Body

Boston - For decades, the power of the placebo effect was thought to lie in patients' belief that they were -- or at least, could be -- receiving a pharmacologically active treatment. A new study by physician-researchers at Beth Israel Deaconess Medical Center (BIDMC) suggests that patients don't need to be deceived to receive benefit from treatment with placebo.

In a randomized clinical trial published in the journal PAIN, researchers found participants with moderate to severe irritable bowel syndrome (IBS) who were knowingly treated with a pharmacologically inactive pill -- referred to as an honest or open-label placebo -- reported clinically meaningful improvements in their IBS symptoms. People who received the open-label placebo experienced improvements that were significantly greater than those reported by participants assigned to a no-pill control group. There was no difference in symptom improvement between those who received open-label or double-blind placebos. The results build on the research team's previous findings and challenge the long-held notion that concealment or deception are key elements in the placebo effect.

"The clinical response to open-label placebo in this six-week trial was high, with 69 percent of participants who received open-label placebo reporting a clinically meaningful improvement in their symptoms," said first and corresponding author Anthony J. Lembo, MD, Professor of Medicine in the Division of Gastroenterology at BIDMC. "IBS is one of the most common reasons for healthcare consultations and absenteeism from work or school. Effective treatment options for IBS are limited, and we hypothesized it may be possible to ethically harness the placebo effect for clinical benefit."

For the rigorously designed clinical trial, researchers enrolled 262 adult participants, 18 to 80 years old with at least moderately severe irritable bowel syndrome, as measured by the validated IBS-Severity Scoring System (IBS-SSS), which measures frequency and severity of abdominal pain and distention, quality of life and other relevant factors across a scale of 0-500. Participants were examined, filled out baseline questionnaires and were randomized into one of three study arms; open-label placebo; double-blind (which included double-blind placebo or double-blind peppermint oil); or no-pill control. During their examinations, all participants discussed the placebo effect, the trial and its aims with their physicians.

The open-label group received pill bottles labeled "open-label placebo," and were told that the pills inside were pharmacologically inert, but could make them feel better through the placebo effect. The double-blind group received pill bottles labeled "double-blind placebo or peppermint oil." Participants in the double-blind group received either a placebo or an identical pill containing peppermint oil, but neither they nor the research team knew which they received. All participants who received pills were instructed to take one pill three times a day, 30 minutes before meals. The no-pill control group received no pills but otherwise followed identical study protocol. During return visits three and six weeks into the study, all participants completed questionnaires, were verbally asked about adverse events and briefly met with a study physician.

Lembo and colleagues -- including senior author, Ted J. Kaptchuk, Director of the Program in Placebo Studies and the Therapeutic Encounter at BIDMC -- found that improvement in IBS-SSS scores from baseline to the six-week endpoint was significantly greater in the open-label placebo group compared to the no-pill control group. Additionally, participants in the double-blind placebo group also saw superior symptom improvement compared to the no-pill control group, but the double-blind and open-label groups were not different from each other.

Next, the researchers performed a post hoc analysis of the participants who experienced large clinical improvements -- those who improved by at least 50 points and by at least 150 points, considered strong and very strong clinical responses, respectively. A greater percentage of participants in the open-label placebo and double-blind placebo groups reported a 50 point reduction in IBS severity score compared to the no-pill control group (approximately 70 percent in each placebo group compared to 54 percent in the no pill control group). Similarly, approximately 30 percent of open-label placebo and double-blind placebo participants reported a 150 point reduction in IBS symptoms, compared to only 12 percent of the no-pill group.

"If the presumption that deception is necessary for placebos to be effective is false, then many theories about the mechanisms that drive placebo effects may need modification," said Kaptchuk, who with colleagues in 2010, published the results of the first randomized controlled trial to show that patients with IBS responded well to treatment with open-label placebo. Subsequent research has demonstrated similar findings in patients with what they call subjective symptoms, including low back pain, knee pain, cancer-related fatigue, migraine headaches, menopausal hot flashes, and allergic rhinitis. "Our finding that openly prescribed placebo may be as effective as double-blinded placebo has implications for clinical practice and for future research, especially in chronic visceral and somatic pain conditions."

BOSTON - (March 25, 2021) - A mechanism has been identified that explains how physical exercise in pregnancy confers metabolic health benefits in offspring. According to researchers, the key lies with a protein called SOD3, vitamin D and adequate exercise, with the outcomes possibly forming the first steps to designing rational diet and exercise programs to use during pregnancy and particularly when mothers may also be overweight or obese.

The study, which was led by authors from the Joslin Diabetes Center at the Harvard Medical School and colleagues from Japan, the US, Canada and Denmark, has been published online by Cell Metabolism.

"We've known for a while that risks for obesity and type 2 diabetes can originate in the critical prenatal developmental period," said senior author Laurie Goodyear. "In particular, there is real concern that the increasing levels of obesity seen in women of reproductive age will transmit disease risk to subsequent generations. It's important to understand that if this is not alleviated, rates of diabetes and obesity will only continue to grow in the coming years."

Many previous studies have linked increased maternal body weight and unhealthy diets to poorer metabolic outcomes in offspring, often many years later. Understanding the mechanisms of how maternal exercise can reverse these effects might lead to interventions that prevent these diseases transmitting across generations, say the authors of the study.

"The findings offer an explanation as to why physical exercise during pregnancy may have metabolic benefits for offspring as they get older," said Goodyear. "We show how physical exercise during pregnancy, in combination with adequate vitamin D levels, enhances levels of a placenta-derived protein called SOD3 (superoxide dismutase 3), and that via a number of intermediate steps, this improves glucose tolerance in offspring."

The findings come from a series of investigations with pregnant mice, comparing groups exposed to voluntary wheel running (i.e., exercise) and groups that were sedentary. Using various techniques, the authors carefully investigated the effects of exercise on parameters such as DNA methylation, cell signaling and gene expression, particularly in relation to glucose metabolism.

In short, they found that SOD3 is an exercise-induced placenta-derived protein that activates a specific signaling pathway that controls DNA demethylation in the livers of offspring, which in turn improves a number of aspects of glucose metabolism in offspring.

They also highlight the critical role of vitamin D as a mediator of SOD3 expression, with their data suggesting that maternal diet had to have sufficient vitamin D levels to influence placental levels of SOD3 and hence any improvements in metabolic health in offspring. They note for example, that high dietary levels of the vitamin in the absence of exercise, and indeed the opposite scenario, did not lead to increases in SOD3 - a consequential point if SOD3 is targeted clinically, they suggest.

Although most of the investigation focuses on mice, the authors did also look at SOD3 levels in pregnant women, finding that those who exercised more did have higher levels of serum and placental SOD3 and that they appeared to be highest during the second trimester of pregnancy.

"In terms of clinical application, it looks like the most efficient way to raise levels of the SOD3 protein is still likely to be via physical exercise," said lead author Joji Kusuyama. He added that there may also be clinical interest in using maternal serum levels of SOD3 as a biomarker to assess the benefits of exercise during pregnancy.

"Our data hints that exercise in combination with optimal vitamin D levels might be particularly beneficial during the 2nd trimester of pregnancy," said Kusuyama. "Although we can't be definitive about this with the current findings, we now plan to look in detail at how diet and exercise type and timing might be optimized with maternal serum SOD3 measurements to obtain maximum benefits for offspring."

The authors note some limitations with the study, including generalizability to all races and ethnicities and that there are still certain aspects of the signaling pathway that require further investigation. Nonetheless, they suggest their findings offer important insights into the role of exercise during pregnancy and the likely dynamic metabolic benefits for offspring.

"This report focuses on SOD3 and the metabolic benefits for offspring of maternal exercise, but there may be wider benefits of this protein on other body organs. For example, we are currently investigating the effects of maternal exercise and SOD3 on brain function in the offspring," said Goodyear. "We are also doing more in-depth investigation of maternal exercise effects on placenta because we found there are a plethora of changes in this tissue, and these placental adaptations may also have life-long effects in offspring. It's early days but understanding how exercise and fitness before and during pregnancy work may be the key to better health for subsequent generations."

Judges don't do court stenography. CEOs don't take minutes at meetings. So why do we expect doctors and other health care providers to spend hours recording notes -- something experts know contributes to burnout?

"Having them do so much clerical work doesn't make sense," said Lisa Merlo, Ph.D., an associate professor of psychiatry and director of wellness programs at the University of Florida College of Medicine. "In order to improve the health care experience for everyone, we need to help them focus more on the actual practice of medicine."

Physician burnout affects patients, too. Stressed doctors are less compassionate and more likely to make mistakes. Clinicians who leave the field or cut back hours reduce patient access to care, and replacing doctors in the midst of a physician shortage drives up costs.

"We can't ignore burnout and expect doctors to just keep picking up the slack," Merlo said.

Electronic health records -- or EHRs -- have enabled better, faster and more accurate communication among health care providers. But the time required to populate them can mean less interaction with patients and more time after hours typing notes, which can be more driven by insurance requirements than usefulness in patient care.

To find solutions, Merlo teamed up with Oliver Nguyen, a research coordinator and IT specialist in the College of Medicine, to evaluate 35 studies of records-related burnout, looking for common threads. Their study, published in the Journal of the American Medical Informatics Association, is part of a special issue on physician burnout.

"The longer clinicians spend on records, especially after hours or on weekends, the more it's associated with burnout," Nguyen said.

As the pandemic stretches health care workers ever thinner, "we're beyond the straw that broke the camel's back," Merlo said. "The system has survived for so long because physicians step up and get the work done out of a sense of altruism and dedication to their patients. But there's only so long you can sustain that."

Physician wellness initiatives have increased during the pandemic, often focusing exclusively on self care. But "adding more yoga classes is not going to address a clinician working on electronic health records at home at 11 p.m.," Merlo said.

Streamlining record-keeping could help. So when Nguyen approached Merlo about optimizing electronic records, she was eager to collaborate. With colleagues at the University of Alabama at Birmingham, the U.S. Navy, Moffitt Cancer Center, the University of South Florida and the University of Central Florida, they uncovered several potential solutions that could help physicians. (Another study looked at nurse burnout; future research will include other health care providers.)

Their recommendations:

Share the load

Overflowing inboxes contribute to burnout. As the pandemic shifts some office visits to videoconference, email and phone communication, "inboxes are blowing up," Nguyen said. A shared inbox that allows office staff to triage messages that don't require a doctor's input, such as insurance questions, can help.

Revisit policy

The Centers for Medicare and Medicaid Services launched the Patients over Paperwork initiative in part to reduce the documentation requirements. If it shows promising results for reducing records burden, Nguyen and Merlo say, it could serve as a model for private insurers to emulate.

Create power users

Even when they're familiar with an EHR interface, doctors might not know about time-saving features like templates and bookmarks. An optimization team that offers proactive support can streamline time spent in the system.

Collaborate on design

"Usability continues to be a struggle for physicians," Nguyen said. More input from users can help when it comes to designing EHRs, as well as selecting and implementing them.

"The good news is, a lot of the issues can be fixed," Merlo said. "If we invest in these resources, we can make this better for patients, for health care providers, for everybody."

Preclinical research from VCU Massey Cancer Center published recently in the Proceedings of the National Academy of Sciences shows that the combination of two existing drugs can exploit the metabolic "hunger" of a particularly aggressive type of neuroblastoma to kill cancer cells without inflicting too much collateral damage to healthy tissue.

Neuroblastoma - a type of cancer that strikes the nervous system of very young children - is one of the deadliest pediatric cancers. And children whose neuroblastoma overexpresses the gene MYCN tend to have the worst prognosis.

While medical advancements have led to high cure rates among pediatric blood cancers, neuroblastoma has proven much more challenging to treat, largely because the gene that makes this cancer so deadly is a tough one to target.

"MYCN is a transcription factor, and it's very difficult to drug transcription factors," said study senior author Anthony Faber, Ph.D., co-leader of the Developmental Therapeutics research program and Natalie N. and John R. Congdon, Sr. Endowed Chair of Cancer Research at VCU Massey Cancer Center and associate professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry. "So, the next best thing is to target what MYCN does in the cell. One thing it does is to crank up metabolic activity - what it's doing to keep the cell alive - and we can work that against itself."

These neuroblastoma cells exist on the brink of metabolic overdrive, gobbling up energy stores as quickly as the cell can replenish them, so Faber's team sought ways to push these cells over the edge, without harming normal cells in the process.

The researchers screened 20 metabolic drug combinations in cancer cells originating from nearly 1,000 different patients and found that neuroblastoma with high MYCN expression was particularly sensitive to a cocktail containing two drugs: phenformin and AZD3965.

Phenformin, which blocks complex I on the surface of mitochondria - the sub-cellular compartment where energy production occurs - was developed in 1957 to treat diabetes. Although the Food and Drug Administration took phenformin off the market in the 1970s following a string of deaths, it's still in use elsewhere in the world and is starting to make a comeback in the U.S. as a cancer drug. Right now, phenformin is being tested in a phase I clinical trial for melanoma.

AZD3965, a much newer type of drug that blocks MCT1 rectors on the surface of cells, is also under phase I clinical investigation, in this case as a treatment for many different types of cancer. MCT1 receptors ferry lactate - another source of energy - out of the cell. But when MCT1 is blocked and lactate accumulates, the cell stops using it to make energy.

Since the receptors targeted by phenformin and AZD3965 participate in energy production through two distinct pathways, blocking them both at once should dramatically disrupt the cellular power supply, leading to stress and ultimately cell death.

Faber's team tested this idea by using mice seeded with MYCN-amplified neuroblastoma patient cells and found that animals treated with both drugs saw greater tumor shrinkage than animals given either drug alone, and the cocktail was well tolerated.

"The data we got with AZD3965 in combination with phenformin might get people to reconsider phenformin," said study lead author Krista Dalton, M.Eng., a Ph.D. student in the VCU Philips Institute for Oral Health Research. "In combination, where we can use lower doses, phenformin might have better tolerability than it previously did on its own."

Noninfluenza respiratory viral infections (NIRV) are associated with illness and death rates similar to influenza in hospitalized adults, according to new research in CMAJ (Canadian Medical Association Journal).

In a study of 2119 adults admitted to two hospitals over three seasons (2015-2018) in Edmonton, Alberta, and Toronto, Ontario, with confirmed viral acute respiratory infections, more than half (54.6%) were NIRV infections compared with influenza viruses (45.4%). Among patients with NIRV infections, 21.1% needed respiratory support, 18.2% required lengthy hospital stays and 8.4% died within 30 days of diagnosis. About 15% of NIRV infections were acquired in hospital.

"These findings show that clinical status changes for patients with NIRV infections were comparable to patients with influenza," writes Dr. Nelson Lee, Division of Infectious Disease, Department of Medicine, University of Alberta, Edmonton, with coauthors. "The associated costs of hospital admission were substantial."

Patients with NIRV infections were generally younger than those with influenza, although many had underlying conditions, such as compromised immune systems.

"Our findings highlight unmet needs and research gaps in therapeutics and vaccines for people at high risk of NIRV infection," the authors conclude.

DALLAS, March 29, 2021 -- As NASA seeks to build a lunar outpost, visit Mars and commercialize spaceflight, the long-term effects of weightlessness on the human heart are of critical importance, according to researchers. By analyzing data from astronaut Scott Kelly's year in space and comparing it to information from extreme long distance, which simulates weightlessness, swimming of Benoît Lecomte, researchers found that low-intensity exercise was not enough to counteract the effects of prolonged weightlessness on the heart, according to new research published today in the American Heart Association's flagship journal Circulation.

Each time a person sits or stands, gravity draws blood into the legs. The work the heart does to keep blood flowing as it counters Earth's gravity helps it maintain its size and function. Removing gravitational effects causes the heart to shrink.

Researchers examined data from retired astronaut Scott Kelly's stint aboard the International Space Station from 2015 to 2016 and elite endurance swimmer Benoît Lecomte's swim across the Pacific Ocean in 2018.

In this new study, researchers evaluated the effects of long-term weightlessness on the structure of the heart and to help understand whether extensive periods of low-intensity exercise can prevent the effects of weightlessness.

"The heart is remarkably plastic and especially responsive to gravity or its absence. Both the impact of gravity as well as the adaptive response to exercise play a role, and we were surprised that even extremely long periods of low-intensity exercise did not keep the heart muscle from shrinking," said Benjamin D. Levine, M.D., the study's senior author and a professor of internal medicine at UT Southwestern Medical Center and director of Texas Health Presbyterian's Institute for Exercise and Environmental Medicine, both in Dallas.

The research team examined the health data of Kelly's year in space aboard the International Space Station and Lecomte's swim across the Pacific Ocean to investigate the impact of long-term weightlessness on the heart. Water immersion is an excellent model for weightlessness since water offsets gravity's effects, especially in a prone swimmer, a specific swimming technique used by long-distance endurance swimmers.

Kelly exercised six days a week, one to two hours per day during his 340 days in space, March 27, 2015 to March 1, 2016, using a stationary bike, a treadmill and resistance activities. Researchers hoped Lecomte's 159-day swim from June 5 to Nov. 11, 2018 of 1,753 miles from Choshi, Japan, during which he averaged nearly six hours a day swimming, would keep his heart from shrinking and weakening. Doctors performed various tests to measure the health and effectiveness of both Kelly's and Lecomte's hearts before, during and after each man embarked on his respective expeditions.

The analysis found:

Both Kelly and Lecomte lost mass from their left ventricles over the course of the experiences (Kelly 0.74 grams/week; Lecomte 0.72 grams/week).

Both men suffered an initial drop in the diastolic diameter of their heart's left ventricle (Kelly's dropped from 5.3 to 4.6 cm; Lecomte's reduced from 5 to 4.7 cm.).

Even the most sustained periods of low-intensity exercise were not enough to counteract the effects of prolonged weightlessness.

Left ventricle ejection fraction (LVEF) and markers of diastolic function did not consistently change in either individual throughout their campaign.

This case study examined two extraordinary feats by two unique individuals. While it is important to understand how the body responds to extreme circumstances, more study is required to understand how these results can be applied to the general population. Analysis of Lecomte's cardiac MRIs from before and after his swim are forthcoming and will also be helpful for the researchers further understand whether long-term effects of weightlessness can be reversed. Kelly did not receive cardiac MRIs, and currently, there are no further follow up plans for him.

DALLAS, March 29, 2021 -- Adults with periodontitis, a severe gum infection, may be significantly more likely to have higher blood pressure compared to individuals who had healthy gums, according to new research published today in Hypertension, an American Heart Association journal.

Previous studies have found an association between hypertension and periodontitis, however, research confirming the details of this association is scarce. Periodontitis is an infection of the gum tissues that hold teeth in place that can lead to progressive inflammation, bone or tooth loss. Prevention and treatment of periodontitis is cost effective and can lead to reduction of systemic markers of inflammation as well as improvement in function of the endothelium (thin membrane lining the inside of the heart and blood vessels).

"Patients with gum disease often present with elevated blood pressure, especially when there is active gingival inflammation, or bleeding of the gums," said lead study author Eva Muñoz Aguilera, D.D.S., M.Clin.Dent., senior researcher at UCL Eastman Dental Institute in London, United Kingdom. "Elevated blood pressure is usually asymptomatic, and many individuals may be unaware that they are at increased risk of cardiovascular complications. We aimed to investigate the association between severe periodontitis and high blood pressure in healthy adults without a confirmed diagnosis of hypertension."

The study included 250 adults with generalized, severe periodontitis (?50% of teeth measured with gum infection) and a control group of 250 adults who did not have severe gum disease, all of whom were otherwise healthy and had no other chronic health conditions. The median age of the participants was 35 years, and 52.6% were female. The research was completed in collaboration with the department of dentistry at the Universitat Internacional de Catalunya in Barcelona, Spain.

All participants underwent comprehensive periodontal examinations including detailed measures of gum disease severity, such as full-mouth dental plaque, bleeding of the gums and the depth of the infected gum pockets. Blood pressure assessments were measured three times for each participant to ensure accuracy. Fasting blood samples were also collected and analyzed for high levels of white blood cells and high sensitivity C-reactive protein (hsCRP), as both are markers of increased inflammation in the body. Additional information analyzed as confounders included family history of cardiovascular disease, age, body mass index, gender, ethnicity, smoking and physical activity levels.

The researchers found that a diagnosis of gum disease was associated with higher odds of hypertension, independent of common cardiovascular risk factors. Individuals with gum disease were twice as likely to have high systolic blood pressure values ?140 mm Hg, compared to people with healthy gums (14% and 7%, respectively). Researchers also found:

The presence of active gum inflammation (identified by bleeding gums) was associated with higher systolic blood pressure.

Participants with periodontitis exhibited increased glucose, LDL ("bad" cholesterol), hsCRP and white blood cell levels, and lower HDL ("good" cholesterol) levels compared to those in the control group.

Nearly 50% of participants with gum disease and 42% of the control group had blood pressure values for a diagnosis of hypertension, defined as ?130/80 mmHg.

"This evidence indicates that periodontal bacteria cause damage to the gums and also triggers inflammatory responses that can impact the development of systemic diseases including hypertension," said corresponding author Francesco D'Aiuto, D.M.D., M.Clin.Dent., Ph.D., professor of periodontology and head of the periodontology unit at the UCL Eastman Dental Institute. "This would mean that the link between gum disease and elevated blood pressure occurs well before a patient develops high blood pressure. Our study also confirms that a worryingly high number of individuals are unaware of a possible diagnosis of hypertension."

D'Aiuto added, "Integration of hypertension screening by dental professionals with referrals to primary care professionals and periodontal disease screening by medical professionals with referrals to periodontists could improve detection and treatment of both conditions to improve oral health and reduce the burden of hypertension and its complications. Oral health strategies such as brushing teeth twice daily are proven to be very effective in managing and preventing the most common oral conditions, and our study's results indicate they can also be a powerful and affordable tool to help prevent hypertension."

This study did not account for other factors that may also impact blood pressure, such as abdominal obesity, salt intake, use of anti-inflammatory medications, hormone treatments or stress, or any other oral health conditions.

DALLAS, March 29, 2021 -- Six pregnancy-related complications - high blood pressure, gestational diabetes, preterm delivery, small-for-gestational-age delivery, pregnancy loss or placental abruption - increase a woman's risk for developing cardiovascular disease (CVD) later in life, according to a new scientific statement from the American Heart Association, published today in the Association's flagship journal Circulation. The statement calls for vigorous prevention of these risk factors and primary prevention of CVD for women who experience these complications as they transition out of pregnancy and postpartum care into primary care, with continued follow-up to monitor CVD risk throughout life.

About 10% to 15% of pregnant women experience adverse pregnancy outcomes, which are maternal or fetal complications, that include the six closely tied to later CVD risk, as well as other measures tied to the health of the baby such as low birth weight, large-for-gestational age and fetal growth restriction.

"Adverse pregnancy outcomes are linked to women having hypertension, diabetes, abnormal cholesterol and cardiovascular disease events, including heart attack and stroke, long after their pregnancies," said Nisha I. Parikh, M.D., M.P.H., chair of the scientific statement writing committee and associate professor of medicine in the cardiovascular division at the University of California at San Francisco. "Preventing or treating risk factors early can prevent cardiovascular disease, therefore, adverse pregnancy outcomes can be a powerful window into cardiovascular disease prevention if women and their health care professionals harness the knowledge and use it for health improvement."

This comprehensive statement reviews the latest scientific literature on adverse pregnancy outcomes and cardiovascular disease, specifically focused on health disparities, lifestyle and prevention recommendations. "The evidence linking adverse pregnancy outcomes to later cardiovascular disease is consistent over many years and confirmed in nearly every study we examined. This statement should inform future prevention guidelines in terms of the important factors to consider for determining women's risk for heart diseases and stroke," Parikh said.

The statement reports the magnitude of risk related to several pregnancy complications:

High blood pressure in pregnancy, called gestational hypertension, increases a woman's risk of cardiovascular disease later in life by 67%, and increases the odds of a stroke by 83%. Gestational hypertension is defined as blood pressure during pregnancy that is at or above 140/90 mm Hg after 20 weeks of pregnancy in a woman with previously normal readings.

Preeclampsia (high blood pressure during pregnancy coupled with signs of damage to liver, kidneys or another vital organ) is a severe condition and is linked to a 2.7 times higher risk of later cardiovascular disease.

Gestational diabetes (new onset of Type 2 diabetes during pregnancy) increases a woman's risk of cardiovascular disease by 68% and increases the risk of Type 2 diabetes after pregnancy by 10-fold.

Having a preterm delivery (childbirth before 37 weeks) has been found to double a woman's risk of developing cardiovascular disease and is strongly associated with later heart disease, stroke and cardiovascular disease.

Placental abruption (separation of the placenta from the uterus before childbirth) is associated with an 82% increased risk of cardiovascular disease.

Stillbirth (death of a baby prior to delivery) is associated with about double the risk of CVD.

More studies examining the association of pregnancy complications and cardiovascular risk in Black, Hispanic and Asian women are needed. Women in these racial/ethnic groups experience more adverse pregnancy outcomes and have higher burdens of cardiovascular disease risk factors and cardiovascular disease compared with white women. The statement writing group suggests aggressive risk factor modification is especially important to prevent cardiovascular disease in women in these racial/ethnic groups who have had adverse pregnancy outcomes.

A healthy diet improves the cardiovascular health of all women, and studies suggest a healthy eating pattern during the three years before pregnancy is associated with lower risks of pregnancy complications. "Adopting a heart healthy diet, healthy sleep patterns and increasing physical activity among women experiencing adverse pregnancy outcomes, should start during pregnancy and continue in post-partum and through the rest of the patient's lifespan. These are important lifestyle interventions to decrease CVD risk," said Parikh.

The statement also notes that lactation/breastfeeding may lower a woman's later-life risk of CVD and metabolic disorders including Type 2 diabetes. The writing group also suggests opportunities to improve the transition of care after pregnancy:

Longer postpartum follow-up care, sometimes referred to as the "fourth trimester," to screen for CVD risk factors and provide CVD prevention counseling.

Improve the transfer of health information between obstetrics professionals and primary care physicians to eliminate inconsistencies in electronic health record documentation, thus improving patient care.

A short and targeted health history for each woman to confirm if they have any of the six risk factors during pregnancy: hypertension in pregnancy, gestational diabetes, preterm delivery, small-for-gestational-age delivery, pregnancy loss or placental abruption.

"If a woman has had any of these adverse pregnancy outcomes, consider close blood pressure monitoring, Type 2 diabetes and lipid screening, and more aggressive risk factor modification and CVD prevention recommendations," Parikh said. "Our data lends support to the prior AHA recommendation that these important adverse pregnancy outcomes should be "risk enhancers" to guide consideration for statin therapy aimed at CVD prevention in women."

The statement also suggests considering preventive medications as appropriate for certain patients. However, more research is needed to better understand the impact of medicines to prevent cardiovascular disease for women after adverse pregnancy outcomes.

In an accompanying editorial, Eliza C. Miller, M.D., M.S., assistant professor of neurology at Columbia University, writes that pregnancy and the postpartum period are a critical time window in a woman's life to identify cardiovascular disease risk and improve a woman's health trajectory. "Pregnancy and the postpartum period should be considered the "golden year" of opportunity for clinicians to identify young women at risk and work with them to improve their cardiovascular health futures," said Miller.

Groundbreaking research from the University of South Australia has delivered world-first national-level guidelines to better inform children's physical activity and screen time in Outside School Hours Care (OSHC).

Developed with input from the OSHC sector, the guidelines aim to address growing concerns of children's sedentary behaviour marked by an increase in regular screen time. Research shows that 31-79 per cent of OSHC sessions are sedentary.

The guidelines specifically encourage energetic play while discouraging screen use:

Before School Care should schedule 45 minutes of physical activities and no more than 30 minutes of screen time.

After School Care should schedule 90 minutes of physical activities and no more than 60 minutes of screen time.

Vacation Care should schedule at least 2-3 hours of physical activities and no more than two hours of screen time across the whole day.

UniSA PhD candidate Rosa Virgara and Professor Carol Maher found that for children to achieve sufficient physical activity during OSHC, it should be provided on a 3:1 ratio - that is, that three times the opportunity for exercise is needed for children to achieve sufficient physical activity during OSHC.

In Australia, less than one in four children achieve the recommended 60 minutes of physical activity each day. On average, primary school-aged children (aged 5-14) spend more than two hours each day sitting or lying down for screen-based activities.

With about 10 per cent of Australian primary school children attending OSHC each year - and these hours accounting for 30 per cent of a child's potential daily recommended physical activity - the guidelines have the potential to affect many children on a regular basis.

UniSA's, Rosa Virgara says having the OSHC sector on board was critical to initiating change.

"Working closely with a broad range of OSHC stakeholders - including OSHC directors and educators, families, health and exercise experts - we've established consistent and workable guidelines to boost children's physical activity while also limiting screen time," Virgara says.

"The main physical activity concept across all aspects of OSHC was that it should be play-based and fun, with ample opportunity for free active outdoor play, rather than being structured and run like a physical education class.

"The emphasis on free play is consistent with other research that shows that over half of children's physical exercise is accumulated during outdoor free play.

"Screen time, if offered at all, should be limited and balanced with physical activities, while quiet sedentary activities should be available to allow children to self-regulate and move freely between active and quiet play."

Senior study author, Professor Carol Maher says that the next steps are to disseminate the new guidelines nationally, and develop resources that help OSHC staff understand their role in promoting healthy physical activity and screen use in OSHC, particular given the transient, casual basis of the OSHC workforce.

"To bring about these changes, OSHC staff will need to be supported with training to help them facilitate physical activities effectively," Prof Maher says.

"It will also be important to connect with children and families to help them understand and accept the new changes, and particularly in relation to screen time.

"Helping kids stay happy and healthy is a responsibility for which we all play a part. It's pleasing to see Australia's OSHC centres so keen to make positive change."

SINGAPORE, 29 March 2021 - A low-cost intervention to improve hypertension--or high blood pressure (BP)--prevention and management can be cost-effectively scaled up for rural communities in low- and middle-income countries, according to findings from a multi-country trial published in The Lancet Global Health.

Led by Duke-NUS Medical School in Singapore, the Control of Blood Pressure and Risk Attenuation--Bangladesh, Pakistan, Sri Lanka (COBRA-BPS) trial, conducted in partnership with the International Centre for Diarrhoeal Diseases Research, Bangladesh (ICDDR,B), Aga Khan University in Pakistan, the University of Kelaniya in Sri Lanka, analysed the budget impact and cost-effectiveness of a package of healthcare measures implemented between 2016 and 2019 in 30 rural communities. These included tapping community healthcare workers, who normally conduct maternal and childcare visits, to provide door-to-door BP monitoring and lifestyle coaching; referrals of people needing professional care to a general practitioner; and the provision of subsidies for travel and additional medication costs to people with low incomes and poorly controlled hypertension.

"Cost-effectiveness studies are important for understanding the value-for-money spent on an intervention, while budget impact analyses indicate its affordability," said Professor Tazeen Jafar, from Duke-NUS' Health Services and Systems Research (HSSR) Programme, who spearheaded the study in all three countries. "These indicators are important for health planners when they have to choose from a variety of interventions for a number of conditions."

Prof Jafar and her team calculated the trial's total costs over each of the three years. Based on this, they calculated how much the trial cost per participant treated and per capita population in each country. Finally, they calculated how much it would cost to scale up the programme country-wide, and how much would be saved by catching and managing hypertension early on.

"Studies have shown that reducing BP also reduces the risk of developing coronary heart disease, stroke and cardiovascular diseases (CVD), thus offering the potential for low-cost interventions targeting BP and other CVD risk factors to be both cost-effective and scalable," explained Professor Eric Finkelstein, also from Duke-NUS' HSSR Programme, and a co-senior author of the study.

The team found the per-participant and per-capita costs of the trial's first year were US$10.65/$0.63 for Bangladesh, $10.25/$0.29 for Pakistan, and $6.42/$1.03 for Sri Lanka. The costs were less for the next two years in Bangladesh and Pakistan but increased slightly in Sri Lanka. These inter-country differences were due to different numbers of community health workers requiring training, general differences in costs and wage rates, and the difference in the prevalence of hypertension.

"Despite having a universally state-funded healthcare system that provides BP-lowering medication free at the point of delivery, the great majority of hypertensives in Sri Lanka have uncontrolled BP," said Professor Asita de Silva, from the University of Kelaniya, who is the principal investigator of the COBRA-BPS study in Sri Lanka. "Improving BP control through cost-effective interventions are extremely important to address this public health challenge and ultimately reduce overall vascular disease burden."

Due to the relatively low costs of the trial, the scientists estimate that scaling it up to country level would cost each government less than $10.70 per participant treated in the first year. Costs in subsequent years would decrease as only refresher trainings would be required.

"Uncontrolled blood pressure is a major risk factor for heart attack, stroke and kidney failure in Bangladesh, and treating such chronic conditions is expensive. The COBRA-BPS intervention is a clear solution for controlling blood pressure at low cost that can be easily scaled up in Bangladesh," said Dr Aliya Naheed, who heads the Initiative for Non-Communicable Disease, Health Systems and Population Studies Division at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), and is the principal investigator of the COBRA-BPS trial in Bangladesh.

The team is currently discussing how to facilitate scaling up the programme in collaboration with provincial health authorities in the three countries.

"Hypertension has reached epidemic proportions in Pakistan, affecting one in three adults 45 years or older," said Dr Imtiaz Jehan, an associate professor at Aga Khan University's Department of Community Health Sciences, and the COBRA-BPS principal investigator in Pakistan. "It is a largely unrecognised illness and lowering BP can be the single most important way to prevent the rising rates of heart disease and deaths in the country."

Prof Jafar added, "This study provides the first clear evidence that a standardised and effective community-based hypertension management programme is affordable and scalable in all three countries."

The researchers anticipate the results can also guide trials in other South Asian countries and are looking to expand the programme throughout the region.

Psoriasis is a chronic disease that causes patients to develop patches of dry, scaly, and itchy skin. It is an autoimmune disorder, which means that it arises from a person's immune system inappropriately targeting that person's own healthy body parts. It is a deeply unpleasant condition, and patients commonly take various medications so that they can live their lives more comfortably.

Professor Min Chen of the Chinese Academy of Medical Sciences and the Peking Union Medical College has conducted extensive research on psoriasis. "There are many patients with psoriasis who also have cardiovascular diseases, such as hypertension, diabetes, hyperlipidemia, and coronary heart disease," she notes. The presence of such cardiovascular diseases is an important consideration when treating patients with psoriasis because, as Prof. Chen explains, "Some of the drugs for psoriasis may increase the risks of these diseases, while some can reduce them." Now, in a recent review article published in Chinese Medical Journal, Prof. Chen and her colleagues provide a summary of the existing scholarly knowledge concerning the associations between the different treatments for psoriasis and risks of cardiovascular diseases.

The authors explore how various drugs influence the long-term risks of what is known as "MACE," an acronym that encompasses myocardial infarction (i.e., heart attack), cerebrovascular accidents (i.e., strokes and similar events), and cardiovascular mortality. They note that some psoriasis treatments, such as tumor necrosis factor-α (TNF-α) inhibitors and methotrexate may actually reduce long-term MACE risk. Conversely, they also note that some interleukin (IL) inhibitors may increase MACE risk. For example, the IL-12/23 inhibitor briakinumab increased MACE risks so much across multiple studies that investigators had to suspend all clinical trials. However, other IL inhibitors such as tildrakizumab and guselkumab do not appear to increase MACE risks. The widely used immunosuppressant cyclosporine A can cause damage to heart muscle tissues. Ultimately, these findings indicate that more research is needed before scientists can rank psoriasis treatments in terms of their effects on long-term MACE risks.

There is currently no consensus among medical scientists on whether systemic treatments for psoriasis can mitigate or worsen arterial plaques, vascular function, and vascular inflammation. There is some evidence that treatments for psoriasis counter inflammation of coronary tissues and can lessen the coronary plaque burdens that contribute to coronary artery disease. Conversely, it has also been found that treatment with TNF-α inhibitors may contribute to an undesirable thickening of the carotid arteries, which are found in the neck and provide blood to the head. Scientists do not yet know whether methotrexate, IL-17 inhibitors, and IL-12/23 inhibitors also have any effect on arterial wall thicknesses.

In addition to the heightened risk of cardiovascular diseases, patients with psoriasis are at an increased risk of developing various risk factors for cardiovascular diseases. These risk factors include obesity, diabetes mellitus, and high blood lipid levels, and the existing literature points to several varied relationships between psoriasis treatment options and risk factors for cardiovascular disease. For example, TNF-α inhibitors may contribute to increased body weight, but IL-17 and IL-12/23 inhibitors may help patients lose weight. Cyclosporine A can increase the risk of diabetes, worsen hypertension, and contribute to unhealthy lipid metabolism profiles.

In conclusion, different psoriasis treatments have different effects on cardiovascular diseases and their risk factors, necessitating a more thorough consideration of each patient's clinical situation before picking a treatment. For example, TNF-α inhibitors and methotrexate are good therapeutic options for patients with psoriasis who are at high risk of experiencing MACE, and inhibitors of IL-17 and IL-12/23 may be beneficial for patients who have arterial plaques.

Prof. Chen expresses hope that these findings will help medical practitioners offer "sound medication advice for patients with psoriasis and cardiovascular complications."

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2021.0008, Zeyi Cheng, Miaomiao Qi, Chengyuan Zhang and Yanxia Mao from Sichuan University, Sichuan, China, Second Hospital of Lanzhou University, Lanzhou, China and The Second Medical School of Lanzhou University, Lanzhou, China consider myocardial fibrosis in the pathogenesis, diagnosis, and treatment of hypertrophic cardiomyopathy.

The authors review the application of myocardial fibrosis in the diagnosis and treatment of HCM, focusing on research progress and the application of magnetic resonance imaging on the basis of the characteristics of fibrosis in the diagnosis and prognosis of HCM.

Hypertrophic cardiomyopathy (HCM) is a type of hereditary cardiomyopathy caused by gene mutation. Its histological features include cardiomyocyte hypertrophy and disarray as well as myocardial fibrosis. Gene mutation, abnormal signal transduction, and abnormal energy metabolism are considered the main mechanisms of myocardial fibrosis. There is a strong correlation between myocardial fibrosis and the occurrence, development, and prognosis of HCM.

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2021.0005, Nikhil H. Shah, Steven J. Ross, Steve A. Noutong Njapo, Justin Merritt, Andrew Kolarich, Michael Kaufmann, William M. Miles, David E. Winchester, Thomas A. Burkart, and Matthew McKillop from UF Division of Cardiovascular Medicine, Gainesville, FL, USA, UVA Division of Cardiovascular Medicine, Charlottesville, VA, USA, The Johns Hopkins Hospital Department of Radiology, Baltimore, MD, USA, The Heart Center, Huntsville, AL, USA, Intermountain Medical Center, St. George, UT, USA and Carolina Cardiology Consultants, Greenville, SC, USA consider appropriate use of implantable cardioverter-defibrillators at a single academic center.

Implantable cardioverter-defibrillators (ICDs) can be life-saving devices, although they are expensive and may cause complications. In 2013, several professional societies published joint appropriate use criteria (AUC) assessing indications for ICD implantation. Data evaluating the clinical application of AUC are limited. Previous registry-based studies estimated that 22.5% of primary prevention ICD implantations were "non-evidence-based" implantations.

On the basis of AUC, the authors aimed to determine the prevalence of "rarely appropriate" ICD implantation at their institution for comparison with previous estimates by reviewing 286 patients who underwent ICD implantation between 2013 and 2016. Appropriateness of each ICD implantation was assessed by independent review and rated on the basis of AUC.

Of 286 ICD implantations, two independent reviewers found that 89.5% and 89.2%, respectively, were appropriate, 5.6% and 7.3% may be appropriate, and 1.8% and 2.1% were rarely appropriate. No AUC indication was found for 3.5% and 3.4% of ICD implantations, respectively. Secondary prevention ICD implantations were more likely rarely appropriate (2.6% vs. 1.2% and 3.6% vs. 1.1%) or unrated (6.0% vs. 1.2% and 2.7% vs. 0.6%). The reviewers found 3.5% and 3.4% of ICD implantations, respectively, were non-evidence-based implantations. The difference in rates between reviewers was not statistically significant.

Compared with prior reports, the prevalence of rarely appropriate ICD implantation was very low. The high appropriate use rate could be explained by the fact that AUC are based on current clinical practice. The AUC could benefit from additional secondary prevention indications. Most importantly, clinical judgement and individualized care should determine which patients receive ICDs irrespective of guidelines or criteria.

Tumor targeting and intratumoral penetration are long-standing issues for cancer therapeutics.

Researchers from the Institute of Process Engineering (IPE) of the Chinese Academy of Sciences and the University of Chinese Academy of Sciences (UCAS) have developed a new platelet-based formulation which demonstrated potent therapeutic effects against cancer in murine models.

The scientists utilized the aggregation and activation features of the platelets to address issues of tumor targeting and intratumoral penetration. Upon carrying photothermal nanoparticles and immunostimulators, this biomimetic formulation also achieves an efficient combination therapy against multiple types of cancer.

This study was published in Science Advances on March 26.

Recently, photothermal therapy (PTT) has attracted increasing attention. Although promising, efficient delivery of PTT still faces a series of issues. The accumulation of photosensitizers, specifically at tumor sites, and subsequent intratumoral penetration are restricted for most anticancer therapies, because of the cancer's heterogeneity and the compact extracellular matrix.

As a new type of delivery vector, platelets have shown their capacity to deliver cargo to tumor sites via several mechanisms, suggesting they are reasonable candidates for tumor targeting and intratumoral penetration.

Hyperthermia can induce tumor cells to release antigens. Such a response not only reveals the inherent relationship between the underlying mechanisms of PTT and immunoactivation, but also encourages the combination of PTT and immunotherapy for improved anticancer therapy.

In this new platelet-based formulation, photothermal nanoparticles and immunostimulators were simply, mildly and efficiently integrated into platelets.

"The photothermal conversion efficiency of this novel photothermal nanoparticle reached 69.2%. Thus, low-power near-infrared light (NIR) irradiation can generate enough local hyperthermia," said Prof. TIAN Zhiyuan from UCAS.

The biomimetic platelets worked as circulating sentinels in the bloodstream and had a sensitive response to vascular damage. As a result, a portion of them acted as spearheads to prime adhesion at defective tumor vascular endothelial cells.

After irradiation with low-power NIR, local hyperthermia resulted in acute vascular damage, which subsequently induced an aggregation cascade of reinforced platelets to form a targeting arsenal in situ.

Subsequently, nanosized proplatelets (nPLTs) were further generated upon these activated platelets. "We observed that nPLTs relayed the cargo into deep tumor tissue, expanding the area of attack," said Prof. WEI Wei from IPE.

Following tumor ablation induced by photothermal therapy, the immunostimulator enhanced the immunogenicity of released tumor-associated antigens, which further induced the body's immunologic response to attack residual, metastatic and recurrent tumors.

The research demonstrated potent therapeutic effects with low-power NIR irradiation in nine different murine models, and, most notably, a sophisticated model based on human platelets, humanized mice and patient-derived tumor xenografts (PDX).

"These results show great promise for utilization of this novel biomimetic platelet platform in high-performance and combined anticancer therapies," said Prof. MA Guanghui from IPE.

A peer reviewer from Science Advances said the study was "well organized and performed." The reviewer also emphasized that "this system is very effective in tumor therapy and has been shown in different tumor models, and I would very much like to see this work translated into clinical applications."

Key takeaways

Surgery is an underused treatment for certain pancreatic cancer patients.
Patients with pancreatic cancer who underwent surgery after chemotherapy lived nearly twice as long as those treated with only chemotherapy.
Findings confirms current recommendations for stage II pancreatic cancer: survival improves when patients receive multimodality therapy, chemotherapy before and/or after surgery.
All analyses of the data delivered the same findings.

CHICAGO (March 26, 2021, 9:00 am CDT): Patients with stage II pancreatic cancer who are treated with chemotherapy followed by resection (an operation that removes the cancerous part of the organ, structure or tissue) live nearly twice as long as patients who receive only chemotherapy, according to a new Journal of the American College of Surgeons study published online in advance of print.

In stage II patients, there is a chance that pancreatic cancer can be removed by resection even after it has spread close to blood vessels. Although chemotherapy can improve outcomes, the risk of surgery is justified because the patients live longer even if the cancerous tissue is not entirely removed, according to the study from researchers at the University of Arizona Department of Surgery, Tucson.

Surgery can improve survival

The researchers found that patients who received chemotherapy followed by resection lived an average of 19.75 months, while those who received only chemotherapy lived an average of 10.12 months. They examined data from the National Cancer Database (NCDB), a joint program of the American College of Surgeons and the American Cancer Society.

"Our results show that surgery is viable in more cases than we thought," said Amanda K. Arrington, MD, MHM, FACS, a surgical oncologist at the University of Arizona Department of Surgery, Tucson.

Pancreatic cancer is the fourth leading cause of cancer deaths in men and women in the U.S.1,2 Survival rates for pancreatic cancer are low because it is a fairly aggressive, fast-growing cancer, Dr. Arrington said. Approximately 10 to 30 percent of these patients present with disease in which resection may be considered an appropriate therapy. Chemotherapy can improve the chances for successful surgery, as about one in three borderline cases are resectable following chemotherapy.3 Even after surgery, however, it is common for pancreatic cancer to return.

While the goal of resection is to remove all of the tumor tissue, it can be difficult to accomplish, especially if the cancer has spread to nearby blood vessels that feed the liver and small intestine. Margin status, or how much cancerous tissue is left post-surgery on the edges of the resected area, is a significant predictor of survival after surgery for pancreatic cancer. Patients with no cancerous tissue left after resection (R0) have improved survival compared with patients with microscopic amounts (R1) or macroscopic amounts (R2) of cancerous tissue left after resection. This study looked at R1 and R2 resection outcomes compared with chemotherapy alone.

Study details

Dr. Arrington and her colleagues searched NCDB data from 2010 to 2015 for stage II pancreatic cancer patients who underwent R1/R2 surgery with or without pre-operational chemotherapy to compare to stage II patients who received chemotherapy alone. They found:

Out of a total of 11,699 stage II pancreatic cancer patients, 9,521 (81.4 percent) were treated with chemotherapy alone, while 2,178 (18.6 percent) underwent surgical resection and had positive margins (R1 or R2).
Of the surgical group, 1,836 (84.3 percent) underwent upfront surgery and 342 (15.7 percent) had chemotherapy followed by surgery.
The R1 or R2 patients that had chemotherapy before resection had the best overall survival at a mean of 19.75 months, followed by the upfront surgery group with a mean survival of 17.77 months, and the chemotherapy alone group with a mean survival of 10.12 months.

The data was analyzed in multiple ways to address potential bias; all analyses of the data delivered the same findings.

Study results confirm current recommendations for stage II pancreatic cancer, which note that survival improves when patients receive multimodality therapy, chemotherapy before and/or after resection. Further, patients benefit from surgery even in extremely difficult cases that end up with a margin positive resection, Dr. Arrington said. The researchers found even when the tumor does not shrink significantly in response to chemotherapy, there are still survival benefits to taking an aggressive surgical approach.

"Based on this study, surgeons can be a little more aggressive and offer surgical treatment more often than not to stage II pancreatic cancer patients," Dr. Arrington said. "There are ongoing studies looking at whether more pancreatic cancer patients, including stage I patients, would benefit from surgery after chemotherapy."

Other study authors include Chiu-Hsieh Hsu, PhD; Kenzie L. Schaefer, BS; Catherine L. O'Grady, MPH; Mohammad Khreiss, MD; and Taylor S. Riall, MD, PhD, FACS, all from the University of Arizona.

"FACS" designates that a surgeon is a Fellow of the American College of Surgeons.

Presented at the Western Surgical Association Annual Meeting (virtual), November 2020.

Study authors have no disclosures related to this research.