Body

A drug that helps us to eat less could help the more than 650 million people around the world who live with obesity. One of the emerging drug candidates that interest researchers is the hormone GDF15 that, when given to rodents, lowers their appetite and body weight. New research from the University of Copenhagen finds that the body produces large amounts GDF15 during extended bouts of vigorous exercise, presumably as a physiological stress signal.

This finding highlights central differences between GDF15 given as a drug (pharmacology), and GDF15 released naturally in response to vigorous exercise (physiology). This is an important distinction in understanding GDF15's role in appetite regulation and energy balance, with implications for its role as a possible anti-obesity drug.

"Whether there are any physiological conditions that implicates GDF15 as a regulator of energy metabolism remains an unsolved mystery," says Associate Professor Christoffer Clemmensen from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

Christoffer Clemmensen, PhD student Trine Sand Nicolaisen and Assistant Professor Anders Bue Klein led the research in collaboration with the Department of Nutrition Exercise and Sports at the University of Copenhagen and the findings were published in Nature Communications.

Their goal was to better understand the physiological role of GDF15 in energy metabolism and behavior. Recent findings in rodents and monkeys suggest that the hormone, when administered pharmacologically, lowers appetite but also promotes nausea and sickness. Other studies have shown that the drug metformin promotes weight loss by increasing the levels of GDF15.

Different pharmocological and physiological effects of GDF15

Little is known about how GDF15 functions when released naturally by the body, however. The researchers set out to fill this knowledge gap with a series of experiments on humans and mice. Among their main findings was that prolonged exercise beyond two hours in humans results in a four to five-fold increase in the circulation of GDF15, suggesting that GDF15 functions as an exercise-induced stress signal.

To test this idea, the researchers used animal models. They found that giving GDF15 to mice as a drug clearly lowered their motivation to exercise and reduced their appetite. But when the mice were vigorously exercised, to stimulate the physiological release of GDF15, it did induce the same response on behavior and food intake.

These findings underscore a difference between physiological GDF15 and pharmacological GDF15. Christoffer Clemmensen stresses that more studies are needed to understand this mismatch and whether GDF15 also has behavioral effects in humans. He and his team will now focus on clarifying the effects of GDF15 when produced by the body.

BINGHAMTON, NY -- Rich nations should not engage in "vaccine nationalism" and keep the COVID-19 vaccine to themselves when poorer nations need them, according to Nicole Hassoun, professor of philosophy at Binghamton University, State University of New York. Hassoun's paper, "Against Vaccine Nationalism," was published in the Journal of Medical Ethics.

While rich countries like the US and UK are starting to vaccinate their populations against COVID-19, poor countries may lack access to a vaccine for years. Canada, for instance, has already secured enough to vaccinate its entire population nine times over, and the US, European Union, UK, Australia, and Japan can vaccinate their populations between 2-8x.

"Vaccine nationalism is neither ethically justified, nor even in rich countries' long term self-interest," said Hassoun. "No one deserves the luck of their birth and few have much control over their country of residence. So when there are four ventilators per 12 million people in some developing countries, and people are being buried in cardboard boxes in mass graves, it is simply unconscionable to argue that wealthy countries can keep their vaccines to themselves or even help their populations first. Vaccine nationalism fails to respect basic human rights and the people that have them."

National leaders make promises and undertake commitments to protect their own, but they can't always prioritize their own citizens, said Hassoun. She believes that when national leaders engage in international efforts they adopt new role responsibilities - doing so often requires national leaders to act for the (global) common good.

"Consider an analogy - suppose a CEO is morally bound to advance the interests of stakeholders but learns that her company is profiting from polluting the Amazon. Is it acceptable for her to continue to allow her company to do so? Clearly not. Similarly, if her company could help avert a genocide or otherwise save many lives at some cost to shareholders, she might be morally bound to do so."

Hassoun also pointed out that it's in rich countries' long-term interests to equitably distribute vaccines.

"The COVID pandemic may continue to circle the globe for much longer (or indefinitely) if we do not fight it where the worst outbreaks are occurring," said Hassoun. "And herd immunity in rich countries is by no means guaranteed. Helping establish basic health infrastructure internationally (to not only vaccinate against COVID but a host of vaccine-preventable diseases) could greatly lower the global burden of disease."

The COVID-19 infection rate among pregnant women was estimated to be 70% higher than in similarly aged adults in Washington state, according to a new study published today in American Journal of Obstetrics and Gynecology. Other key findings include:

The study also showed that the number of COVID-19 infections in pregnant patients from nearly all communities of color in Washington was high. There was a twofold to fourfold higher prevalence of pregnant patients with COVID-19 infections from communities of color than expected based on the race-ethnicity distribution of pregnant women in Washington in 2018.

A high number of pregnant women with COVID-19 received their medical care in a language other than English. This indicates that public health outreach to enhance vaccination rates in these communities is crucial.

"Our data indicates that pregnant people did not avoid the pandemic as we hoped that they would, and communities of color bore the greatest burden," said Dr. Kristina Adams Waldorf, an ob-gyn with the University of Washington School of Medicine and the report's senior author. "We were disheartened to see the higher infection rates in communities of color as well as in patients with limited English proficiency."

COVID-19 vaccine allocation is based priority lists set by each state's department of health, which can vary. In some states, pregnancy is considered a high-risk health condition for COVID-19 vaccine allocation in Phase 1B. Texas, New Hampshire, New Mexico and Alaska are among the states that prioritize pregnant women for COVID-19 vaccines in schedule Phase 1B.

"The vaccine distribution plans vary quite a bit, state-by-state, and pregnant women are written out of the allocation prioritization in about half of U.S. States. Many states are not even linking their COVID-19 vaccine allocation plans with the high-risk medical conditions listed by the CDC - which include pregnancy, Adams Waldorf said.

"The higher infection rates in pregnant patients, coupled with an elevated risk for severe illness and maternal mortality due to COVID-19, suggests that pregnancy should be considered a high-risk health condition for COVID-19 vaccine allocation in Phase 1B all across the United States," she added. "The time to act is now."

She said this study is unique in the United States because it is the first to address the question of infection rates in pregnancy in a large population that represents the majority of pregnancies in the state. The data can inform vaccine policy and guide public health workers and physicians in trying to mitigate COVID-19 in vulnerable populations.

The multisite study included 35 hospitals and clinics that compose the Washington State COVID-19 in Pregnancy Collaborative led by Adams Waldorf and Erica Lokken, an epidemiologist at the UW School of Public Health. The group identified 240 pregnant women who acquired COVID-19 from March through June 2020. This number represents all such known cases at the collaborating sites, which account for 61% of births in the state each year.

"Higher infection rates in pregnant patients may be due to the overrepresentation of women in many professions and industries considered essential during the COVID-19 pandemic - including healthcare, education, service sectors," said Lokken. Pregnant women may also have larger households, children in daycare or playgroups, and be caregivers within an extended family, she added.

This study data fills critical gaps and provides an important estimate of regional COVID-19 infection rates in the pregnant population, Waldorf said. The Centers for Disease Control and Prevention's estimated infection rates may not be representative, she said.

"COVID-19 case reports are missing pregnancy status in up to 65% of reports for women of reproductive age. As a result, the number of pregnant patients infected with COVID-19 was likely underrepresented in national numbers," the authors concluded.

"When the data is woefully incomplete for specific groups, like pregnant women, it is easy to assume that they haven't been impacted by the pandemic. This was not the case," said Adams Waldorf.

Pregnant healthcare workers have received the COVID-19 vaccine, and Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, has reported no "red flags" in preliminary data about post-vaccination well-being of this population.

Adams Waldorf urges pregnant women to discuss the risks and benefits of COVID-19 vaccination with their prenatal care provider. More ob-gyns have begun recommending that pregnant women take the vaccine.

"We want to use information from this study to be more prepared for the next pandemic and to not brush pregnant women to the side. They need to have a seat at the table when it comes to vaccine trials and vaccine allocation," Adams Waldorf said.

Hamilton, ON (February 16, 2021) - A McMaster stem cell research team has made an important early step in developing a new class of therapeutics for patients with a deadly blood cancer.

The team has discovered that for acute myeloid leukemia (AML) patients, there is a dopamine receptor pathway that becomes abnormally activated in the cancer stem cells. This inspired the clinical investigation of a dopamine receptor-inhibiting drug thioridazine as a new therapy for patients, and their focus on adult AML has revealed encouraging results.

AML is a particularly deadly cancer that starts with a DNA mutation in the blood stem cells of the bone marrow that produce too many infection-fighting white blood cells. According to the Canadian Cancer Society about 21% of people diagnosed with AML will survive at least five years.

"We have successfully understood the mechanism by which the drug benefited patients, and we are using this information to develop a new, more tolerable formulation of the drug that is likely to work in some of the patients," said senior author of the paper Mick Bhatia, a professor of biochemistry and biomedical sciences at McMaster. He also holds the Canada Research Chair in Human Stem Cell Biology.

The phase one study of 13 patients is being featured on the cover of the journal Cell Reports Medicine published today.

Bhatia said the team has continued to carefully analyze and further refine their therapeutic approach and results of the initial trial.

"Together, these achievements highlight the importance of the new paradigm of that issues impacting patients can be taken to the lab bench and solutions back to patients. These "bed to bench, and back to bed" approaches and partnerships to advance novel therapeutics Canadians suffering from cancer," he added.

Reston, VA--Molecular imaging can successfully predict response to a novel treatment for ER-positive, HER2-negative metastatic breast cancer patients who are resistant to hormonal therapy. According to research published in the February issue of the Journal of Nuclear Medicine, positron emission tomography (PET) imaging using an imaging agent called 18F-fluoroestradiol can help to determine which patients could benefit from treatments that could spare them from unnecessary chemotherapy.

Nearly two-thirds of invasive breast cancers are ER-positive, and endocrine therapy is the mainstay of treatment for these tumors because of its favorable toxicity profile and efficacy. Should cancer progress in these patients, however, salvage endocrine therapy with molecularly targeted agents or chemotherapy can help.

"In some ER-positive breast cancer patients, cancer progression can be a result of a gradual resistance to endocrine therapy," noted Hannah M Linden, MD, FACP, Athena Distinguished Professor and breast medical oncologist at the University of Washington Fred Hutchison Cancer Research Center and Seattle Cancer Care Alliance in Seattle, Washington. "Histone daecetylase inhibitors (HDACIs) have been proposed as a mechanism to reverse endocrine resistance, and clinical studies have shown promising results when combining endocrine therapy with HDACIs to restore endocrine sensitivity."

To further explore the efficacy of this combination therapy, researchers designed a study in which 18F-FDG PET imaging with 18F-fluoroestradiol was conducted on patients receiving vorinostat, a potent HDACI, along with an aromatase inhibitor, a type of endocrine therapy. Scans were performed at baseline, week two and week eight of the study. Subjects included ER-positive/HER2-negative breast cancer patients who had previously responded well to endocrine therapy while on an aromatase inhibitor. Eight of the study participants were treated with vorinostat followed by an aromatase inhibitor, while 15 were treated with both at the same time.

After eight weeks, eight patients had stable disease, and six of the eight patients were stable for more than six months. Higher baseline 18F-fluoroestradiol uptake was associated with longer progression-free survival. 18F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18F-FDG uptake did not show a significant decrease, which is expected with tumor regression.

"We test ER expression in a metastatic biopsy once at the beginning of the patient's journey," explained Linden, "and we make decisions all along--when to give chemotherapy, when to use endocrine therapy, whether or not to use targeted agents--based o

UCLA RESEARCH ALERT

FINDINGS

A new study led by researchers at the UCLA Jonsson Comprehensive Cancer Center helps identify which patients with prostate cancer will benefit most from the use of prostate-specific membrane antigen PET imaging, PSMA PET, a novel imaging technique that recently was approved by the U.S. Food and Drug Administration.

By studying different variables and risk factors, researchers created a model that can be used in the clinic to identify patients who may have more extensive disease than anticipated and identify patients who are at higher risk of prostate cancer spreading to lymph nodes in the pelvis and beyond. The team found the percent of positive cores -- a metric that reflects volume of disease -- is a powerful predictor of increased nodal, metastatic and any upstaging in men with newly diagnosed high-risk prostate cancer. Patients with PPC greater than 50% and had a Gleason score of 9 or 10 (Gleason grade group 5) are the most likely to benefit from getting the PSMA PET scan.

BACKGROUND

The PSMA PET scan is an emerging imaging modality with improved sensitivity and specificity over conventional imaging for prostate cancer staging. It uses positron emission tomography (PET) in conjunction with a tracer that is highly effective in detecting prostate cancer throughout the body so the precise location of the full extent of disease can be visualized. The PSMA PET scan identifies cancer that is often missed by current standard-of-care imaging techniques. However, this scan is still not widely available and resource allocation may be a problem. Therefore, it is imperative to identify patients who are most likely to benefit from this novel imaging technique.

METHOD

The team looked at 213 men who were enrolled in two prospective clinical trials at UCLA that used the PSMA PET scan as a part of primary staging of the disease. They used a multivariable logistic regression model to assess for predictors of upstaging and developed a risk calculator to further quantify the risk for each individual patient.

IMPACT

The findings could help predict which patients may have more cancer than anticipated, spreading to pelvic lymph nodes and beyond. An easy-to-use nomogram (calculator) was also developed as part of the effort. This is crucial for designing optimal treatment plans for each individual patient.

DALLAS, Feb. 15, 2021 -- Understanding the sex differences in cardiovascular disease presentation and outcomes remains a major research priority demonstrated by the record number of submissions for this year's Go Red for Women® special issue of the American Heart Association's flagship journal Circulation, published online today. Circulation editors said more than 100 manuscripts were submitted this year, the most ever in the five years in which the current editorial board has published the special issue.

"Undeniably, cardiovascular disease remains the number one killer of women around the world, taking the lives of 1 in 3 women. Even one life lost is too many, because we know much of heart disease and stroke is preventable and treatable," said Circulation Editor-in-Chief Joseph A. Hill, M.D., Ph.D. "Support for ongoing research, as well as female participation in pivotal clinical trials, are imperative to effectively address sex disparities in heart disease and stroke care as part of our effort to improve cardiovascular health for women. These are critical in our fight against heart disease and stroke in women."

The first Go Red for Women Circulation special issue was published in February 2004. Since then, the journal has featured articles related to women and cardiovascular health most every February in recognition of American Heart Month. For the past five years, Hill and his editorial team have dedicated the February issue to the ongoing and unique challenges that face women in the fight against heart disease and stroke. This year's Go Red for Women issue covers a broad array of topics specifically about cardiovascular disease in women, presented as original research articles, research letters, state of the art reviews, perspectives, editorials and a cardiology news story.

Below are highlights of some of the manuscripts in this issue, which can be accessed in full here.

Association between sex and treatment outcomes of atrial fibrillation ablation versus drug therapy: results from the CABANA Trial - Andrea M. Russo, et al.

Researchers in this clinical trial randomized 2,204 atrial fibrillation (AFib) patients (37% women) who were 65 or older or were under age 65 but had at least one risk factor for stroke to receive treatment with either catheter ablation or drug therapy to control heart rhythm.

There was no significant difference in the primary outcome of death, disabling stroke, serious bleeding or cardiac arrest in men versus women. Adverse events related to either therapy were low in both men and women, without significant sex differences. Catheter ablation compared with drug therapy reduced AFib recurrence in both men and women.

Whereas prior non-randomized data have suggested higher procedural complications in women compared with men, this was not seen in this randomized trial. Researchers said recommendations for ablation should not be discouraged based on concern for adverse events in women, and since ablation offers comparable benefits for women and men, sex should not be used as a basis for selecting a management strategy for treatment of AFib.

Comparison of the efficacy and safety outcomes of edoxaban in 8,040 women versus 13,065 men with atrial fibrillation in the ENGAGE AF TIMI 48 Trial - Robert Giugliano, et al.

In a secondary analysis of the ENGAGE AF TIMI 48 clinical trial, researchers set out to examine the efficacy and safety profile of the anticoagulant edoxaban in women versus men. The 21,105 patients (8,040 women) with AFib and an elevated risk for stroke in the trial were randomized to a higher-dose or a lower-dose of the newer anticoagulant edoxaban or to warfarin, which is an older anticoagulant that must be closely monitored and tends to carry some risks. Follow-up continued for about three years.

At baseline, women had a higher level of FXa activity, which is a critical protein in the clotting process, placing women at potentially increased risk of thrombosis relative to men. Treatment with high-dose edoxaban reduced FXa levels to a greater extent in women than in men, resulting in similar intensity of anticoagulation.

Compared with warfarin, the treatment effect of the higher dose of edoxaban on the risk of stroke or other major clotting events and on major bleeding was similar in women and men. However, the high-dose edoxaban reduced the risk of severe bleeding outcomes including hemorrhagic stroke to a greater extent in women than in men.

Researchers said the safety advantage of edoxaban in women is enhanced for multiple bleeding endpoints compared with men, suggesting that edoxaban is a particularly attractive option for the treatment of women with atrial fibrillation.

Gender based differences in outcomes among resuscitated patients with out-of-hospital cardiac arrest - Purav Mody, et al.

Researchers examined data for 20,508 patients in the Continuous Chest Compression trial to understand experiences of resuscitated, out-of-hospital, cardiac arrest patients. Of the 4,875 successfully resuscitated patients in the primary study cohort, 1,825 (37.4%) were women and 3,050 (62.6%) were men.

Overall, compared to men, women were older (67.5 vs. 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% vs. 54.9%) and had a lower proportion of cardiac arrests that were witnessed (55.1% vs. 64.5%) or had a shockable rhythm (24.3% vs. 44.6%).

The EMS response time, epinephrine dose and amount of fluid administered during resuscitation were similar in men and women. Women had a marginally longer duration of resuscitation compared with men (14.6 minutes vs. 13.5 minutes). Discharge survival was significantly lower in women (22.5% vs. 36.3%).

Researchers said their study demonstrates the existence of gender disparities in post-resuscitation care and highlights the need for future qualitative studies focused on decision-making and care being provided in the post-resuscitation phase to narrow gender-based differences in cardiac arrest outcomes.

Trends in recurrent coronary heart disease following myocardial infarction among US women and men between 2008 and 2017 - Sanne A.E. Peters, et al.

In this study, data were collected from 770,408 women and 700,477 men in the U.S.,

Researchers found:

From 2008 to 2017, age-standardized recurrent MI rates per 1,000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men.
Recurrent coronary heart disease event rates decreased from 166.3 to 133.3 in women and from 198.1 to 176.8 in men.

Heart failure hospitalization rates decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men.

All-cause mortality decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men.

Researchers said rates of all tracked events in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high and rates of everything except heart failure hospitalization continue to be higher among men than women.

Other studies in this special issue include:

Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of MINOCA in women - Harmony Reynolds, et al. (Findings from this study were previously presented as Late-Breaking Science at the American Heart Association's Scientific Sessions 2020.)

Sex-stratified gene regulatory networks reveal female key-driver genes of atherosclerosis involved in smooth muscle cell phenotype switching - Hester den Ruijter, et al.

Cardiac remodeling during pregnancy with metabolic syndrome: a prologue of pathological remodeling - Steven Houser, et al.

Sex, permanent drug discontinuation and study retention in clinical trials: insights from the TIMI trials - Michelle O'Donoghue, et al. (This paper has an accompanying editorial: Adherence to study drugs - a matter of sex? - Sofia Sederholm Lawesson, et al.)

Sex differences in blood pressure associations with cardiovascular outcomes - Susan Cheng, et al.

Sudden cardiac arrest in young women - Eloi Marijon, et al.

Temporal trends in the proportion of women physician speakers at major cardiovascular conferences - Celina Yong, et al.

Regional heterogeneity in the coronary vascular response in women with chest pain and non-obstructive coronary artery disease - Malik Elharram, et al.

Related differences in cardiac channelopathies: implications for clinical practice - Babken Asatryan, et al.

Maternal stroke: A call for action - Islam Elgendy, et al.

Efficacy of neprilysin inhibition in women with HFpEF: beyond phenotypes and natriuretic peptides - Christopher deFilippi, et al.

The cascading effects of COVID-19 on women in cardiology - Nosheen Reza, et al.

Transcatheter mitral valve edge-to-edge repair for secondary mitral regurgitation: why sex matters - Dharam Kumbhani, et al.

Rising pre-pregnancy hypertension, preeclampsia disparities raise alarm - Bridget Kuehn

Authors' disclosures and funding sources for all studies in the special issue are listed in the individual manuscripts.

"By publishing some of the best science on cardiovascular disease in women, our hope is that this issue of Circulation will catalyze the conduct of transformative and disruptive research in this area, enabling us to further our understanding of sex differences in CVD presentation and outcomes and effectively address sex disparities in cardiovascular care," said Hill, who is a professor of internal medicine and molecular biology, Chief of Cardiology at UT Southwestern Medical Center and director of the Harry S. Moss Heart Center in Dallas, Texas

To raise awareness about how participation in research could further scientific understanding of cardiovascular health, the American Heart Association and Verily, Alphabet's life sciences and health care arm, are collaborating on Research Goes Red™. Research Goes Red aims to empower women to contribute to health research. Learn more at http://www.goredforwomen.org/researchgoesred.

A pair of UCR studies reveal that living with a romantic partner helps people feel more socially connected during COVID-19. But no other pandemic-era social dynamic carries notable benefits, the researchers found: not your kids, not kibitzing with your bestie on Facetime, and not your adorable-adoring pets.

"Research prior to the pandemic has long shown that partners are one of the strongest predictors of social connection and well-being," said UCR researcher Karynna Okabe-Miyamoto, lead co-author of the study, published recently in the journal Plos One. "And our research during the current COVID-19 pandemic has shown the same. Living with a partner uniquely buffered declines in social connection during the early phases of the pandemic."
By April 2020, many workplaces and stores had been shuttered, and social distancing measures had been implemented. The social existence of many people was relegated to the four walls of their homes, and their families became their only social connections.

The effectiveness of social distancing in reducing virus transmission had been established even before COVID-19. Researchers were curious about how to protect psychological health when such measures are in place.

The first study was conducted in Canada and included 548 undergraduate students. The second was conducted in the United State and United Kingdom and included 336 participants.

In the studies, participants reported their perceived social connection before and during the pandemic. They were asked to rate statements such as "I felt close and connected with other people who are important to me" and "People are around me, but not with me." They were also asked to declare their social distancing adherence and whether they travel outside of the home for work.

Looking at participants before and during the pandemic, the authors wrote that people living with a romantic partner were most likely to improve in social connection after social distancing measures.

But the size of one's household during the pandemic made little difference in feelings of social connectedness. Nor did being in the company of one's children, or one's pets. Working outside the home did nothing to help people feel socially connected, nor did video calls with friends and family.

"Living with a partner - but not how many people or who else one lives with - appeared to confer benefit during these uncertain and unprecedented times," the authors wrote.

Researchers wrote the finding is consistent with past research that affirms romantic relationships lead to a greater sense of wellbeing and feeling connected. "In part," the authors wrote, "because happier people are more likely to find partners."

The researchers say policy makers should consider measures that place a priority on maintaining social connection, balanced against transmission risk.

Findings from a new Geisel-led study, published in the Journal of General Internal Medicine, reveal that there is substantial variation across different regions of the country in the intensity of fracture-associated drug (FAD) use among long-term care facility residents, and that areas with greater use of these prescription drugs experience higher hip fracture rates.

In recent decades, the use of prescription medications has increased dramatically in the U.S. due to factors such as improvements in the ability to detect disease, expanding treatment options, and an aging population. For many Americans over age 65, these medications provide an effective means of managing disease and improving quality of life and longevity.

However, many commonly prescribed drugs--such as opioid pain killers, sleep aids, diuretics, antidepressants, and antacids--are known to carry an increased risk of breaking a bone, by increasing falls, weakening bones, or both. This is especially true for patients whose fracture risk is already high due to conditions like osteoporosis.

"In our previous research, we showed that combining three or more FADs carried up to a four-fold risk of hip fracture for Medicare beneficiaries, and that exposure to these medications for residents of long-term care facilities was nearly twice that of those living in the community setting," says Rebecca Emeny, PhD, MPH, a research scientist at The Dartmouth Institute for Health Policy and Clinical Practice and lead author on the study.

In this study, the investigators sought to determine how much regional variation exists in the intensity of FAD use (from a list of 21 FADs) in long-term care facilities and to assess the association between this intensity and hip fracture rates. They analyzed Medicare administrative data and the prescription records of 422,111 long-term care residents, comparing FAD use across hospital referral regions, and observed more than 36,409 hip fractures among these residents over an eight-year period (2006-2014).

Areas with the greatest multiple FAD use intensity (with at least three FADs prescribed) were in the southeast, in Gulfport and Oxford, Mississippi; Alexandria and Monroe, Louisiana; and Miami, Florida; while the lowest intensity areas were in Bronx, New York; Bend, Oregon; Albuquerque, New Mexico; Honolulu, Hawaii; and Sun City, Arizona.

The researchers found an average difference of 12 percent in the range of FAD prescribing when comparing hospital referral regions. They also determined that the risk of fractures was about 14 percent higher for residents in the highest intensity prescribing areas when compared to the lowest.

"Seeing such variation in the intensity of prescribing of these risky drugs across this vulnerable population adds to the evidence that guidelines aren't necessarily being followed," says Emeny. "We hope these results contribute to a more considerate weighing of risks and benefits when combinations of these medications are prescribed."

Certain plasma microRNAs could serve as diagnostic biomarkers in mild traumatic brain injury, a new study from the University of Eastern Finland shows. The biomarkers were discovered in an animal model and they were successfully used also to diagnose mild traumatic brain injury in a subgroup of patients. The study was published in the International Journal of Molecular Sciences.

Mild traumatic brain injury is difficult to detect by contemporary conventional imaging methods. In fact, most patients do not exhibit visible structural damage to the brain, which could be detected by computer tomography. Even without visible structural damage, it is extremely important to diagnose mild traumatic brain injury since patients' ability to work and their overall quality-of-life might become deteriorated. There is a major unmet medical need to identify accurate, affordable, and widely accessible diagnostic biomarkers that could be used to better diagnose patients with mild traumatic brain injury, and to guide them to symptomatic, timely and rehabilitative treatment.

Blood-based biomarkers enable minimally invasive and cost-effective diagnostics. Earlier studies have shown that many biomarkers hold promise for characterising the severity of traumatic brain injury, and they can provide molecular-level information about the ongoing pathological changes. In the newly published study, researchers set out to find microRNAs that could serve as biomarkers to diagnose traumatic brain injury. MicroRNAs, or miRNAs, are small RNA molecules that regulate the expression of protein-coding genes. The researchers sequenced blood plasma samples from an animal model both after mild and severe traumatic brain injury. The miRNAs showing the greatest potential on the basis of the sequencing data were selected for further, polymerase chain reaction (PCR) based analysis.

"We have been developing a suitable analysis and measurement method especially for miRNAs that can be found in small amounts in plasma, and this method is based on digital droplet PCR," Dr Noora Puhakka from the A. I. Virtanen Institute for Molecular Sciences at the University of Eastern Finland says.

"Humans and animals share many identical miRNAs, and this makes them excellent candidates for translational studies, where results achieved in animal models are sought to be applied in humans. However, it has proven challenging to reproduce results from different studies and different sets of data. This is why assessing the quality of measurement methods, and reproducibility, is an extremely important part of biomarker research."

The objective of the newly published study was to identify plasma miRNA biomarkers that are sensitive and specific to mild traumatic brain injury in an animal model, and to explore whether they could also be used to diagnose mild traumatic brain injury in humans.

"We found two interesting biomarkers in the animal model, the plasma miRNAs miR-9a-3p and miR-136-3p, which we then decided to analyse in blood samples taken from patients with traumatic brain injury. Elevated levels of these biomarkers allowed us to identify some of the patients who had experienced a mild traumatic brain injury," Dr Puhakka says.

In other words, plasma miR-9a-3p and miR-136-3p proved to be potential biomarker candidates to diagnose mild traumatic brain injury both in the animal model and in patients.

"Both of these miRNAs are more abundant in the brain than in other tissues, and their elevated levels in plasma could possibly be due to brain injury and the level of its seriousness. However, further research in larger patient cohorts is still needed."

It does not happen often. But on rare occasions, physicians make mistakes and may make a wrong diagnosis. Patients may have many diseases all at once, where it can be difficult to distinguish the symptoms of one illness from the other, or there may be a lack of symptoms.

Errors in diagnosis may lead to incorrect treatment or a lack of treatment. Therefore, everyone in the healthcare system tries to minimise errors as much as possible.

Now, researchers at the University of Copenhagen have developed an algorithm that can help with just that.

'Our new algorithm can find the patients who have such an unusual disease trajectory that they may indeed not suffer from the disease they were diagnosed with. It can hopefully end up being a support tool for physicians', says Isabella Friis Jørgensen, Postdoc at the Novo Nordisk Foundation Center for Protein Research.

The algorithm revealed possible lung cancer

The researchers have developed the algorithm based on disease trajectories for 284,000 patients with chronic obstructive pulmonary disease (COPD), from 1994 to 2015. Based on these data, they came up with approximately 69,000 typical disease trajectories.

'In the National Patient Registry, we have been able to map what you could call typical disease trajectory. And if a patient shows up with a very unusual disease trajectory, then it might be that the patient is simply suffering from a different disease. Our tool can help to detect this', explains Søren Brunak, Professor at the Novo Nordisk Foundation Center for Protein Research.

For example, the researchers found a small group of 2,185 COPD patients who died very shortly after being diagnosed with COPD. According to the researchers, it was a sign that something else might have been wrong, maybe something even more serious.

'When we studied the laboratory values from these patients more closely, we saw that they deviated from normal values for COPD patients. Instead, the values resembled something that is seen in lung cancer patients. Only 10 per cent of these patients were diagnosed with lung cancer, but we are reasonably convinced that most, if not all of these patients actually had lung cancer', explains Søren Brunak.

Data that will provide an immediate benefit

Although the algorithm was validated through data from COPD patients, it may be used for many other diseases. The principle is the same: the algorithm uses registry data to map the typical disease trajectories and can detect if some patients' disease trajectory stand out so much that something may be wrong.

'Naturally, our most important goal is for the patients to get their money's worth with respect to their health care. And we believe that in the future, this algorithm may end up becoming a support tool for physicians. Once the algorithm has mapped the typical disease trjaectories, it only takes 10 seconds to match a single patient against everyone else', says Søren Brunak.

He emphasises that the algorithm must be further validated and tested in clinical trials before it can be implemented in Danish hospitals. But he hopes it is something that can be started soon.

'In Denmark, we often praise our good health registries because they contain valuable data for researchers. We use them in our research because it may benefit other people in the future in the form of better treatment. But this is actually an example of how your own health data can benefit yourself right away', says Søren Brunak.

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Zika vaccine candidate shows promise in phase I trial
Abstract: https://www.acpjournals.org/doi/10.7326/M20-5306

Editorial: https://www.acpjournals.org/doi/10.7326/M21-0397

URL goes live when the embargo lifts

The Zika virus candidate, Ad26.ZIKV.001, a replication-incompetent human adenovirus serotype 26 (ad26) vector showed promising safety and immunogenicity in a phase I clinical trial. Researchers say the vaccine warrants further development should the need reemerge. The findings are published in Annals of Internal Medicine.

Zika virus (ZIKV) infection is transmitted via mosquito or sexually and may cause severe congenital disease after maternal-fetal transmission. The incidence of Zika virus has declined since the 2015-2016 outbreak, but geographic expansion of the Aedes aegypti mosquito to areas where population-level immunity is low poses a substantial risk for future epidemics. Currently, no vaccine is available.

Researchers from Janssen Vaccines and Prevention and Beth Israel Deaconess Medical Center randomly assigned 100 healthy participants to either a 1- or 2-dose regimen of Ad26.ZIKV.001 or placebo to assess the safety and immunogenicity of the Zika vaccine candidate. They found that 2 doses of Ad26.ZIKV.001 were safe, caused mild to moderate reactogenicity, and induced persistent neutralizing antibody responses. Transferred antibodies were found to be protective in a mouse Zika challenge model. Antibody responses up to 1 year after vaccination were observed in at least 80% of participants in both 2-dose (high and low) groups, indicating that a low dose would be sufficient. A single-dose vaccine had lower peak neutralizing antibody responses than the 2-dose strategies but nevertheless showed durable antibody titers at 1 year, and thus may be a useful tool in curbing future Zika epidemics.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. The corresponding authors, Nadine C. Salisch, PhD, and Dan H. Barouch, MD, PhD, can be reached at NSalisch@its.jnj.com.

2. Study suggests Zika blood screening policy may not be necessary or cost effective

Abstract: https://www.acpjournals.org/doi/10.7326/M20-6879

Editorial: https://www.acpjournals.org/doi/10.7326/M21-0397

URL goes live when the embargo lifts

A modeling study finds that universal screening of blood donations for Zika virus may not be necessary or cost effective, as the risk of serious adverse events from transfusion-transmitted Zika virus is exceedingly low. A resurgence of Zika that is even larger than the 2016-17 pandemic (which the author says is not likely) would be needed for the expected rate of serious adverse events from transfusion-transmitted Zika to exceed once-per-decade levels. The findings are published in Annals of Internal Medicine.

A 2019 simulation study found that screening the blood supply for Zika, which began in 2016, was not cost-effective in the 50 states during the first year. Despite these findings, the Blood Products Advisory Committee recommended continuing universal screening, which costs blood centers a collective $8 to $13 million each month. Discussions on this policy have been tabled due to the coronavirus pandemic, but the modeler suggests that this data could help to inform regulatory decisions.

A researcher from Stanford University used a simulation model to estimate the relationship between the rate of Zika-infectious donations and the rate of adverse outcomes due to transfusion-transmitted Zika in the 50 states without screening and estimate the 2018 cost-effectiveness of universal screening. At the rate of Zika-infectious donations from 2018, the report estimates that the rate of serious adverse events from transfusion-transmitted Zika would be below 1 congenital Zika syndrome case every 1,484 years and 1 Guillain-Barre syndrome case every 1,035 years. The report also estimates that universal screening with mini-pooled nucleic acid testing (the current standard) costs $5.1 billion per quality-adjusted life year gained (98% Credible Interval $0.77 - $16 billion). According to the study author, collaboration between modelers and policy-makers could enhance the policy relevance of modeling studies.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. The corresponding author, W. Alton Russell, can be reached directly at altonr@stanford.edu.

3. Immune checkpoint inhibitors may not cause serious flare ups in patients with preexisting autoimmune diseases

Abstract: https://www.acpjournals.org/doi/10.7326/M20-3419

URL goes live when the embargo lifts

Immune checkpoint inhibitors (ICI) may not trigger serious flare ups in patients with melanoma and preexisting autoimmune diseases. However, adverse events may be more likely in patients with inflammatory bowel disease (IBD). Findings from a nationwide cohort study are published in Annals of Internal Medicine.

ICI can increase survival and lead to long-lasting responses in patients with melanoma. But because ICIs have been shown to cause immune-related adverse events mimicking immunologic diseases, patients with preexisting autoimmune disease have been excluded from clinical trials.

Researchers from Leiden University Medical Center, the Netherlands studied over 4,000 patients enrolled in the Dutch Melanoma Treatment Registry to test the hypothesis that serious immune-related adverse events would occur more frequently in patients treated with ICI with advanced melanoma and autoimmune diseases than in patients without autoimmune diseases. They also compared baseline characteristics, treatment choices, response, and survival after ICI.

The researchers found that tumor response to ICI treatment and incidence of immune-related adverse events of grade 3 or higher were similar in patients with and without preexisting autoimmune disease of rheumatologic or endocrine origin in daily clinical practice. For patients with IBD, the researchers noted higher incidence of severe colitis and early discontinuation of treatment due to toxicity. These findings suggest that physicians do not need to withhold ICI in patients with the most common autoimmune diseases. However, close monitoring in patients with IBD is advised.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. The corresponding author, Ellen Kapiteijn, MD, PhD, can be reached directly at h.w.kapiteijn@lumc.nl.

Also in this issue:

Perioperative Management of Patients on Glucocorticoids

Caputo
Consult Guys
https://www.acpjournals.org/doi/10.7326/W20-0018

Trends in Endocarditis Associated with Injection of Illicit Drugs

Centor
Annals On Call
https://www.acpjournals.org/doi/10.7326/A20-0007

The links between cardiovascular disease and cognitive impairment begin years before the appearance of the first clinical symptoms of either condition. In a study carried out at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in partnership with Santander Bank and neuroimaging experts at the Barcelonaβeta Brain Research Center (BBRC, the research center of the Fundación Pasqual Maragall), the investigators have identified a link between brain metabolism, cardiovascular risk, and atherosclerosis during middle age, years before the first appearance of symptoms.

The report, published in the Journal of the American College of Cardiology (JACC), is important because it suggests that intervention in a modifiable condition (cardiovascular disease) could prevent the development of dementia, a disease for which there is currently no cure.

Dr. Valentín Fuster, CNIC and Mount Sinai Heart General Director, Physician-in-Chief of the Mount Sinai Hospital. and a lead author on the study, explained that "although everybody knows about the importance of caring for ourselves and controlling cardiovascular risk factors in order to avoid a heart attack, the association of these same risk factors with cognitive decline may increase awareness of the need to acquire healthy habits from the earliest stages of life."

Moreover, the results provide yet more support for the importance of implementing primary cardiovascular prevention strategies in middle age as a valuable therapeutic approach to slowing or even halting brain alterations that could contribute to future cognitive decline.

Cognitive impairment

The advanced stages of vascular disease and dementia often occur together, but until now this association has not been documented at earlier stages. The CNIC-coordinated study, led by Dr. Marta Cortés Canteli, shows that in middle age, years before any clinical signs appear, atherosclerosis and cardiovascular risk factors already show an association with low metabolism in brain regions implicated in the future development of dementia, especially Alzheimer disease.

The advanced stages of neurodegenerative and vascular diseases often occur together, and research in recent years has established close links between cognitive decline and a number of cardiovascular risk factors, including hypertension, obesity, and high cholesterol.

Using advanced imaging by positron emission tomography (PET), the research team quantified brain metabolism in more than 500 participants in the PESA-CNIC-Santander study. The participants had an average age of 50 years and no symptoms, but already had evidence of atherosclerosis in their arteries.

PESA-CNIC-Santander, directed by Dr. Valentín Fuster, is a prospective study of more than 4000 asymptomatic middle-aged participants who have been exhaustively assessed for the presence and progression of subclinical atherosclerosis since 2010.

The new study reveals a link between elevated risk of a cardiovascular event and low brain metabolism. "When brain metabolism declines, the brain's ability to handle adverse events can be compromised. Depending on the brain area affected, this can lead to a range of distinct problems," explained study co-first author Dr. Cortés Canteli, a CNIC investigator and Miguel Servet fellow.

Cardiovasular risk

"We found that a higher cardiovascular risk in apparently healthy middle-aged individuals was associated with lower brain metabolism in parietotemporal regions involved in spatial and semantic memory and various types of learning," said Dr. Cortés Canteli. Dr. Juan Domingo Gispert, head of the Neuroimaging group at the BBRC, noted that "the brain areas showing low metabolism in participants with higher cardiovascular risk are the same areas affected in Alzheimer disease, suggesting that these individuals may have higher than normal vulnerability to this disease."

"We think that cardiovascular risk factors the affect the large vessels carrying blood from the heart to the brain also affect the small vessels in the brain," asserted Dr. Fuster.

The study is the largest of its type to date in a healthy middle-aged population and could signal a paradigm change in the understanding of the links between vascular and brain disease, say the authors.

Among the modifiable cardiovascular risk factors most closely associated with a reduction in brain metabolism, the investigators saw the biggest effect with hypertension. "We found that the same risk factors that damage the heart and the large arteries, and especially hypertension, are closely linked to the decline in brain metabolism years before the appearance of symptoms," said Dr. Fuster.

Atherosclerotic plaques

The research team also found that a higher number of plaques in the carotid arteries, which carry blood to the brain, was associated with lower brain metabolism in areas of the limbic system and the parietal lobe, both of which are intimately linked to the development of Alzheimer disease.

"The next step will be to determine whether individuals with subclinical atherosclerosis in the carotid arteries and low brain metabolism at the age of 50 go on to experience cognitive decline 10 years later," said Dr. Cortés Canteli.

Dr. Juan Domingo Gispert remarked that "there is abundant evidence linking cardiovascular risk factors and Alzheimer disease. If we can gain a more precise understanding of this relationship at asymptomatic disease stages, we will be in a position of design new strategies to prevent Alzheimer, matching the success of current strategies to prevent cardiovascular disease."

These results will be a major stimulus for the implementation of early intervention strategies to reduce the incidence of cognitive decline in old age.

Years of suffering and billions of euro in global health care costs, arising from osteoporosis-related bone fractures, could be eliminated using big data to target vulnerable patients, according to researchers at Lero, the Science Foundation Ireland Research Centre for Software.

A study of 36,590 patients who underwent bone mineral density scans in the West of Ireland between January 2000 and November 2018, found that many fractures are potentially preventable by identifying those at greatest risk before they fracture, and initiating proven, safe, low-cost effective interventions.

The multi-disciplinary study, led by Lero's Prof. John J. Carey, Consultant Physician in Medicine and Rheumatology, Galway University Hospital, Mary Dempsey, Mechanical Engineering and Dr Attracta Brennan, Computer Science, NUI Galway has just been published in the British Medical Journal.

The Irish dual-energy X-ray absorptiometry (DXA) Health Informatics Prediction (HIP) project on bone mineral density now plans to assess current diagnostic classification and risk prediction algorithms for osteoporosis and fractures, according to Prof. Carey.

"This will identify which predictors are most important for Irish people at risk for osteoporosis, and develop new, accurate and personalised risk prediction tools using the large, multicentre, longitudinal follow-up cohort.

"Furthermore, the dataset may be used to assess, and possibly support, the assessment and management of other chronic conditions such as cardiovascular disease, cancer and other illnesses due to the large number of variables collected in this project," he added.

Prof. Carey points out that while Ireland has one of the highest osteoporosis rates globally, currently there is no national public or government policy to address the healthcare requirements of osteoporotic fractures, with costs rising rapidly.

"In Ireland, public hospital bed days have increased by almost 50% in the past decade for osteoporotic fractures and outnumber heart attacks, cancer, diabetes and many other illnesses that receive much greater attention," he added.

"Preliminary estimates suggest the number of fragility fractures and deaths following fracture for Irish adults aged 50 years and older in 2020 was similar or greater to the numbers with COVID infection, but there is no daily report on the numbers tested, hospitalised or who die following a fracture. Use of these and other data could help close those gaps," he added.

Prof. Carey says there is a global osteoporosis health crisis, with predictions of American medical costs associated with osteoporotic-related fractures including productivity losses and caregiving expenditure to exceed $94 billion (€77.6bn) annually by 2040.

Prof. Carey said previous studies have shown, for example in 2010, approximately 43,000 European deaths were fracture-related while expenditure related to osteoporosis exceeded €37 billion.

"A modest 5% reduction in those costs would result in an annual saving of €1.85bn at 2010 prices," he added.

"We now have big datasets, similar to the one utilised in our study, available throughout the globe. Cost-effective, innovative forms of data interrogation such as AI (Artificial Intelligence) will enable the timely identification and treatment of patients vulnerable to osteoporosis fractures, providing them with better care and using precious resources efficiently. There will be many opportunities to provide better patient outcomes and save billions of euro," he added.

Prof. Carey believes this collaboration between clinicians, big data scientists, engineering and computer scientists in Ireland, Britain and China will help leverage innovation, critical thinking and international partnerships to accelerate their programme and opportunities.

Director of Lero, Professor Brian Fitzgerald, said the utilisation of AI, as envisaged by Prof Carey and his team, shows how software development initiatives can directly impact people's lives at a fundamental level. Lero is a world leader in research on connected health and human performance.

"When Lero's work can help alleviate suffering, improve patient outcomes and free up resources, then we are doing the job we were established to do, and that's very rewarding for all concerned," he added.

CORVALLIS, Ore. - Statistical modeling developed by Oregon State University researchers has confirmed that changes to melanoma patients' gut microbiome led them to respond to a type of treatment capable of providing long-term benefit.

Findings were published in Science.

The modeling technique invented by Andrey Morgun of the OSU College of Pharmacy and Natalia Shulzenko of Oregon State's Carlson College of Veterinary Medicine is known as transkingdom network analysis.

The human gut microbiome is a community of more than 10 trillion microbial cells from about 1,000 different bacterial species, and transkingdom network analysis integrates multiple types of "omics" data - metagenomic, metabolomic, lipidomic, proteomic, etc. - in determining how interactions among specific types of gut microbes help or hinder biological functions in the host.

In this case, the microbial interactions involved how well the body responds to a type of cancer treatment known as anti-programmed cell death protein therapy, abbreviated to anti-PD-1 therapy. It allows immune cells to react more strongly to cancer.

"It was pretty dramatic," said Morgan, associate professor of pharmaceutical sciences. "We found altering the gut microbiome can take a patient with advanced melanoma who has never responded to immunotherapy, which fails about 60% of the time with this kind of cancer, and convert the patient into one who responds to it."

Morgun and former OSU postdoctoral researcher Richard Rodrigues, now at the National Cancer Institute, were part of a collaboration led by immunologists Giorgio Trinchieri and Amiran Dzutsev from NCI and medical oncologists Hassane Zarour and Diwakar Davar of the University of Pittsburgh that tested fecal microbiota transplants' ability to help melanoma patients benefit from anti-PD-1 immunotherapy.

The scientists collected fecal samples from patients who responded particularly well to the therapy and in a clinical trial gave the samples, via colonoscopy, to advanced melanoma patients who had never before responded to immunotherapy.

The patients then received the anti-PD-1 drug pembrolizumab, and this time it had the desired effect, turning non-responders into responders. Transkingdom network analyses confirmed the microbiome's role.

"Putting everything together, we showed that the fecal microbiota transplants and anti-PD-1 drug can change the gut microbiome and effectively reprogram a tumor's microenvironment so anti-PD-1 resistance is overcome," Morgun said.

Of 15 patients with advanced melanoma - an aggressive form of skin cancer - who received the combined treatment, six of them showed either tumor reduction or disease stabilization that lasted for more than a year.

"The promising findings clearly warrant more investigation in bigger clinical trials," Morgun said. "That way we can better identify microbial, bloodstream and intratumor biomarkers to select melanoma patients most likely to benefit from microbiome-based therapy. We really expect that eventually we'll identify a collection of bacteria with a high success percentage for converting immunotherapy non-responders into responders."