Body

DALLAS, August 5, 2020 --The chemicals in cannabis have been linked to an increased risk of heart attacks, heart failure and atrial fibrillation in observational studies; however, a full understanding of how use of cannabis affects the heart and blood vessels is limited by a lack of adequate research, according to a new Scientific Statement from the American Heart Association (AHA) published today in its flagship journal Circulation.

According to the statement, although cannabis, also known as marijuana, may be helpful for conditions such as spasticity associated with multiple sclerosis, among others, cannabis does not appear to have any well-documented benefits for the prevention or treatment of cardiovascular diseases. Preliminary studies have found that cannabis use could negatively impact the heart and blood vessels.

"Attitudes towards recreational and medicinal use of cannabis have changed rapidly, and many states have legalized it for medical and/or recreational use. Health care professionals need a greater understanding of the health implications of cannabis, which has the potential to interfere with prescribed medications and/or trigger cardiovascular conditions or events, such as heart attacks and strokes," said Robert L. Page II, Pharm.D., M.S.P.H., FAHA, chair of the writing group for the statement and professor in the department of clinical pharmacy and the department of physical medicine/rehabilitation at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Aurora, Colorado.

A recent study cited in the statement suggests that cannabis use is present in 6% of heart attack patients under 50 years of age. Another study found that cannabis users ages 18 to 44 had a significantly higher risk of having a stroke compared to nonusers. "Unfortunately, most of the available data are short-term, observational and retrospective studies, which identify trends but do not prove cause and effect," said Page.

The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid), the component of the plant that induces a "high," and CBD (cannabidiol), which can be purchased over the counter, but to date, the FDA has only approved one CBD-derived product. Importantly, the FDA has not approved any other cannabis, cannabis-derived, or cannabidiol (CBD) products currently available on the market.

Some studies have found that within an hour after cannabis is smoked, THC may induce heart rhythm abnormalities, such as tachycardia, premature ventricular contractions, atrial fibrillation and ventricular arrythmias. Acutely, THC also appears to stimulate the sympathetic nervous system, which is responsible for the "fight or flight" response, resulting in a higher heart rate, a greater demand for oxygen by the heart, higher blood pressure while laying down and dysfunction within the walls of the arteries.

In contrast, studies on CBD, which does not produce a "high" or intoxication, have found associations with reduced heart rate, lower blood pressure, increased vasodilation (ability of the arteries to open), lower blood pressure and potentially reduced inflammation. Inflammation is linked to atherosclerosis, the slow narrowing of the arteries that underlies most heart attacks and, possibly strokes.

Smoking and inhaling cannabis, regardless of THC content, has been associated with cardiomyopathy (heart muscle dysfunction), angina (chest pain), heart attacks, heart rhythm disturbances, sudden cardiac death and other serious cardiovascular conditions. In states where cannabis has been legalized, an increase in hospitalizations and emergency department visits for heart attacks has been observed.

The way cannabis is consumed may influence how it affects the heart and blood vessels. "Many consumers and health care professionals don't realize that cannabis smoke contains components similar to tobacco smoke," said Page. Smoking and inhaling cannabis, regardless of THC content, has been shown to increase the concentrations of blood carboxyhemoglobin (carbon monoxide, a poisonous gas) five-fold, and a three-fold increase in tar (partly burnt combustible matter), similar to the effects of inhaling a tobacco cigarette.

Carbon monoxide intoxication from inhaled tobacco or cannabis has been associated with several heart problems, such as heart muscle disease, chest pain, heart attacks, heart rhythm disturbances and other serious conditions.

Cannabis use should be discussed in detail with a health care professional so that an individual's potential health risks can be reviewed. "If people choose to use cannabis for its medicinal or recreational effects, the oral and topical forms, for which doses can be measured, may reduce some of the potential harms. It is also vitally important that people only use legal cannabis products because there are no controls on the quality or the contents of cannabis products sold on the street," said Page.

In addition to the poisonous compounds in cannabis smoke, vaping cannabis may also result in serious health outcomes, especially when it is mixed with vitamin E acetate oils, which are linked to EVALI (e-cigarette or vaping product use-associated lung injury), the potentially fatal illness that emerged among e-cigarette users last year.

"People who use cannabis need to know there are potentially serious health risks in smoking or vaping it, just like tobacco smoke. The American Heart Association recommends that people not smoke or vape any substance, including cannabis products, because of the potential harm to the heart, lungs and blood vessels," said Rose Marie Robertson, M.D., FAHA, the deputy chief science and medical officer for the American Heart Association and co-director of the AHA Tobacco Center for Regulatory Science.

The statement also discusses cannabis use among older adults, people diagnosed with cardiovascular diseases and other populations including youth. Some studies have suggested that cannabis use - both CBD and THC - may be safe and effective for older populations. Though they are the least likely to use cannabis, older adults often use it to reduce neuropathic pain (common among people with type 2 diabetes), improve quality of life and decrease prescription drug use (including opioids).

Additionally, benefits for patients with age-related diseases, including Parkinson's and Alzheimer's, have also been reported in some studies; however, there is very little research on the long-term effects of cannabis use among this group of people. Another concern about older adults using cannabis is the potential of interactions with other medications, including blood thinners (anti- coagulants), anti-depressants, antipsychotics, antiarrhythmics for heart rhythm abnormalities, and statin drugs, which reduce cholesterol levels.

For people diagnosed with heart disease, cannabis should be used with extreme caution because cannabis increases the heart's need for oxygen at the same time as it decreases available oxygen supply, which could cause angina (chest pain). In addition, in some studies, cannabis triggered a heart attack in people with underlying heart disease. Other studies have linked cannabis use to a higher risk of strokes and heart failure.

Research into the effects of cannabis on the heart and blood vessels has been limited because cannabis is categorized as a Schedule I controlled substance by the U.S. Drug Enforcement Agency (DEA). Schedule I controlled substances are defined as having no accepted medical use, a high potential for abuse and an unacceptable safety profile. The AHA's Scientific Statement suggests that the DEA remove cannabis from the Schedule I of the U.S. Controlled Substances Act so that it can be widely studied by scientists. Forty-seven U.S. states, the District of Columbia, and 4 of 5 U.S. territories allow some form of cannabis use, and its use has risen considerably over the past decade, particularly among people 18-25 years of age. Although many states have legalized medical and/or recreational cannabis use, cannabis growing, sales and use are illegal at the federal level, further complicating scientific research.

"We urgently need carefully designed, prospective short- and long-term studies regarding cannabis use and cardiovascular safety as it becomes increasingly available and more widely used," Page said. "The public needs fact-based, valid scientific information about cannabis's effect on the heart and blood vessels. Research funding at federal and state levels must be increased to match the expansion of cannabis use - to clarify the potential therapeutic properties and to help us better understand the cardiovascular and public health implications of frequent cannabis use."

Legalization of cannabis for medical purposes should align with patient safety and efficacy. Legalization for recreational use will remain a significant concern until more research can be conducted on the safety and long-term population health effects across the life course and the equity and social justice impact of these laws. In those states where cannabis is legal for recreational or medical purposes, there should be a robust public health infrastructure that is adequately funded and implemented to minimize its impact on CVD mortality especially among young people those who have heart disease. The statement calls for the federal government to create standardized labelling about the amount of THC and CBD and require it on all legal cannabis products.

The Association believes cannabis should be tightly integrated into comprehensive tobacco control and prevention efforts that include age restrictions for purchasing, retailer compliance, excise taxes, comprehensive smoke-free air laws, professional education, screening within the clinical environment - for example, when a patient is admitted to the hospital and routinely screened to avoid medication interactions or potential toxicity - and coverage of cessation treatment programs by insurers, Medicare and Medicaid. These efforts should be adequately funded, and at least some portion of the revenue from cannabis taxation should be directed toward programs and services that improve public health.

DALLAS, Aug. 5, 2020 -- Recommended medications for peripheral artery disease and coronary artery disease are underused among Hispanic and Latino people, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

Peripheral artery disease, or PAD, causes the arteries, which flow away from the heart, to narrow due to the buildup of plaque, and previous research suggests approximately 8.5 million Americans have PAD. The most common symptom of PAD is pain or tiredness in the legs while walking that goes away with rest. In addition to decreased well-being, PAD can lead to serious complications including leg amputation and other cardiovascular diseases, such as narrowing of the heart's arteries, heart failure or stroke.

The American College of Cardiology/American Heart Association 2005 Practice Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) recommends antiplatelet therapy (low dose aspirin or a blood thinner such as clopidogrel) and cholesterol-lowering statin therapy for PAD patients, as prescribed by a physician. However, limited access to health care among various racial/ethnic groups often results in poorer outcomes for many chronic health conditions including peripheral artery disease. Previous research has shown that the recommended medications are underused among people with peripheral artery disease, in general; however, little information is available about their use among Hispanic and Latino populations.

"Heightened attention and more efforts to improve treatment are needed in the care of PAD patients to prevent future cardiovascular events and leg amputation," said lead author Simin Hua, M.H.Sc., an associate researcher in the department of epidemiology and population health at Albert Einstein College of Medicine in New York City. "These efforts might include improving health care access, educating patients and advocating that physicians offer guideline-adherent treatment. This is especially important because many Hispanic/Latino individuals in the U.S. face issues such as lack of health insurance and high burden of cardiovascular risk factors."

Study participants included 1,244 self-identified Hispanic or Latino adults, between 18-74 years old, in Chicago, Miami, San Diego and in the Bronx borough of New York City. The average age of those with peripheral artery disease was 53; the average age for those with coronary artery disease was 56; and 59% of participants with peripheral artery disease and 42% of those with coronary artery disease were female. Participants had a previous peripheral artery disease diagnosis by a physician in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) from 2008-2011. HCHS/SOL is an ongoing, community-based, prospective study to estimate the burden of cardiovascular disease and other chronic diseases and to identify the associated risk factors among the U.S. Hispanic/Latino populations from six backgrounds, including Dominican, Cuban, Central American, Mexican, Puerto Rican and South American.

During an in-person interview and health examination conducted in English and Spanish, the majority of participants (826) self-reported a peripheral artery disease diagnosis from a doctor, with the remaining participants (418) self-reporting a diagnosis of coronary artery disease alone. Other data collected included highest level of education, socioeconomic status, place of birth (in the U.S. or not), preferred language, health insurance coverage, number of doctor visits in the past year and cardiovascular risk factors (current smoking, hypertension, Type 2 diabetes, high cholesterol and obesity). Participants were instructed to bring to the appointment the medications they had taken within the past month. Based on this information, the investigators calculated the percentage of participants taking medication to lower blood pressure or cholesterol and to prevent blood clots.

Researchers found:

Overall, among patients with PAD: 26% took medications to lower cholesterol and 31% took medications to prevent blood clots;

Yet, among patients with coronary artery disease alone: 42% took medications to lower cholesterol and 47% took medications to prevent blood clots.

Among the 521 patients with both PAD and high blood pressure, 57% were taking medications to reduce their blood pressure; while 68% of the 315 patients with high blood pressure and coronary artery disease took medications to lower their blood pressure.

Compared to other participant subgroups, Hispanics of Mexican background reported the lowest usage of all three classes of cardiovascular medications in the study and were the least likely to have health insurance.

"The need for medications did not seem to receive the same level of attention for patients with PAD compared to those with coronary artery disease, even though both patient groups can benefit from these cardiovascular medications," Hua said.

Researchers noted several limitations could have affected the study's results. For example, the study did not include any participants who did not self-identify as Hispanic or Latino for comparison. It also did not include information about any medication usage over time, or whether participants were not prescribed medications or were not taking their prescribed medications. In addition, study participants could have inaccurately self-reported their PAD diagnosis.

In an analysis of women who started pregnancy when taking antidepressant medications, investigators identified three trajectories of antidepressant dispensing during pregnancy: more than half stopped their treatment, a quarter maintained their treatment throughout pregnancy, and one-fifth discontinued it for a minimum of three months and then resumed it during the postpartum period.

The analysis, which is published in the British Journal of Clinical Pharmacology, included all pregnant women with information in the General Sample of Beneficiaries database affiliated with the French Health Insurance System, from 2009 to 2014.

The researchers noted that no sociodemographic or medical characteristics were associated with any trajectory group. Women who continued antidepressant treatment tended to have more frequent obstetric complications and postpartum psychiatric disorders. Among women who interrupted treatment, prescription of benzodiazepines and anxiolytics decreased initially but rose postpartum to a higher level than before pregnancy.

"Monitoring the pregnancy of women taking antidepressants requires a lot of attention. It is important to assess the appropriateness of treatment at the time of pregnancy announcement and to monitor for psychiatric symptoms throughout pregnancy when treatment has been stopped," said senior author Catherine Laporte, MD, PhD, of the Université Clermont Auvergne, in France. "General practitioners are very often called upon for non-obstetric health problems during pregnancy, so they must be made aware."

A recent analysis of a US commercial insurance database found that adults with rheumatoid arthritis had a lower risk of developing type 2 diabetes than other individuals, including those with other types of arthritis.

The analysis, which is published in Arthritis Care & Research, compared adults with rheumatoid arthritis with four other groups: individuals from the general population without rheumatoid arthritis, individuals with hypertension, individuals with osteoarthritis, and individuals with psoriatic arthritis. A total of 449,327 people were included.

During the median of 1.6 years of follow-up, the rate of type 2 diabetes development was lowest in the rheumatoid arthritis group (7.0 per 1,000 people per year) and highest (12.3 per 1,000 people per year) in the hypertension group. After adjustments, rheumatoid arthritis was associated with a 24% to 35% lower risk of developing type 2 diabetes compared with the four other groups.

"While systemic inflammation in rheumatoid arthritis increases the risk of cardiovascular disease, our findings unexpectedly show that having rheumatoid arthritis itself does not confer an increased risk of type 2 diabetes compared with four different comparator groups," said senior author Seoyoung C. Kim, MD, ScD, MSCE, of Harvard Medical School. "Since all rheumatoid arthritis patients included in our study were treated with at least one disease-modifying antirheumatic drug, our study is unable to test the association between no treatment or undertreatment for rheumatoid arthritis and risk of type 2 diabetes."

The prevalence of gout--a form of arthritis characterized by severe pain, redness, and tenderness in joints--increased across the world at an alarming rate from 1990 to 2017, according to an analysis published in Arthritis & Rheumatology.

The analysis found that there were approximately 41.2 million prevalent cases of gout in 2017, with the rate of new diagnosed cases being 92 per 100,000 people, an increase of 5.5% from 1990.

Gout was more common in males and in older individuals. Also, the burden of gout was generally highest in developed regions and countries. High body mass index and impaired kidney function were risk factors for gout.

"The increasing trend of gout burden is most likely to continue as the global aging population is on the rise," said senior author Emma Smith, PhD, of The University of Sydney, in Australia. "Attempts to lessen the disease onset and future burden of gout require better awareness, especially of risk factors, and early diagnosis and treatment."

Smoking has been linked to a higher risk of bone fractures. Researchers have now identified certain lung-related factors that may help to predict an individual smoker's fracture risk. The findings are published in the Journal of Bone and Mineral Research.

In the study of 9,187 adults who currently or formerly smoked, there were 361 new hip fractures reported over a median follow-up of 7.4 years. Known risk factors associated with experiencing a hip fracture included older age, female sex, osteoporosis, previous spine and hip fracture, rheumatoid arthritis, and diabetes. Certain lung-specific risk factors--such as the presence of emphysema and exacerbations of chronic obstructive pulmonary disease (COPD)--were also identified.

"We need to look beyond traditional risk factors when making osteoporosis screening and management decisions in our patients with COPD. A former smoker with frequent COPD exacerbations or significant emphysema on chest CT scan may be at greater risk of fracture than would be expected based on age or sex or other underlying comorbidities alone," said lead author Jessica Bon, MD, MS, of the University of Pittsburgh.

In a study of 552 adults aged 70 to 93 years old, 80% of participants had at least one skin disease that required treatment, and the most common conditions were fungal skin infections, rosacea, actinic keratosis, and eczema. ?

The study, which is published in the Journal of the American Geriatrics Society, also found that more than a third of participants (39.1%) had three or more simultaneous skin diseases.

Skin diseases were more common in males than in females, and there were weak associations between different skin diseases and socioeconomic status and living status (living alone or with a spouse/other family member).?

"This research emphasizes the importance of whole body skin evaluations in older patients, as skin diseases are common in this age group," said lead author Suvi-Päivikki Sinikumpu, MD, PhD, of the University Hospital of Oulu, in Finland. "A whole body skin examination may reveal hidden skin symptoms and ensures timely diagnoses and appropriate treatment."

Results from a study published in the Journal of Internal Medicine suggest that bacterial infections may elevate the risk of coronary heart disease in individuals with type 1 diabetes.

Among 3,781 individuals with type 1 diabetes, 370 developed coronary heart disease over an average follow-up of 13.7 years. Antibiotic purchases, reflecting bacterial infections in outpatient care, were significant risk factors for coronary heart disease, with a 21% increased risk for each annual antibiotic purchase.

A high blood level of bacterial lipopolysaccharides (large molecules derived from the outer layer of gram-negative bacteria) was also a risk factor for coronary heart disease.

"In broader terms, the present study demonstrates how infections associate with the development of late diabetic complications and perhaps even more importantly, how infections associate with the development of coronary heart disease, as the latter relationship has been disputed during recent years," said lead author Johan Rasmus Simonsen, MD, of the Folkhälsan Research Center, in Finland. "Interestingly, in our study this association to incident coronary heart disease was seen specifically with antibiotic purchases, making the potential pathophysiologic mechanisms behind this finding intriguing and warranting further studies."

CLEVELAND, Ohio (August 5, 2020)--Coronary artery disease (CAD) is a leading cause of death in both men and women. Women are more susceptible to CAD during the menopause transition because of loss of ovarian function leading to estrogen deficiency. A new study suggests the risk of CAD could be identified earlier by looking at reproductive risk factors. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

CAD is the most common type of cardiovascular disease. Because women have different symptoms than men, and most traditional health studies have focused on men, women are often misdiagnosed or the diagnosis and treatment may be delayed, creating greater risk for an adverse cardiac event or death.

Previous studies have provided mixed conclusions regarding the association between various reproductive risk factors, such as pregnancy and ovarian function, and CAD. However, most of these studies were small and only evaluated a limited number of risk factors. This new study is one of the first known larger studies (involving nearly 1,500 postmenopausal women) to consider a broad range of reproductive risk factors. These include pregnancy factors, such as the number and type of pregnancy and age at first birth, as well as ovarian function factors including age at menarche, age at menopause, and reproductive life span.

Researchers in this study sought to compare reproductive factors among postmenopausal women with no apparent CAD, nonobstructive CAD, and obstructive CAD, which is the most serious form of CAD and typically leads to the worst prognoses. Because of its seriousness, the researchers specifically focused on identifying reproductive risk factors for obstructive CAD.

They concluded that multigravidity (three or more pregnancies), early menopause, and a shorter reproductive life span are independent risk factors for angiographic obstructive CAD in postmenopausal women. Such information could be valuable in helping prevent and minimize the effect of CAD in women because pregnancy and ovarian function could serve as early indicators of a woman's risk long before symptoms appear, allowing for earlier life-changing counseling and/or pharmacologic treatment.

Study results appear in the article "Reproductive risk factors for angiographic obstructive coronary artery disease among postmenopausal women."

"This study expands our knowledge about the link between reproductive factors such as early menopause and shorter reproductive life span and increased cardiovascular risk. Indeed, there is a growing body of evidence suggesting that early loss of ovarian function results in accelerated aging. Future research should be directed toward identifying ways to delay ovarian aging," says Dr. Stephanie Faubion, NAMS medical director.

Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women and one in five men aged over 50 suffer from osteoporotic bone fractures.

Osteoporosis is caused by excessive activity of bone resorbing cells, while activity of bone-forming cells is reduced. In healthy individuals, a balanced activity of these two cell types allows constant bone turnover to maintain healthy and strong bones.

In osteoporosis, disproportionate bone resorption leads to low bone mineral density and consequently weak and fracture-prone bones. When new bone formation is unable to catch up with bone loss, bone eventually weakens, and becomes more prone to fractures.

Current medicines have disadvantages

Most current osteoporosis therapies include the use of bisphosphonates, which block the activity of bone resorbing cells, and thus prevent excessive bone resorption. However, prolonged treatment with these drugs eliminates the necessary bone turn-over leading to increased fracture risk and other unwanted side effects. Therefore, there is an urgent need to develop new strategies that overcome the limitations of current treatments.

There are now new progresses in this area. They have been developed in a cooperation of Professors Christoph Winkler (Department of Biological Sciences, National University of Singapore, NUS) and Manfred Schartl (Biocenter, Julius-Maximilians-Universität Würzburg, JMU, Germany); the results have been published in the journal PNAS.

Small protein mobilises bone resorbing cells

Using genetic analysis in a small laboratory fish model, the Japanese medaka (Oryzias latipes), the research team identified a small protein, the chemokine CXCL9, that, under osteoporotic conditions, diffuses towards reservoirs that hold bone resorbing cell precursors. These precursors produce a receptor, CXCR3, on their cell surface. Upon activation by CXCL9, the precursors are mobilised and migrate long distances in a highly directed fashion towards the bone matrix, where they start resorbing bone.

Known inhibitors are highly effective

Both CXCL9 and its receptor CXCR3 have long been known to modulate the migration of immune cells to inflammation sites, for example in psoriasis and rheumatoid arthritis. There are several chemical inhibitors blocking CXCR3 activity that have had little success in clinical tests for the treatment of psoriasis. The research team showed that these inhibitors are highly effective in blocking bone resorbing cells' recruitment and protecting bone from osteoporotic insult.

Finely tuned therapies seem possible

The conclusion of the professors Schartl and Winkler: "Our studies provided new avenues to osteoporosis therapy. The new strategy allows a fine-tuned modulation of osteoclast numbers that are recruited to bone matrix rather than a widespread blockage of osteoclast activity as in traditional therapies. This has major advantages as excessive bone resorption can be prevented in a targeted manner but normal bone turn-over will still continue. This offers potential to avoid increased fracture risks in osteoporosis patients and to maintain healthy bone for improved quality of life."

Christoph Winkler is an alumnus of JMU. He was a PhD student and research assistant in Manfred Schartl's team and followed the call for a professorship in Singapore in 2007. He returned to JMU for a while in 2016 - for a sabbatical, financially supported by the Würzburg University Board. During this time, the ground was prepared for the cooperation the results of which can now be read in PNAS.

Stem cells are heavily studied around the world with the hope to revive damaged body parts unable to regenerate itself. Injured heart muscles are one of these areas which remain impaired in adults who have experienced heart attacks. Once a part of a heart tissue is injured due to restricted blood flow during a heart attack, treatment options are dire to fix the function of the heart to previous capacity. Stem cells are promising because they can be manipulated to generate healthy cells to replace diseased cells. No other cells hold this promise. There are a few issues to clear before stem cell treatments can be implemented clinically for heart regeneration and one major obstacle is to understand why irregular, abnormal heartbeats occur two to four weeks after iPS cell-derived heart muscle cells are transplanted to the heart. The heartbeat stabilizes on its own after 12 weeks but researchers set out to find out why the arrhythmia occurs.

A team led by Hajime Ichimura of Shinshu University thought that perhaps the reason for this phenomenon was "due to the change in the properties of the cells after transplantation". To investigate, the team prepared heart muscle cells from iPS cells. Heart muscles start to form twenty days into cultivation. On the twentieth day, the researchers harvested the cells and cryopreserved them. The experiment was done in vitro and in vivo. They observed the cells at two weeks, four weeks, and the twelfth week. The samples grown in vitro was a sheet, or two dimensional, and 3D samples were also prepared to be closer in form to the graft in vivo.

The research team used the thawed cells grown for twenty days during the in vivo experiments as well. They transplanted the cells to rat hearts, observing the prognosis at two weeks, four weeks and the twelfth week. These in vivo experiments had a trial with healthy hearts, and hearts with induced myocardial infarction, better known as a heart attack.

Corresponding author Professor Yuji Shiba has worked on heart transplant research previously in the paper: Allogeneic Transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts published 2016 in Nature. He states "the study into stem cells has been happening for almost 20 years and only recently have scientists started to understand mechanisms clinically."

The previous study of macaques noted the arrhythmia between the 2nd and 4th weeks. It was thought that the arrhythmia occurs from the activity of the transplanted cells. Arrhythmia during a heart attacks is often noted as "re-entry" or when the electricity inside the heart goes haywire and loops around inside the heart. Two previous groups who studied arrhythmia in hearts of transplanted cells thought it was not caused by re-entry, but that it is the activity of the transplanted cells. Therefore, this team set out to find the cause through observing the properties of the various cells according to time points.

They created the embryonic stem cell-derived cardiomyocyte cells and observed its electrical properties. There are two types of heart muscle cells made from iPS cells. "Working-type", which like the name implies, contracts and relaxes to produce exertion. The other is called "nodal-like", which acts like an electric pacemaker. Please look at Figure 1, 3 and 5.

After the twelfth week in vivo, the graft starts to grow, but immediately after transplantation it is very small. At the twelfth week the small graft has grown and consists mostly of working-type cells. The nodal-like cells has decreased significantly by then. The researchers believe that the arrhythmia decreases then, because the number of and activity of the nodal-like cells have decreased, causing extra electrical activity to decrease.

So why does the nodal-like cells decrease the in vivo? They tried many experiments but could not find a satisfactory explanation. One explanation they finally found was by looking at the proportion of proliferating cells before transplantation, SHOX2 is abundant. Looking at the percentage of KI-67 positive cells two weeks after transplantation, it was observed that nodal-like cells don't multiply after transplantation.

The group confirmed this at the RNA level, examining through PCAtools analysis. They looked at human fetal heart RNA and human adult heart RNA. They tested tissue in graft in vivo in rats. In vitro, the sample increased. In vivo it increased too, to more than 1800, while in vitro it increased 15. The KCNJ2 and MYL7 are working type cell markers that increase. The gene expression study verifies the other studies that the working-type cells increase significantly after transplantation.

Regenerative medicine of the heart has been studied for more than 20 years, and only now are clinical trials and surgeries starting to take place. As of now, the arrhythmia after stem cell transplantation is the biggest obstacle facing regenerative medicine for the heart. Researchers are gradually starting to understand the mechanism. If left on its own, the arrythmia solves itself, only appearing during the second to forth weeks after transplantation. It was not understood why it happens and how it resolves itself. This study helps to explain that phenomenon.

"This research was made possible by the many people who helped me clear each hurdle of technique in which I was inexperienced," Professor Hajime Ichimura states. "There are many steps to clear before the ultimate goal of clinical application in people, and there are other hurdles than arrhythmia."

Professor Yuji Shiba thinks, "perhaps if doctors could remove the nodal-like cells before transplantation, arrhythmia would not occur during future transplantation of heart cell grafts."

WHAT:

The investigational vaccine known as mRNA-1273 protected mice from infection with SARS-CoV-2, the virus that causes COVID-19, according to research published today in Nature. Scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and the biotechnology company Moderna, based in Cambridge, Massachusetts, along with collaborators from the University of North Carolina at Chapel Hill, Vanderbilt University Medical Center in Nashville, and the University of Texas at Austin conducted the preclinical research. NIAID Vaccine Research Center (VRC) scientists worked with investigators from the University of Texas at Austin to identify the atomic structure of the spike protein on the surface of the novel coronavirus. This structure was used by VRC and Moderna in the development of the vaccine candidate.

The findings show that the investigational vaccine induced neutralizing antibodies in mice when given as two intramuscular injections of a 1-microgram (mcg) dose three weeks apart. Additional experiments found that mice given two injections of the 1-mcg dose and later challenged with SARS-CoV-2 virus either 5 or 13 weeks after the second injection were protected from viral replication in the lungs and nose. Importantly, mice challenged 7 weeks after only a single dose of 1 mcg or 10 mcg of mRNA-1273 were also protected against viral replication in the lung.

The investigational vaccine also induced robust CD8 T-cell responses in mice. It did not induce the type of cellular immune response that has been linked to vaccine-associated enhanced respiratory disease (VAERD). This rare, allergic-type inflammation was seen in individuals vaccinated with a whole-inactivated respiratory syncytial virus (RSV) vaccine in the 1960s. VAERD can occur when a vaccine induces an immune response that is not strong enough to protect against infection. The investigators vaccinated mice with sub-protective doses of mRNA-1273 and then challenged the mice with SARS-CoV-2. The mice showed no evidence of enhanced lung pathology or excessive mucus production, indicating the vaccine did not cause enhanced disease, the authors write.

The authors note that the data from these studies, combined with data from studies in nonhuman primates and Phase 1 clinical testing, support the evaluation of mRNA-1273 in clinical efficacy trials. They also explain how their prior research on a candidate MERS-CoV vaccine paved the way for a rapid response to the COVID-19 outbreak. "This is a demonstration of how the power of new technology-driven concepts like synthetic vaccinology facilitates a vaccine development program that can be initiated with pathogen sequences alone," the authors write.

Obesity management should focus on outcomes that patients consider to be important, not weight loss alone, and include a holistic approach that addresses the root causes of obesity, according to a new clinical practice guideline published in CMAJ (Canadian Medical Association Journal).

"People with obesity experience weight bias and stigma, which contribute to increased complications and mortality, independent of weight or BMI," says Dr. Sean Wharton, co-lead of the guideline and adjunct professor at McMaster University, Hamilton, Ontario. "The first step to obesity management is to recognize your own bias. If you see people living with obesity as lacking willpower, or as noncompliant, then you likely have weight bias. Obesity needs to be managed with a focus on giving unbiased care to patients, showing compassion and empathy and using evidence-based interventions with an emphasis on patient-centred outcomes."

The comprehensive guideline, developed by Obesity Canada and the Canadian Association of Bariatric Physicians and Surgeons, is based on the latest evidence, which reflects substantial advances in the epidemiology, determinants, assessment, treatment and prevention of obesity. An update to the 2006 guideline, the new guidance incorporates the perspectives of people with lived experience of obesity as well as experts in the management of obesity.

Over the past 30 years, the prevalence of obesity has increased substantially around the globe, with a threefold increase in Canada. The prevalence of severe obesity has increased even further, with more than 1.9 million Canadian adults affected.

The new guideline targets primary health care professionals, policy-makers, people living with obesity and their families.

Key recommendations:

1. Ask permission to discuss weight: Health care practitioners must recognize obesity as a chronic disease with stigma and should not assume all patients with obesity are prepared to address it. This step helps to manage bias against people living with obesity.

2. Assess their story: Discuss the patient's history to understand the root causes of obesity, combined with physical examination, calculation of body mass index (BMI) and other investigations.

3. Advise on management: Discuss treatment options, such as nutrition and exercise, psychological interventions, medications to achieve and maintain weight loss, and bariatric surgery.

4. Agree on goals: Collaborate on a personalized, sustainable long-term action plan with realistic expectations.

5. Assist with barriers and drivers of weight gain: Barriers include lack of access to health care providers with expertise in obesity, lack of coverage of obesity medications by drug plans in Canada and long wait times for bariatric surgery.

"Working with people to understand their context and culture, integrating their root causes, which include biology, genetics, social determinants of health, trauma and mental health issues, are essential to developing personalized plans," says Dr. David Lau, co-lead of the guideline and professor at the University of Calgary. "These plans can become part of a long-term therapeutic relationship with follow-up of obesity-related chronic diseases."

Boston - Vitamin D supplementation does not protect against depression in middle-age or older adulthood according results from one of the largest ever studies of its kind. This is a longstanding question that has likely encouraged some people to take the vitamin.

In this study, however, "There was no significant benefit from the supplement for this purpose. It did not prevent depression or improve mood," says Olivia I. Okereke, MD, MS, of Massachusetts General Hospital (MGH's Psychiatry Department.

Okereke is the lead author of the report and principal investigator of this study, which will be published in JAMA on Aug. 4. It included more than 18,000 men and women aged 50 years or older. Half the participants received vitamin D3 (cholecalciferol) supplementation for an average of five years, and the other half received a matching placebo for the same duration.

Vitamin D is sometimes called the "sunshine vitamin" because the skin can naturally create it when exposed to sunlight. Numerous prior studies showed that low blood levels of vitamin D (25-hydroxy vitamin D) were associated with higher risk for depression in later life, but there have been few large-scale randomized trials necessary to determine causation. Now Okereke and her colleagues have delivered what may be the definitive answer to this question.

"One scientific issue is that you actually need a very large number of study participants to tell whether or not a treatment is helping to prevent development of depression," Okereke explains. "With nearly 20,000 people, our study was statistically powered to address this issue."

This study, called VITAL-DEP (Depression Endpoint Prevention in the Vitamin D and Omega-3 Trial), was an ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among nearly 26,000 people in the US.

From that group, Okereke and her colleagues studied the 18,353 men and women who did not already have any indication of clinical depression to start with, and then tested whether vitamin D3 prevented them from becoming depressed."

The results were clear. Among the 18,353 randomized participants, the researchers found the risk of depression or clinically relevant depressive symptoms was not significantly different between those receiving active vitamin D3 supplements and those on placebo, and there were no significant differences were seen between treatment groups in mood scores over time.

"It's not time to throw out your vitamin D yet though, at least not without your doctor's advice," says Okereke. Some people take it for reasons other than to elevate mood.

"Vitamin D is known to be essential for bone and metabolic health, but randomized trials have cast doubt on many of the other presumed benefits," said the paper's senior author, JoAnn Manson, MD, DrPH, at Brigham and Women's Hospital.

What The Article Says: JAMA Surgery Editor Melina Kibbe, M.D., writes in this editorial: "The implications of these data demonstrating that fewer women are submitting manuscripts to JAMA Surgery during the pandemic are potentially far reaching. First and foremost, the adverse effect of the pandemic on the academic career progression of women may be significant. As publications are the currency of academia and one of the main metrics assessed for promotion and tenure, women may face future challenges in this arena. The reduction of manuscript submissions by women likely represents only one aspect of the spectrum of problems women are facing in academic medicine."

Authors: Melina Kibbe, M.D., of the University of North Carolina at Chapel Hill, is the author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamasurg.2020.3917)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

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Media advisory: The full study is linked to this news release.

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