Category: Substance Use

Categories : Obstetrics & Gynaecology Substance UseTags :

Prenatal CBD and THC Stunts Prozac Responsiveness in Offspring

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Scientists have found that significant amounts of THC and CBD, the two main components of cannabis enter the embryonic brain of mice in utero and impair the mice’s ability as adults to respond to fluoxetine (Prozac).

The study suggests that when the developing brain is exposed to THC or CBD, normal interactions between endocannabinoid and serotonin signaling may be diminished as exposed individuals become adults.

“Hemp-derived CBD is a legal substance in the US, and we are in a time of increasing state-level legalisation of cannabis. Therefore, use of cannabis components have increased across most levels of society, including among pregnant women. The study marks the beginning of an effort to understand the effects of THC and CBD on the endogenous cannabinoid system (ECS) in the developing brain and body,” explained Hui-Chen Lu, director of the Linda and Jack Gill Center and professor in the Department of Psychological and Brain Sciences in the IU Bloomington College of Arts and Sciences.

Researchers studied four groups of pregnant mice. Some received daily moderate doses of either THC, CBD, or a combination of equal parts THC and CBD; a control group had placebo injections throughout pregnancy. Using mass spectrometry, IU psychological and brain sciences professor Heather Bradshaw tested embryos and found that CBD and THC both could cross the placenta and reach the embryonic brain.

“The surprising part is that maternal exposure to CBD alone — a drug that is often considered as safe and harmless and is a popular ‘natural’ therapy for morning sickness — resulted in a lasting impact on adult mice offspring,” Lu said. “Both prenatal THC and CBD exposure impaired the adult’s ability to respond to fluoxetine. The results suggest taking a cautious approach to using CBD during pregnancy.”

There is however some evidence for CBD’s effectiveness in treating chronic pain and anxiety, though currently the only FDA-approved indication for CBD is the treatment of severe seizure disorders.

“We still know very little about the effects of CBD on the developing brain,” Prof Lu said.

The new paper is one of the first studies to see the potential negative impact of CBD on the developing brain and later behaviours. However observational studies in the 1980s saw increased anxiety and depression in offspring of mothers who used the lower-strength cannabis available at the time. Since women may take cannabis products for nausea and vomiting, this has relevance for public health awareness.

Study co-author Ken Mackie, Gill Chair of Neuroscience at IU Bloomington, said researchers know that prenatal cannabis exposure may increase the risk for anxiety and depression, so it is important to evaluate the response to a class of drug used to treat anxiety and depression.

Though normal mouse behaviours were seen in many tests, one test — to determine their response to stress — had a strongly atypical result. In all groups, the mice responded normally to a stressful situation. As expected, fluoxetine increased stress resilience in mice whose mothers had received the placebo. However, the drug was ineffective in mice whose mothers had received THC, CBD or their combination.

Fluoxetine works by increasing the amount of serotonin available at brain synapses, an effect known to require the endocannabinoid system. This internal system of receptors, enzymes and molecules both mediates the effects of cannabis and plays a role in regulating various bodily systems, such as appetite, mood, stress and chronic pain.

To test if maternal exposure to THC and/or CBD impaired endocannabinoid signaling in the adult offspring, the researchers tested whether boosting the ECS with a drug would restore fluoxetine’s effectiveness. They found that the ECS boosting restored normal fluoxetine responses in mice that had received THC or CBD while their brains were developing.

Source: Indiana University

Journal reference: de Sousa Maciel, I., et al. (2021) Perinatal CBD or THC Exposure Results in Lasting Resistance to Fluoxetine in the Forced Swim Test: Reversal by Fatty Acid Amide Hydrolase Inhibition. Cannabis and Cannabinoid Research. doi.org/10.1089/can.2021.0015.

Categories : Mental Health Substance UseTags :

The Delicate Balance of the Endocannibinoid Pathway

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Scientists have uncovered an unexpected link between a synapse protein that has been implicated in neuropsychiatric disorders and the endocannabinoid pathway.

These findings suggest a role for the endocannabinoid system in conditions including bipolar disorder, according to Peter Penzes, PhD, the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences, professor of Physiology and Pharmacology, and senior author of the study.

“The endocannabinoid system could be disrupted in patients with bipolar disease, or it could be the opposite: medical marijuana could have therapeutic potential for these patients,” said Prof Penzes, who is also director of the Center for Autism and Neurodevelopment. “These are the questions that need to be answered.”

Cannabis mimics naturally occurring endocannabinoids in the brain, which is how it produces its effect in humans. Since the specific function of endocannabinoids is still not fully understood, the legalisation of marijuana in many US states has prompted more investigation into its biological pathways, Prof Penzes said. The endocannabinoid system is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults.

Endocannabinoids are produced by an enzyme known as diacylglycerol lipase alpha (DAGLA), which is concentrated in synapses. Endocannabinoids dampen synaptic strength, which is why marijuana has calming effects.

Prof Penzes and colleagues have previously studied ankyrin-G, another synapse protein which regulates transmission speed across synapses. Aberrant over- or under-expression of ankyrin-G has been associated with disorders such as bipolar disorder, schizophrenia and autism.

Studying mice with ankyrin-G genetically deleted, they made a surprising discovery: Ankyrin-G seemed to stabilise DAGLA at synapses, increasing the efficiency of DAGLA.

“It’s a delicate mechanism that regulates dendritic spine morphology,” said lead author Sehyoun Yoon, PhD, research assistant professor of Physiology.

These findings comport with another recent study, led by investigators at Icahn School of Medicine at Mount Sinai and published in Nature Genetics. The study showed that both DAGLA and ankyrin-G (ANK3) are risk genes for bipolar disorder in a genome analysis of over 40,000 patients.

“It’s almost like somebody who is leading a double life, Dr. Jekyll and Mr. Hyde,” Prof Penzes said. “Ankyrin-G has this entire separate function.”

The convergence of ankyrin-G with the endocannabinoid pathway opens up an entire new world of possibilities, both for investigating disease risk and possible therapies.

“Cannabis may contribute to increased risk for mental disorders, which has actually been shown in schizophrenia,” Prof Penzes said. “Conversely, cannabis could be beneficial in some brain disorders, which prompted trials of medical marijuana in patients with autism.”

Prof Penzes said in future he plans to examine the downstream effects of this biological pathway, both in normal subjects and in disease.

Source: Northwestern University

Journal information: Sehyoun Yoon et al, cAMP Signaling–Mediated Phosphorylation of Diacylglycerol Lipase α Regulates Interaction With Ankyrin-G and Dendritic Spine Morphology, Biological Psychiatry (2021). DOI: 10.1016/j.biopsych.2021.03.023

Categories : Substance UseTags :

Performance Enhancers Linked to Criminality

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A new study shows that both anabolic steroid use as well as legal performance-enhancing substances is longitudinally associated with criminal offending.

Although anabolic steroid use was known to be associated with criminal offending, the possibility of a similar link between use of legal performance-enhancing substances, such as creatine, and criminal offending remained unknown. 

To address this, researchers analysed a sample of over 9000 US participants from the National Longitudinal Study of Adolescent Health (Add Health). The results show a need for more research on performance-enhancing substances to understand the complex social problems associated with their use.

“This is the first study to identify relationships between legal performance-enhancing substance use and criminal offending,” said lead author Kyle T. Ganson, PhD, MSW, assistant professor at the University of Toronto’s Factor-Inwentash Faculty of Social Work. “This finding is acutely salient because these substances are easily accessible and commonly used, particularly among young people.”

The study highlights the importance of clinical professionals screening for performance-enhancing substance use and assessing patterns of criminal offending among young people.

“We need more research to identify effective prevention and intervention techniques to ensure that we reduce the use of these substances, as well as curtail any connection with criminal offending,” said co-author Jason M. Nagata, MD, MSc, assistant professor at the University of California, San Francisco’s Department of Pediatrics.

“The associations found in this study are likely explained by an intersection of behavioral, psychological, and sociocultural influences,” says Ganson. “We therefore need to target this problem from a multitude of angles, including clinically and via public health and policy interventions.”

Source: EurekAlert!

Journal information: Ganson, K.T., et al. (2021) Performance-Enhancing Substance Use and Criminal Offending: A 15-Year Prospective Cohort Study. Drug and Alcohol Dependence. doi.org/10.1016/j.drugalcdep.2021.108832.

Categories : Mental Health Substance UseTags :

Possible Cannabis Link to Suicidality in Young Adults

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Cannabis use among young adults was associated with increased risks of thoughts of suicide (suicidal ideation), suicide plan, and suicide attempt, according to a population analysis.

These associations remained regardless of whether someone was also experiencing depression, and the risks were greater for women than for men. The study was conducted by researchers at the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

“While we cannot establish that cannabis use caused the increased suicidality we observed in this study, these associations warrant further research, especially given the great burden of suicide on young adults,” said senior author NIDA Director Nora Volkow, MD. “As we better understand the relationship between cannabis use, depression, and suicidality, clinicians will be able to provide better guidance and care to patients.”

The number of cannabis-using adults in the US more than doubled from 22.6 million in 2008 to 45.0 million in 2019. Over the same period the number of adults with depression also increased, as did those reported suicidal ideation or who committed suicide. However the link between cannabis and suicidality is not well understood. 

Setting out to address, NIDA researchers examined data from the 2008-2019 National Surveys on Drug Use and Health (NSDUH). NSDUH collects nationally representative data among the US civilian population age 12 or older on cannabis use and use disorder, depression, suicidality, and other behavioural health indicators. In addition to determining the associations between these factors, the researchers examined whether the associations varied by gender. They examined data from 281 650 young adults ages 18 to 35 years, the age range where most mood and substance use disorders emerge.

Four levels of past-year cannabis use were compared: no cannabis use; nondaily cannabis use; daily cannabis use (use on at least 300 days per year); and presence of cannabis use disorder, assessed on specific criteria for a pattern of continued cannabis misuse. The prevalence of major depressive episodes based on specific diagnostic criteria measured through the survey was used to measure depression. To identify suicidality trends, the tean separately assessed the trends in the prevalence of past-year suicidal ideation, plan, and attempt as reported in the 2008-2019 NSDUH surveys.

The study found that even nondaily cannabis users were more likely to have suicidal ideation and to plan or attempt suicide than complete non-users. These associations remained regardless of comorbid depression. In people without a major depressive episode, about 3% of those who did not use cannabis had suicidal ideation, compared with about 7% of those with nondaily cannabis use, about 9% of those with daily cannabis use, and 14% of those with a cannabis use disorder. In people with depression, 35% of non-users had suicidal ideation, compared to 44% of nondaily cannabis users, 53% of daily cannabis users, and 50% of those with cannabis use disorder. Similar trends existed for the associations between different levels of cannabis use and suicide plan or attempt.

Additionally, the researchers found that women with any cannabis use were more likely to have suicidal ideation or report a suicide plan or attempt than men with the same levels of cannabis use. For example, among individuals without major depressive episode, the prevalence of suicidal ideation for those with vs without a cannabis use disorder was 13.9% vs. 3.5% among women and 9.9% vs. 3.0% among men. In individuals with both cannabis use disorder and major depressive episode, the prevalence of past-year suicide plan was 52% higher for women (23.7%) than men (15.6%).

“Suicide is a leading cause of death among young adults in the United States, and the findings of this study offer important information that may help us reduce this risk,” explained lead author Beth Han, MD. PhD, MPH, from NIDA. “Depression and cannabis use disorder are treatable conditions, and cannabis use can be modified. Through better understanding the associations of different risk factors for suicidality, we hope to offer new targets for prevention and intervention in individuals that we know may be at high-risk. These findings also underscore the importance of tailoring interventions in a way that take sex and gender into account.”

Source: National Institutes of Health

Categories : Substance UseTags :

Nearly 9% of Alcohol Consumed by Underage Drinkers

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Underage youth consumed $17.5 billion worth, or 8.6 percent, of the alcoholic drinks sold in 2016 in the US. Nearly half of youth consumption was made up of products from three alcohol companies: AB Inbev, MillerCoors and Diageo. The study findings were published in the Journal of Studies on Alcohol and Drugs.

In a landmark study of youth alcohol consumption by brand, the authors collected large amounts of data to estimate, for the first time in two decades, the monetary value of youth alcohol consumption. And for the first time, they were able to attribute those revenues to specific companies.

“The alcohol industry has said they don’t want minors to drink, but when we counted up the drinks, it was clear that they were making billions of dollars from these sales,” said co-lead author Pamela J. Trangenstein, PhD, assistant professor of health behaviour at the University of North Carolina Gillings School of Global Public Health. “There is a clear disconnect when an industry advocates prevention but then makes billions of dollars from prevention’s failure.”

Alcohol is the number one substance used among people ages 12 to 20. Although underage drinking has fallen in recent years, alcohol is still responsible for approximately 3500 deaths annually for under 21s, according to the Centers for Disease Control and Prevention.

In the US, the minimum drinking age is 21, although before 1984 states set their own drinking age. According to the CDC, raising the drinking age to 21 saw a 16% reduction in motor vehicle accident deaths, and there is evidence that this limit protects drinkers from alcohol and other drug dependence, adverse birth outcomes, and suicide and homicide.

“Our prior studies have repeatedly shown that youth are exposed to and influenced by alcohol marketing,” commented co-author David H Jernigan, PhD, professor at Boston University. “If alcohol companies are truly committed to preventing youth drinking, they should be willing to put these revenues into an independent agency able to address underage drinking without a conflict of interest.”

The Institute of Medicine and National Research Council, the science advisory body for the US Congress, made that recommendation in their 2003 report on underage drinking. In 2006, the legislation was passed entirely devoted to curbing underage drinking. While that legislation authorised $18 million in spending, the full amount has never been used. 

“Community coalitions in North Carolina and across the country are constantly begging for dollars to support their work on underage drinking,” said Prof Trangenstein. “Our study identifies a clear source for that badly needed funding. Families and communities are paying the price, while big alcohol companies are reaping all the benefits.”

Source: Journal of Studies on Alcohol and Drugs

More information: Eck, R. H., Trangenstein, P. J., Siegel, M., & Jernigan, D. H. (2021). Company-specific revenues from underage drinking. Journal of Studies on Alcohol and Drugs, 82, 368–376. DOI: 10.15288/jsad.2021.82.368

Categories : Hospitals Substance UseTags :

Only Total Alcohol Bans Relieve Pressure on SA Hospitals

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A new study found that alcohol bans could be a sensible policy to help South Africa through new health crises, according to a study published on Monday.

Based on local hospital admission data, the authors said that their work demonstrates that “alcohol prohibition correlates with a decrease in health seeking behaviour for injury”.

Several organisations in the liquor industry have started pre-emptive lobbying in the face of possible new alcohol bans as COVID infections are rising in a third wave. At the same time, The Southern African Alcohol Policy Alliance is pressuring the government to institute tougher alcohol controls to pre-empt the new wave of infections. 

The study was published in the journal Drug and Alcohol Review.

The authors, all associated with Stellenbosch University or the South African Medical Research Council, which helped fund their work, compared data from Worcester Regional Hospital for 2020 with the same from 2019, across trauma admissions, trauma operations, and stab wound admissions, “as a proxy for intentional injury”.

A pattern of decreased hospital use was observed in 2020 when there were bans and partial bans, and a resurgence following even the partial lifting of bans.

“Each time a complete ban was instituted, there was a significant drop in trauma volume which was lost by allowing alcohol (even partial sales),” the researchers wrote.

Specifically, there was a 59–69% decrease in trauma volume between pre-Covid-19 and the first complete ban period. When alcohol sales were partially rein-stated, trauma volume significantly increased by 83–90% then dropped again by 39–46% with the second alcohol ban.”

The study “demonstrates a clear trend of decreased trauma admissions and operations during complete alcohol prohibition compared to when alcohol sales were allowed or only partially restricted,” the authors wrote.

They concluded that an alcohol ban is an effective way to reduce strain on healthcare infrastructure.

“These findings suggest that temporary, complete bans on alcohol sales can be used to decrease health facility traffic during national emergencies.”

The authors considered the possibility other measures such as the curfew could have affected the result, but argued that it was unlikely.

Source: Business Insider

Categories : Substance UseTags :

Cannabis Vaping Soared in High School Students Before COVID

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Man vaping. Photo by Nery Zarate on Unsplash

With reports of severe lung illnesses related to vaping making headlines in 2019, cannabis use skyrocketed among high school students were soaring.

Cannabis vaping involves inhaling evaporated oils, or vapours from heated concentrates known as dabs. Joseph J Palamar, PhD, of New York University reported on his study in the Journal of Adolescent Health.

The long-running Monitoring the Future study results showed that 4.9% (95% CI 4.3%-5.5%) of high school students reported “frequent” vaping of cannabis products — 10 times or more in the previous month — up from 2.1% in 2018 (95% CI 1.7%-2.6%). Rates of any cannabis vaping in the previous month also rose significantly, from 7.5% in 2018 (95% CI 6.7%-8.4%) to 14.0% in 2019 (95% CI 13.1%-14.9%).

These increases accompanied an unsettling outbreak of respiratory illnesses, until it was eclipsed by the COVID pandemic. Nearly 3000 Americans, mostly young adults, fell ill with EVALI — e-cigarette or vaping-associated lung injury — and 68 died, noted Dr Palamar. Epidemiological and lab research eventually identified vitamin E acetate as the likely cause. The substance is a common component of illicit cannabis vaping products, even though a substantial minority of victims denied use of such products.

Dr Palamar’s study drew on Monitoring the Future data on 4072 students in 10th and 12th grades in 2018 and 8314 in 2019. The study also highlighted other trends.

Cannabis vaping in the past month nearly tripled among female students from 2018 to 2019, while rates for students in general age 18 and older rose 2.5-fold. Social activity, as indicated by reports of “going out” four to seven times a week, was linked to increased rates of cannabis vaping. There were also small increases in cannabis vaping among students reporting other psychoactive drug use including opioids, cocaine, “tranquilisers”, and non-LSD hallucinogens.

The study did not address the extent to which school closures and social restrictions resulting from the COVID pandemic affected these trends, and it will be some before data from Monitoring the Future can answer this as the survey was stopped in March 2020 when the pandemic closed schools.

Nevertheless, the available 2020 data showed that the number of 10th graders saying cannabis was “fairly easy” or “very easy” to obtain had dropped sharply, accelerating a trend underway for more than 20 years. This was despite the spread of legal marijuana.

Dr Palamar noted several limitations to his study and to Monitoring the Future in general. Data on drug use was self-reported, and the survey took place at schools, meaning that students “chronically absent or who dropped out are underrepresented,” he wrote. There were also some subgroups such as those vaping cannabis daily, that were too small for analysis.

Source: MedPage Today

Journal information: Palamar J “Increases in frequent vaping of cannabis among high school seniors in the United States, 2018-2019” J Adolesc Health 2021; DOI: 10.1016/j.jadohealth.2021.03.034.

Categories : Gender Substance UseTags :

Alcoholic Liver Disease Is ‘Astronomical’ in Young Women

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Image by ds_30 from Pixabay

Rates of alcoholic liver disease are skyrocketing in young women, doctors in the US have warned. Much of it has to do with added pressures on women in the pandemic.

Alcoholic liver disease — including milder fatty liver and the permanent scarring of cirrhosis, as well as alcoholic hepatitis — are up 30% over the last year at the University of Michigan’s health system, said Dr Jessica Mellinger, a liver specialist there. Severe liver disease and cirrhosis can see survival rates as low as 10%.

The route by which liver disease develops varies according to the individual, although obesity, genetics and underlying health conditions play a role. Moderate consumption of alcohol, a glass or two of wine daily, is unlikely to contribute to it.

However, Dr Mellinger says that along with her colleagues, she has seen alcohol consumption edging upward, to a bottle of wine per day which results in increased risk of serious liver disease.

Since the beginning of the pandemic, no data on overall increases in serious alcoholic liver disease has yet been compiled by The Centers for Disease Control and Prevention. But, Dr Mellinger said, “in my conversations with my colleagues at other institutions, everybody is saying the same thing: ‘Yep, it’s astronomical. It’s just gone off the charts.’ “

The age demographic is also changing. “We’re seeing kids in their late 20s and early 30s with a disease that we previously thought was kind of exclusive to middle age,” she said.

The pressures of the COVID pandemic are partly to blame, and in many cases the extra burden is falling on women – who are already more susceptible to alcohol because they have a smaller water volume to distribute alcohol into and their bodies do less ‘first pass’ metabolism of alcohol in the stomach. Popular culture and advertising also encourages women to drink.

Psychological factors such as eating disorders and trauma from sexual abuse also fuel the disease.

“Whether this is early life sexual trauma or they are in a recent or ongoing abusive relationship, we see this link very, very closely,” said psychiatrist Dr Scott Winder, a clinical associate professor at the University of Michigan who treats liver disease patients. “Just the sheer amount of trauma is really, really tragic.”

The lack of overlap between the various fields in this complex relationship results in what he calls a “tragic gap”.

“The cultures of hepatology and the cultures of psychology and psychiatry are very disparate; we see patients very differently,” so physicians aren’t coordinating care, even when they should, he said.

Advanced liver disease may leave no other recourse than a liver transplant.
“Unfortunately, transplantation is finite,” said Dr Haripriya Maddur, a hepatologist at Northwestern University. “There aren’t enough organs to go around. What it unfortunately means is that many of these young people may not survive, and die very young — in their 20s and 30s. It’s horrific.”

Some people such as Jessica Duena, a teacher who was diagnosed with alcoholic hepatitis at 34, and was hospitalised several times following the death of her boyfriend from heroin, have managed to turn the disease around and are encouraging others to do the same. 

She wrote about her long-held secret in the Louisville Courier-Journal: “I’m Jessica, I’m the 2019 Kentucky State Teacher of the Year, I’m an alcoholic and I’ve been suffering in silence for years.”

She received hundreds of responses, mostly women like herself who were in similar circumstances.

“What I’ve noticed is quite a few of the women, typically, they were either educators, they were moms or they happened to be nurses or attorneys,” Duenas said. They poured their hearts out about the crushing and constant stress of kids, work and home life.

They also complained of the pressures outside the home. “Imagine being a teacher who gets evaluated on how your students do, given the situation today,” Duenas says. “I mean, that makes me want to drink for them, you know — like that’s a terrible pressure to be under.”

Duenas has started writing about the stories of such people who reach out to her on her website, www.bottomlesstosober.com.

Source: NPR

Categories : Ageing Cardiovascular Disease Substance UseTags :

Recreational Substances Including Cannabis Linked to Heart Disease

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Alcohol, tobacco and cannabis are among recreational drugs that contribute to early-onset atherosclerotic cardiovascular disease (ASCVD) in young people, a study has found.

The study drew on data of more than a million people receiving primary care services throughout the VA Healthcare System in 2014 or 2015, of whom there were 135 703 with premature ASCVD.

A number of independent predictors for first-event ASCVD for men (from age 55) and women (from 65) were picked up. Tobacco (adjusted odds ratio [OR] 1.97) and alcohol use (OR 1.50)  conferred significant additional risk, but the greatest risk increase of generally legal substances was cannabis use (OR 2.65). Cocaine use (OR 2.44), amphetamine use (OR 2.74) and other drug use (OR 2.53) all had very high risk increases.

Those using four or more substances had the greatest risk at nearly nine times normal. Women also had much stronger effect sizes for premature ASCVD than men.

In an accompanying editorial Anthony Wayne Orr, PhD, and colleagues at LSU Health Shreveport, wrote: “Substance use disorders have been associated with an acceleration of the ageing process. We are only young once, and we should do everything in our power to maintain that state as long as we can.”

The editorialists suggested a nationwide ASCVD education campaign targeting people with substance use disorders.

“In addition, clinicians and primary care providers should begin screening their adult and young adult patients with a history of a substance use disorder for symptoms of premature or extremely premature ASCVDs at earlier stages in their patients’ lives,” suggested the editorialists.

Limitations included it being an observational study, lack of socioeconomic data and the cohort being mostly white males, as well as not being able to discern between prescription and recreational amphetamine use.
“Retrospective studies are limited by the available data. While this study supports the association between substance use disorder and early-onset ASCVD, the effect of substance use frequency, dose, and duration cannot be reliably ascertained in this patient sample,” the editorialists stated.

The editorialists recommended that specific biomarkers for substance use-associated cardiovascular disease be identified, and therapeutic window characterised to limit these chronic effects of substance use disorder.

Source: MedPage Today

Journal information: Mahtta D, et al “Recreational substance use among patients with premature atherosclerotic cardiovascular disease” Heart 2021; DOI: 10.1136/heartjnl-2020-318119.

Editorial information: Scott ML, et al “Young at heart? Drugs of abuse cause early-onset cardiovascular disease in the young” Heart 2021; DOI: 10.1136/heartjnl-2020-318856.