that can be used to investigate a wide-range of vital pathways in any organism.

"The sequencing of whole genomes has transformed life sciences, leading to breakthroughs in medicine, agriculture, and basic research," explains Matthew Brooks, an NIH-postdoctoral fellow in New York University's Department of Biology and the paper's lead author. "The challenge now is to determine how the genes that are encoded by an organism are regulated and work together in networks that allow plants and animals to respond to their environment."

The scientists, working in NYU's Center for Genomics and Systems Biology, focused on gene regulatory networks, which consist of transcription factors and the target genes that they regulate. These gene regulatory networks enable organisms to adapt to fluctuating surroundings.

However, multi-cellular organisms, where there are a large number of transcription factors and target genes they potentially regulate, present a challenge for mapping all connections. The nature of the interactions within these complex networks are difficult to experimentally validate using common methods.

In order to overcome these obstacles, the team, which also included researchers at NYU's Courant Institute of Mathematical Sciences, combined innovative experimental and computational methods to characterize the gene network underlying nitrogen responses. The research centered on the plant Arabidopsis, a model organism for research as it's the first plant to have its entire genome sequenced.

Rather than taking the standard approach of altering the expression of one gene at a time in whole plants, which can take many months for even a single transcription factor, the group scaled-up a cell-based technique that enabled them to experimentally determine more than 85,000 connections between 33 early nitrogen-responsive transcription factors and the target genes they regulate in approximately two months' time. Collectively, the 33 transcription factors regulate 88 percent of the nitrogen response genes in plants. In an approach they call Network Walking, the scientists could use this vast amount of data to chart a path for a transcription factor from its direct gene targets in root cells to indirect gene targets in plants.

"All organisms alter gene expression in response to nutrient and developmental signals, enabling them to survive and grow in their environment," observes Gloria Coruzzi, a professor in NYU's Department of Biology and the paper's senior author. "But understanding and experimentally validating the sequence of interactions within these extremely complex gene regulatory networks is a difficult task. Our approach presents a way to rapidly uncover and validate these intricate relationships, offering a potential pathway to engineer or breed more efficient, economical, and environmentally sound methods to grow plants and crops-- but our experimental and computational Network Walking approaches can be applied to any system in biology, agriculture, or medicine."

Veterinary professionals have sounded the alarm in this week's Vet Record after treating the first UK case of a dog with the potentially fatal infection, leishmaniosis, that is thought to have been passed on by another dog, rather than by travel to an area where the infection is endemic.

Canine leishmaniosis is caused by the parasite Leishmania infantum, carried by the female sand fly and transmitted in its bite. It is zoonotic, so can be passed on to people.

Dogs have been known to pick up the infection after being bitten or wounded by another infected dog. But up to now, this has not been reported in the UK, where cases to date have been associated with blood transfusion, breeding programmes, or overseas travel.

But a 3 year old neutered male shih tzu cross, which had been with its owner since a puppy and had none of the known risk factors for infection, was nevertheless diagnosed with leishmaniosis in Hertfordshire.

Dog to dog transmission is the most likely explanation, suggest the authors, because another dog in the household that had been imported from Spain, had had to be put down six months earlier after developing severe leishmaniosis.

"To the authors' knowledge, this is the first reported case of leishmaniosis in the UK in a dog without a history of travel to an endemic area," they write, adding that extra vigilance is now needed to guard against the spread of the infection.

"In an era of increased foreign travel of dogs and increased importation of dogs to the UK, it is likely that the number of dogs seropositive for L infantum will continue to increase," they warn.

"Leishmania-infected dogs may present an infection risk to other dogs, even in the absence of natural vectors, as direct transmission between dogs is possible," they add.

A second case of canine leishmaniosis in a dog with no obvious risk factors has now also come to light in a different part of the UK.

In a recently published letter in Vet Record, vets describe the case of a 3-year-old fully vaccinated male neutered English pointer that was eventually diagnosed with leishmaniosis.

The dog had never travelled outside of the UK, or beyond the borders of Essex, where it lived. But its owners had lived in Spain and travelled to the Jalón Valley (between Alicante and Valencia) without their pet in the summer of 2018.

Unlike the first case, this dog was not living, or in regular contact with another infected dog, and it may be that infected sand flies were inadvertently brought back in the owners' transport, luggage, or clothing, suggest the authors.

"However, the increased importation of infected dogs into the UK also makes incidental socialising with infected dogs increasingly likely," they point out.

The case also "serves as a reminder that we should not be complacent about the risk of Leishmania infantum establishing in the UK, even in the current absence of the sand fly vector," they warn.

Junior Vice President of the British Veterinary Association (BVA), Daniella Dos Santos, comments: "The increase in cases of non-endemic diseases such as leishmaniasis is extremely concerning, with more than a quarter of vets surveyed by BVA last year mentioning seeing cases of this rare disease in practice.

"Leishmaniasis is mainly associated with pets who have recently travelled outside of the UK or 'trojan' rescue dogs from abroad with unknown health histories, which is why we have called on the government to strengthen existing pet travel legislation and its enforcement for the sake of animal and human health in the UK."

She advises pet owners planning on overseas travel with their dog to seek advice from a vet first, while those who already own an imported rescue dog, should contact their local vet for advice on testing and treatment for any underlying conditions.

"Anyone looking to get a dog should consider adopting from a UK rehoming charity or welfare organisation instead of rescuing from abroad," she recommends, "as the unintended consequences from trojan dogs can be severe for the health and welfare of UK's pets and, in some cases, humans too."

Blood pressure and stroke risk increase steadily with increasing alcohol intake, and previous claims that 1-2 alcoholic drinks a day might protect against stroke are dismissed by new evidence from a genetic study involving 160,000 adults.

Studies of East Asian genes that strongly affect how much alcohol people choose to drink show that alcohol itself directly increases blood pressure and the chances of having a stroke, according to a new study published in The Lancet. It was known that stroke rates were increased by heavy drinking, but it wasn't known whether they were increased or decreased by moderate drinking.

Although people who have one or two alcoholic drinks a day had previously been observed to have a slightly lower risk of stroke and heart attack than non-drinkers, it was not known whether this was because moderate drinking was slightly protective, or whether it was because non-drinkers had other underlying health problems (eg, being former drinkers who had stopped because of illness). At least for stroke, the genetic evidence now refutes the claim that moderate drinking is protective.

In East Asian populations, there are common genetic variants that greatly reduce alcohol tolerability, because they cause an extremely unpleasant flushing reaction after drinking alcohol. Although these genetic variants greatly reduce the amount people drink, they are unrelated to other lifestyle factors such as smoking. Therefore, they can be used to study the causal effects of alcohol intake.

As the genetic factors that strongly affect drinking patterns are allocated randomly at conception and persist lifelong, this study is the genetic equivalent of a large randomised trial, and can therefore sort out cause-and-effect relationships reliably - a method called "Mendelian randomisation."

Lead author Dr Iona Millwood, from the Medical Research Council Population Health Research Unit at the University of Oxford, UK, says: "Using genetics is a novel way to assess the health effects of alcohol, and to sort out whether moderate drinking really is protective, or whether it's slightly harmful. Our genetic analyses have helped us understand the cause-and-effect relationships." [1]

Researchers from Oxford University, Peking University, and the Chinese Academy of Medical Sciences led a large collaborative study of over 500,000 men and women in China who were asked about their alcohol intake and followed for ten years. In over 160,000 of these adults the researchers measured two genetic variants (rs671 and rs1229984) that substantially reduce alcohol intake.

Among men, these genetic variants caused a 50-fold difference in average alcohol intake, from near zero to about four units (drinks) per day. The genetic variants that decreased alcohol intake also decreased blood pressure and stroke risk. From this evidence, the authors conclude that alcohol increases the risk of having a stroke by about one-third (35%) for every four additional drinks per day (280 g of alcohol a week), with no protective effects of light or moderate drinking.

Professor Zhengming Chen, co-author from the Nuffield Department of Population Health, University of Oxford, says: "There are no protective effects of moderate alcohol intake against stroke. Even moderate alcohol consumption increases the chances of having a stroke. The findings for heart attack were less clear-cut, so we plan to collect more evidence." [1]

Of the men with genetic measurements, about 10,000 had a stroke and 2,000 had a heart attack during about ten years of follow-up, so more information is needed on heart attacks.

Few women in China drink alcohol (less than 2% of women in the study drank in most weeks, and when they did drink they consumed less than men), and the genetic variants that cause alcohol intolerance had little effect on blood pressure or stroke risk. Women in this study therefore provide a useful control group, which helps confirm that the effects of these genetic variants on stroke risk in men were caused by drinking alcohol, not by some other mechanism.

The authors highlight that it would be impossible to do such a study in Western populations, where almost nobody has the relevant genetic variants. However, these findings about the effects of alcohol in Asia should be applicable worldwide. Because the study was conducted in China, the alcohol consumed was mainly spirits, but they expect the findings to apply to alcohol in other drinks.

In China, more years of life are lost to stroke than to any other disease. This study estimates that, among Chinese men, alcohol is a cause of 8% of all strokes from a blood clot in the brain and 16% of all strokes from bleeding into the brain.

Co-author Professor Liming Li, from Peking University, says: "Stroke is a major cause of death and disability. This large collaborative study has shown that stroke rates are increased by alcohol. This should help inform personal choices and public health strategies." [1]

Writing in a linked Comment, Professor Tai-Hing Lam and Dr Au Yeung, from the University of Hong Kong, Hong Kong Special Administrative Region, China, call for a WHO Framework Convention for Alcohol Control (FCAC), similar to the Framework Convention on Tobacco Control (FCTC): "Alcohol control is complex and stronger policies are required. The alcohol industry is thriving and should be regulated in a similar way to the tobacco industry."

Ageism may be linked with poorer health in older people in England, according to an observational study of over 7,500 people aged over 50 published in The Lancet Public Health journal. Despite the known prevalence of age discrimination and existing evidence that other forms of discrimination, like racism, are linked to poorer health, this is the first study to examine the association between ageism and health and wellbeing.

Considering the demographic changes underway in high-income countries and the steadily increasing population of older people in the UK, these findings highlight the vital need to tackle ageism to improve the health and wellbeing of people as they age.

1,943 of 7,731 (25%) over 50-year olds surveyed experienced age discrimination. Those who reported age discrimination were more likely to rate their health as fair or poor compared to those who had not reported it (29% versus 24%).

Certain serious health problems were also more common among those who reported age discrimination compared to those who had not - including heart disease (17% versus 13%), chronic lung conditions (7% versus 5%), limiting longstanding illnesses (39% versus 33%), and depressive symptoms (19% versus 12%).

In addition to worse reports of their existing health, participants who reported age discrimination were more likely to develop a serious health problem during the study's six-year study period compared to those who did not report age discrimination - including higher rates of diabetes (6% versus 5%), heart disease (4% versus 3%), stroke (5% versus 3%), chronic lung disease (5% versus 3%), a limiting longstanding illness (26% versus 21%), or depressive symptoms (10% versus 7%).

The authors note that the follow-up data was only available for 5,595 of the 7,731 participants included in the original analyses. Participants who dropped out in the intervening six years tended to be older and less affluent, which may have led to conservative numbers of newly developed conditions.

Notably, 45% (883/1,943) of participants who reported age discrimination also reported discrimination based on other personal characteristics (eg. sex, physical disability) and the negative health effects were most pronounced in this group. The authors therefore stress that other factors, like socioeconomic status and disability, may intersect with and compound experiences of age discrimination.

Advocating for an approach that aims to tackle discriminatory behaviours in society and mitigate the effects of discrimination of older people, study author, Dr Sarah Jackson from University College London, UK, says: "As a society, we need to increase public awareness of what constitutes ageism and how it can affect health and wellbeing so we can build collective movements, like those that brought about legislative and social change for other forms of discrimination. On a clinical level, raising the issue of age discrimination with older patients could help to identify those at risk of future health problems." [1]

The research was conducted using data from the English Longitudinal Study of Ageing, a nationally representative sample of over 50-year olds. Participants reported experiences of age discrimination and rated their own health via self-completed questionnaires and face-to-face computer-assisted personal interviews in 2010-11. Follow-up questionnaires and interviews collected data on participants' health after a six-year period to record any health conditions they had developed since.

There are some limitations to the study. Age discrimination was self-reported so is subject to recall bias and reflects the participants own perceptions, rather than the act of discrimination itself. To minimise bias, participants were asked about a range of types of discrimination (not only age discrimination). Health conditions were also self-reported.

The authors discuss several possible ways that ageism could negatively impact health. Firstly, previous studies have shown that exposure to age discrimination can provoke stress responses harmful to both mental wellbeing and physical health. Secondly, people may use unhealthy behaviours, like smoking, drinking, poor diet or physical inactivity, to cope with experiences of age discrimination.

Thirdly, they suggest that age discrimination in healthcare could mean that older patients are not receiving the same standard of care as their younger counterparts. 41% (804/1,943) of those who reported experiencing age discrimination specified has said that they "receive poorer service or treatment than other people from doctors or hospitals" and the authors point out that age-related biases in recommended treatments are common. For example, older patients with cancer are less likely to receive treatments that aim to cure the disease and older people are rarely included in clinical trials for drugs to treat heart disease. [2, 3]

Finally, the authors highlight the lack of existing research into ageism and health, despite an established body of evidence that examines other forms of discrimination as social determinants of health and wellbeing. In light of this, they call for more research into how ageism operates to inform interventions and policies to tackle it.

Writing in a linked Comment, Professor Martin Gulliford, King's College London, UK, says: "The public health community has been slow to acknowledge the central role of discrimination in health inequality... Although the interrelationships between age, socioeconomic status, health status and experienced discrimination are complex, these findings suggest that not only does age discrimination cause short-term psychological distress to older people, but could also have an important effect on their long-term mental and physical health." [1]

Due to advances in treatment, an ever-increasing number of patients are living longer as metastatic cancer survivors. They and their doctors face a host of new challenges that require immediate attention.

It used to be when you were diagnosed with metastatic cancer, you were told to get your affairs in order, period. Now, with advances in research and treatment, a diagnosis of metastatic disease is no longer an immediate death sentence. Many of these patients, who once would have died within months, are now living extended years. But it's not as simple as it sounds. Two Johns Hopkins Kimmel Cancer Center professionals know this all too well.

Terry Langbaum, M.A.S., a long-time cancer center administrator, has survived multiple cancer diagnoses and lives firsthand with the challenges and complications that come with life as a cancer survivor with no current options for cure. In a perspective published in the April 4 issue of the New England Journal of Medicine (NEJM), Langbaum and Thomas Smith, M.D., a medical oncologist with recurrent prostate cancer, address the challenges confronting those living with metastatic cancer. They also strongly recommend that researchers study this topic and share their findings with the medical community caring for this emerging and ever-growing population.

"Long-term survivors with metastatic cancer ... have not been well-studied, though diagnoses of incurable cancer will have substantial effects on patients' families, on workplaces and on U.S. health care resources in the coming years," the authors write in the NEJM piece.

In the article, Langbaum, administrative director at Johns Hopkins Comprehensive Transplant Center, and Smith, professor of oncology and palliative care at the Johns Hopkins University School of Medicine, share highly personal examples of the urgent demand for more awareness of this population and its needs.

Five months after receiving total androgen blockade for recurring prostate cancer, Smith experienced a swift and serious return of depression, from which he'd suffered decades earlier. This time, severe mood swings and thoughts of suicide landed him in the hospital.

Members of his care team were surprised to learn that this common treatment for prostate cancer increases patients' relative risk of depression by 41 percent. This followed a serious and potentially life-threatening transient ischemic attack, possibly due to his treatment, as well as months of unrelenting severe hot flashes and insomnia due to the androgen deprivation. Smith hopes that others will receive warnings or preemptive referrals to avoid or at least minimize the fallout.

For Smith, the incident provided a startling example of just how ill-prepared patients and their care providers can be in facing this new frontier of metastatic cancer survivorship, which presents a mix of hope and uncertainty for patients, their families and their health care providers. Beyond the immediate medical issues this circumstance raises, Smith and Langbaum point out that patients must also cope with ongoing burdens that are psychosocial, financial (many new therapies cost more than $10,000 per month), emotional and physical. Only one person at Johns Hopkins, Lillie Shockney, R.N., Ph.D., has been studying how to best help people face these challenges.

In addition to addressing the unforeseen burdens facing a growing number of metastatic cancer survivors, the authors also present some possible strategies to ease their journey. They include developing coping mechanisms adopted from other chronic, life-shortening conditions; providing therapy to help diminish patients' feelings of despair; offering mechanisms of support to both patients and their providers; and coordinating care management among primary care, oncology, and palliative care professionals to improve the patient experience.

The authors sum up the perspective piece with an urgent call for action. They write: "We believe the time has come to study metastatic cancer survivors and better educate the medical community about the needs and challenges of this growing population."

Boston, MA -- Infectious diseases experts and transplant physicians and surgeons at Brigham and Women's Hospital have blocked the transmission of hepatitis C from infected organ donors to recipients in need of hearts or lungs. The DONATE HCV Trial Team reports that hepatitis C-infected thoracic organs can be safely transplanted, detecting no signs of the disease and good outcomes for the transplanted organs in all patients treated with a preemptive, short course of antivirals. In a paper published in the New England Journal of Medicine, the team describes a four-week antiviral treatment regimen started within hours of organ transplantation surgery, preventing establishment of hepatitis C virus (HCV) infection in all patients, and, in so doing, expanding the pool of eligible heart and lung donor organs.

"There was a 100 percent success rate in terms of HCV treatment and six-month graft survival," said corresponding author Ann Woolley, MD, MPH, of the Division of Infectious Diseases at the Brigham. "Direct acting antivirals have revolutionized the field of hepatitis C treatment and have also created an opportunity to transplant organs from hepatitis C positive donors. While transplants from hepatitis C positive donors have previously been done, the best approach to doing this -- when to initiate treatment and how long to treat patients after transplant -- as well as the outcomes for heart and lung transplant recipients have not previously been systematically studied. This is the largest clinical trial to date for HCV thoracic organ transplantation and provides clear evidence that this shortened regimen, initiated within hours of transplant, can prevent the establishment of hepatitis C in the recipients and lead to excellent outcomes for patients."

In their paper, the researchers present data on the 35 patients who had enrolled in the study by February 2018. Each of those 35 patients met the trial's primary endpoints -- all had undetectable hepatitis C viral loads and functioning transplanted organs six months or more after transplant surgery. Given the study's successful outcomes, enrollment continues and the team has now enrolled a total of 69 participants to date.

The team found that nearly all of the patients who received organs from HCV viral load positive donors had evidence of HCV virus immediately post-transplantation. However, very early preemptive treatment prevented HCV from establishing infection, despite the fact that patients were taking high-dose, induction immunosuppressive medications as part of the transplant process. All recipients cleared the virus by about two weeks and hepatitis C viral loads remained undetectable thereafter.

"It was critically important to us to determine that this treatment not only prevented transmission of hepatitis C but also didn't worsen outcomes for our transplant patients," said co-author Steve Singh, MD, former surgical director of the Heart Transplantation and Mechanical Circulatory Support in the Department of Cardiac Surgery. "Our short-term findings to date suggest that graft survival is just as excellent in patients who were transplanted with thoracic organs from hepatitis C positive donors as it was in those who received thoracic organs from non-hepatitis C positive donors during the same period."

Although the number of organ transplants in the U.S. has increased over the last five years, it is estimated that about 1,000 patients die every year waiting for a lung or heart transplant. Drug intoxication deaths have led to a rise in available organs for transplantation, but donor hepatitis C viral infection has been a leading reason that otherwise medically suitable organs are deemed ineligible for transplantation.

Direct-acting antivirals, such as sofosbuvir/velpatasvir, are used to treat patients infected with hepatitis C. Standard treatment for people who are chronically infected with hepatitis C is typically 8-to-12 weeks, depending on the treatment regimen used. Other studies have found that it is feasible to treat kidney and liver transplant patients with these drugs early after transplantation, and such treatments are beginning to be used to treat heart and lung transplant recipients. Woolley and colleagues set out to treat a much larger cohort of patients with a shortened course of therapy and collected data on outcomes over a longer period of time.

The authors noted the importance of a shorter duration of antiviral treatment leading to successful outcomes for patients.

"HCV infection has been a long-standing reason to decline donation of suitable organs," said co-author Lindsey Baden, MD, director of Clinical Research in the Division of Infectious Diseases at the Brigham. "What the data show is that transmission does occur, but a short, four-week course of antiviral therapy led to rapid HCV clearance. These data demonstrate how preemptive therapy can stop transmission thus decreasing medication burden, drug interactions, and cost."

The team also analyzed safety outcomes, finding that there were no hepatitis C-attributable adverse events. The researchers reported a numerical increase in acute cellular rejection among lung transplant patients, but this trend was not statistically significant.

"This study provided a unique opportunity to explore the utilization of thoracic organs from hepatitis C positive donors for transplantation, which to date have been underutilized despite being relatively common in the current donor population," said co-author Hilary Goldberg, MD, MPH, the medical director of the Lung Transplant Program and the former lead for the Solid Organ Transplant Quality Assurance and Process Improvement Program at the Brigham. "I am very encouraged by the results so far, and the potential that this study may allow us to provide transplantation successfully to the many recipients who might otherwise never have access to it."