Tag: substance use

Categories : NeurologyTags :

Cannabis Use in Adolescence has Visible Effects on Brain Structure

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Photo by Anna Shvets

Cannabis use may lead to thinning of the cerebral cortex in adolescents according to a recent study.  The study demonstrates that THC – or tetrahydrocannabinol, an active substance in cannabis – causes shrinkage of the dendritic arborisation, neurons’ “network of antennae” whose role is critical for communication between neurons. This results in the atrophy of certain regions of the cerebral cortex – bad news at an age when the brain is maturing.  

The study, led by Graciela Pineyro and Tomas Paus, involved researchers at CHU Sainte-Justine and professors at the Université de Montréal Faculty of Medicine, was published in The Journal of Neuroscience.

“If we take the analogy of the brain as a computer, the neurons would be the central processor, receiving all information via the synapses through the dendritic network,” explains Tomas Paus, who is also a professor of psychiatry and neuroscience at Université de Montréal. “So a decrease in the data input to the central processor by dendrites makes it harder for the brain to learn new things, interact with people, cope with new situations, etc. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”

A multi-level approach to better understand the effect on humans

This project is notable for the complementary, multi-level nature of the methods used. “By analysing magnetic resonance imaging (MRI) scans of the brains of a cohort of teenagers, we had already shown that young people who used cannabis before the age of 16 had a thinner cerebral cortex,” explains Tomas Paus. “However, this research method doesn’t allow us to draw any conclusions about causality, or to really understand THC’s effect on the brain cells.”  

Given the limitations of MRI, the introduction of the mouse model by Graciela Pineyro’s team was key. “The model made it possible to demonstrate that THC modifies the expression of certain genes affecting the structure and function of synapses and dendrites,” explains Graciela Pineyro, who is also a professor in the Department of Pharmacology and Physiology at Université de Montréal. “The result is atrophy of the dendritic arborescence that could contribute to the thinning observed in certain regions of the cortex.”  

Interestingly, these genes were also found in humans, particularly in the thinner cortical regions of the cohort adolescents who experimented with cannabis. By combining their distinct research methods, the two teams were thus able to determine with a high degree of certainty that the genes targeted by THC in the mouse model were also associated to the cortical thinning observed in adolescents. 

With cannabis use on the rise among North American youth, and commercial cannabis products containing increasing concentrations of THC, it’s imperative that we improve our understanding of how this substance affects brain maturation and cognition. This successful collaborative study, involving cutting-edge techniques in cellular and molecular biology, imaging and bioinformatics analysis, is a step in the right direction for the development of effective public health measures.

Source: University of Montreal

Categories : Neurology Substance UseTags :

Meth and PCP Cognitive Deficits Stem from a Common Neurotransmitter Switch

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The effects of sustained drug abuse can manifest in many ways. Loss of memory and reduced cognitive functions are some of the effects that can persist for years. Neurobiologists at the University of California San Diego have now identified a mechanism in the brain that generates drug-induced cognitive impairments.

The researchers investigated how methamphetamine and phencyclidine (PCP or “angel dust”), which take effect by activating different targets in the brain, induce a similar reduction in cognitive ability. How could the same difficulties in memory emerge in response to drugs that trigger different actions in the brain?

The results of this investigation, led by Assistant Project Scientist Marta Pratelli in Professor Nicholas Spitzer’s laboratory, appear in Nature Communications. They showed that meth and PCP caused neurons to change the way they communicate through a process known as neurotransmitter switching.

Neurotransmitter switching is a form of brain plasticity, an evolving area of research investigating how the brain changes function and structure in response to experience. In recent years, Spitzer and his colleagues have also identified roles for neurotransmitter switching in autism spectrum disorder, post-traumatic stress disorder and in exercise.

Examining the cerebral cortex of mice, the investigators found that meth and PCP each caused a switch from the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) in the same neurons in the prelimbic region, an area of the frontal cortex involved in executive functions. This switch was linked to a decrease in memory task performance since drug-treated mice performed well in the tasks when the expression of GABA was blocked.

Further experiments showed that even after repeated exposure to the drugs, the researchers were able to reverse this neurotransmitter switch using molecular tools to locally decrease the brain’s electrical activity or using clozapine, an antipsychotic drug. Each of these treatments reversed the memory loss, restoring the performance of mice in the cognitive tasks.

“These results suggest that targeted manipulation of neuronal activity may be used to ameliorate some of the negative effects of repeated drug abuse,” said Pratelli.  

In this new study, the researchers found that a drug-induced increase in the release of dopamine, a neurotransmitter involved in reward, and an increase in the electrical activity of neurons in the cerebral cortex, were required to produce the neurotransmitter switch.

“This study reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs,” said Spitzer.

The researchers note in their paper that a deeper understanding of brain mechanisms tied to loss of memory from drug use could boost prospects for new treatments, not only resulting in therapy for meth and PCP consumption, but for other disorders as well.

Source: University of San Diego California

Categories : AddictionTags :

Hair Analysis Reveals Double the Number of Adolescent Substance Users

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Far more children and adolescents could be using drugs than admitted to in surveys, according to a new US survey using hair analysis to test for actual drug intake. Published in the peer-reviewed journal American Journal of Drug and Alcohol Abuse, the study of nearly 1300 children aged 9–13 found that, in addition to the 10% self-reporting drug use, an additional 9% had used drugs as determined by hair analysis.

The paper suggests hair analysis far outweighs the accuracy of assessing drug use compared to survey alone, and experts recommend that future research should combine both methods.

“It’s vital that we understand the factors that lead to drug use in teenagers, so that we can design targeted health initiatives to prevent children from being exposed to drugs at a young age,” says study leader Natasha Wade, an assistant professor of psychology at the University of California, San Diego.

Adolescent substance use is a serious public health issue, with 5% of US 8th graders (ages 13–14) reporting cannabis use in the last year. The numbers are even higher for alcohol and nicotine use, with 26% of 8th graders admitting to drinking and 23% to smoking nicotine in the past year. These numbers are worrying, as substance use in adolescence is linked to negative life outcomes, but they may be even higher.

To find out a multidisciplinary team of experts, led by Dr Wade, asked 1390 children whether they had taken drugs in the last year. Hair samples were then also taken so that independent tests could confirm whether recent drug-taking had taken place.

Of the children who were asked if they had taken drugs, 10% agreed that they had. Hair analyses also showed that 10% of adolescents overall tested positive for at least one drug, with 6.1% testing positive for cannabinoids, 1.9% alcohol, 1.9% amphetamines, and 1.7% cocaine.

However, the children that self-reported drug-taking were not the same as those who tested positive through hair samples. In fact, of the 136 cases that self-reported any substance use and 145 whose hair samples were positive for any drug, matches were found for only 23 cases.

Most importantly, hair drug analysis revealed an additional 9% of substance use cases over and above self-report alone, nearly doubling the number of identified substance users to 19%.

“A long-standing issue in substance use research, particularly that relating to children and adolescents, is a reliance on self-reporting despite the known limitations to the methodology. When asked, children may mis-report (unintentionally or intentionally) and say they take drugs when they don’t, or conversely deny taking drugs when they actually do,” Dr Wade adds.

“But rather than scrapping self-reporting of drug use altogether, a more accurate picture of teenage substance use can be gained by measuring both.

“Self-reporting has its own strengths, for instance young people may be more willing to disclose substance use at a low level, but are less likely to when frequent drug-taking patterns emerge.

“Conversely, hair assays are not sensitive enough to detect only one standard drink of alcohol or smoking one cannabis joint. Instead, the method is better at detecting frequent and moderate to heavy drug use.

“Combining both methodologies is therefore vital to accurately determine the levels of substance use in the teenage population.”

Commenting on the findings of their paper, the authors also add however, that it is important to note that there is a chance that some, perhaps even many, of these youth are unaware that they even used a substance, as it could have been given to them by a parent or peer or they may have simply forgotten they had used it.

Source: Taylor & Francis Group

Categories : Mental Health Substance UseTags :

Access to Medical Marijuana Increases Risks for Abuse

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Cannabis plants
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A study found that access to medical marijuana to treat pain, anxiety, or depression symptoms led to cannabis use disorder (CUD) in a significant minority of individuals while failing to improve their symptoms. The Massachusetts General Hospital (MGH) study was published in JAMA Network Open. 

In the US, individuals are able to gain access to cannabis products using medical marijuana cards (MMCs), usually issued by a doctor. Researchers found the greatest risk of developing the addictive symptoms of CUD was in those seeking relief from anxiety and depression. This finding indicates the need for stronger safeguards over the dispensing, use, and professional follow-up of people who legally obtain cannabis through MMCs.

“There have been many claims about the benefits of medical marijuana for treating pain, insomnia, anxiety and depression, without sound scientific evidence to support them,” said lead author Jodi Gilman, PhD, with the Center for Addiction Medicine at MGH. “In this first study of patients randomised to obtain medical marijuana cards, we learned there can be negative consequences to using cannabis for medical purposes. People with pain, anxiety or depression symptoms failed to report any improvements, though those with insomnia experienced improved sleep.”

Dr Gilman was particularly disturbed by the fact that individuals with symptoms of anxiety or depression – the most common conditions which people seek medical cannabis for – were the ones most vulnerable to developing cannabis use disorder. CUD symptoms include a vicious circle of needing more cannabis because of growing tolerance, and seeking out cannabis to treat the psychological problems it causes.

“Medical” cannabis has surged in popularity in the US, as so far 36 of its 50 states have commercialised its use for myriad health conditions through medical marijuana cards. These cards require written approval of a licensed physician who, under the current system, is often not the patient’s primary care provider but rather a ‘cannabis doctor’ who may provide authorisation to patients with only a cursory examination, no recommendations for alternative treatments, and no follow-up. The medical marijuana industry effectively functions outside the regulations that apply to most fields of medicine.

The researchers started their trial in 2017 with 269 adults (average age of 37) who were interested in obtaining a medical marijuana card. One group was allowed to get MMCs immediately, while the second group, designed to serve as a control, was asked to wait 12 weeks before obtaining a card. Both groups were tracked over 12 weeks. The team found that the odds of developing CUD were nearly two times higher in the MMC cohort than in the wait list control group, and that by week 12, 10% of the MMC group had developed a CUD diagnosis, with the number rising to 20% in those seeking a card for anxiety or depression.

“Our study underscores the need for better decision-making about whether to begin to use cannabis for specific medical complaints, particularly mood and anxiety disorders, which are associated with an increased risk of cannabis use disorder,” said Dr Gilman. Regulation and distribution of cannabis to people with medical marijuana cards needs to be greatly improved, no matter the specific condition they are issued for. “There needs to be better guidance to patients around a system that currently allows them to choose their own products, decide their own dosing, and often receive no professional follow-up care.”

Source: Massachusetts General Hospital

Categories : Substance UseTags :

LSD Microdosing Study Shows no Benefit

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Published in Addiction Biology, a study into the effects of LSD “microdosing” found no evidence to back up proponents’ claims that it can improve mood and cognitive function. 

The study’s lead author, Chicago University Professor Harriet de Wit, noted that the study doesn’t disprove microdosing’s possible benefits, and that more investigation is needed. The study does show that taking small doses of LSD is safe. Prof De Wit said the findings demonstrate the important role clinicians can play when it comes to therapeutics claims about recreational drugs.

“These drugs are already being used out in the world, and it’s important for us to test them under controlled conditions, ensure their safety and see whether there’s some validity to the benefits people claim,” she said. “That’s something that has been missing from the conversation.”

The researchers studied the effects of four repeated low doses of LSD, administered under lab conditions every three to four days. One group of participants received 13 micrograms of the drug, a second group received 26 micrograms, and the third received a placebo. To put these low doses into context, the doses of LSD that are used to “trip” or to get high are typically 100–200 micrograms, she said.

LSD was chosen for the study because it’s the most commonly used psychedelic drug in microdosing.

Participants received the drugs during five-hour, supervised laboratory sessions. They also attended a drug-free follow-up session three to four days after the last dose. Participants were not told what kind of drug was being tested in the study – whether it was a stimulant, a tranquiliser or a hallucinogen – or that the study was about microdosing.

“We removed any expectations that this was a psychedelic drug,” Prof de Wit explained. “Because in the real world, people’s expectations can strongly influence their responses.”

To assess their mood and mental performance, the participants completed cognitive and emotional tasks both during the drug administration sessions and at the drug-free follow-up session. Some participants who received the higher dose reported feeling a modest “high” during the drug sessions, but the effects were mild.

The drug did not improve mood or affect participants’ performance on cognitive tests, either during the drug sessions or at the follow-up session.

Prof De Wit said the results came as a disappointing surprise. “Because so many people claim to have experienced benefits from microdosing, we expected to document some kind of beneficial effect under laboratory conditions,” she said.

Neurobiological reasons had also suggested that LSD might improve mood, because LSD acts through serotonin receptors, where traditional antidepressants are known to act.

“We can’t say necessarily that microdosing doesn’t work,” Prof de Wit said. “All we can say is that, under these controlled circumstances, with this kind of participant, these doses, and these intervals, we didn’t see a robust effect.”

People who microdose often have strong expectations of beneficial effects. “It is possible that these expectations contribute to the apparent benefits, or they may interact with the pharmacological effect of the drug,” she said.

LSD was confirmed to be safe, an unsurprising find which is in line with previous human and animal studies.

In fact, de Wit noted, participants appeared to build a tolerance to LSD over the course of the study, with the strongest “high” reported at the first session, and the perception of a drug effect diminishing at each subsequent session. That’s a good sign because it confirms the drug does not stay in the body or accumulate over time, she said.

Getting authorisation to use a controlled substance made the experiment challenging, as did the participants’ necessary time commitment. However, Prof de Wit emphasised the importance of such research, especially as practices like microdosing become commercialised.

“There are a lot of companies getting into the drug business, either with psychedelic drugs, or drugs like cannabidiol,” she noted. “And really there’s not very much empirical support to back up their claims. So, I think we have a responsibility to investigate and validate the claims.”

Source: University of Chicago

Categories : Obstetrics & Gynaecology Substance Use UncategorizedTags :

Effects of Fathers’ Prenatal Alcohol Exposure Manifests in Offspring

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Researchers have discovered that males exposed to alcohol in utero later pass on those effects to their offspring during foetal development, through reduced placental efficiency. The study appears in FASEB Journal.

Dr Michael Golding, an associate professor at Texas A&M University has spent years investigating the father’s role, with regard to drugs and alcohol, in foetal development. Studies have shown that males pass down more than just their genetics, Dr Golding said, but exactly how that process works and the its consequences are still largely unknown.

“When you look at the data from throughout human history, there’s clear evidence that there’s something beyond just genetics being inherited from the male,” Dr Golding said. “So, if that data is solid, we’ve got to start looking more at male behaviour.

“Say you had a parent who was exposed to starvation – they could pass on what you might call a ‘thriftiness,’ where their kids can derive more nutrition from less food,” he said. “That could be a positive if they grow up in a similar environment, or they could grow up in a time when starvation isn’t an issue and they might be more prone to obesity or metabolic syndromes. That kind of data is clearly present in clinical data from humans.”

Epigenetics, which is Dr Golding’s area of study of how things beyond genes, such as behaviour and environment, affect development is called. One of the big questions in the search for answers on how male prenatal behaviour can impact foetal growth has been the way these epigenetic factors manifest.

The team has shown that prenatal exposure to alcohol in males can manifest in the placenta: in mice, offspring of fathers exposed to alcohol have a number of placenta-related difficulties, including increased foetal growth restriction, enlarged placentas, and decreased placental efficiency.

“The placenta supplies nutrients to the growing foetus, so foetal growth restriction can be attributed to a less efficient placenta. This is why placental efficiency is such an important metric; it tells us how many grams of foetus are produced per gram of placenta,” said Thomas, a graduate student at Texas A&M. “With paternal alcohol exposure, placentas become overgrown as they try to compensate for their inefficiency in delivering nutrients to the foetus.”

However,while these increases happened frequently in male offspring, the frequency varied greatly based on the mother; however, the same increases were far less frequent in female offspring. Dr Golding thinks that although information is passed from the father, the mother’s genetics and the offspring’s sex are also involved.

“This is a novel observation because it says that there’s some complexity here,” Dr Golding said. “Yes, men can pass things on to their offspring beyond just genetics, but the mom’s genetics can interpret those epigenetic factors differently, and that ultimately changes the way that the placenta behaves.”

These results don’t draw a clear line in how drinking in human males prior to conception impacts foetal development, but they continue to at least point to it being a question that needs to be explored. 

Dr Golding is hoping that more questions will be asked about male prenatal behaviour so that there’s more data from which to work.

“The thing that I want to ultimately change is this stigma surrounding the development of birth defects,” Dr Golding said. “There’s information coming through in sperm that is going to impact the offspring but is not tied to the genetic code; it’s in your epigenetic code, and this is highly susceptible to environmental exposures, so the birth defects that we see might not be the mother’s fault; they might be the father’s or both, equally.”

Source: Texas A&M University

Categories : Substance UseTags :

Many Youths with Substance Use Disorder Also Have Autism Traits

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One in five teens and young adults seeking treatment for substance use may have traits characteristic of a previously unrecognised autism spectrum disorder (ASD), according to a study by researchers at Massachusetts General Hospital (MGH).

The study, published in The American Journal on Addictions, found that among patients with an average age of 18.7 years being treated in an outpatient substance use disorder (SUD) clinic, 20% had elevated scores on the Social Responsiveness Scale-2 (SRS-2), a parent- or teacher-reported measure that has been shown to reliably identify the presence and severity of social impairment among individuals along the autism spectrum, and to distinguish autism from other disorders.

Lead author James McKowen, PhD, said this is the first study examining the prevalence of autistic traits among young people with SUD.

“Usually studies of substance use disorder in autism are done in those with an autism diagnosis already,” he said. “We have looked at this question from the other side, asking how many people with substance use disorder have autism.”

The researchers asked parents of 69 youths reporting for the first time to a specialty outpatient psychiatric SUD clinic to fill out the SRS-2 form. The form is designed to measure an individual’s social awareness, cognition, communication and motivation, and restricted interests and repetitive behaviours.

Though few differences were found between those with elevated autistic trait scores and those with lower, non-autistic scores in terms of demographic or psychiatric factors, adolescents with higher SRS-2 scores had a nearly eightfold higher likelihood of stimulant use disorder, and a fivefold higher risk for opioid use disorder.

According to the researchers, the findings highlight the importance of assessing patients in a SUD treatment setting for autistic traits.

“For clinicians, the big takeaway point from this study is that we need to get better at screening and certainly training in the presence of autism spectrum disorder,” said Dr McKown. Clinicians treat the SUD “but don’t have specialty developmental training, particularly for issues around autism.”

The researchers are developing a free clinical therapy protocol that can help clinicians better address the issues of autistic traits in patients with SUD.

Source: Massachusetts General Hospital

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 : 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 : 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.