Tag: paediatrics

20% of Healthy Children May Have Benign Bone Tumours

Around 20% of healthy children may possess benign tumours, according to a review of radiographs taken nearly a century ago.

Although it sounds alarming, non-ossifying fibromas and other common benign bone tumours in symptom-free children are not dangerous. Such bone tumours are often discovered on x-rays taken for other causes, such as a fracture. 

“Understandably, these tumours cause a lot of anxiety for patients and families as they await confirmation that the tumour is benign,” said Christopher Collier, MD, Indiana University School of Medicine, Indiana University. “They need reassurance and often ask how common these tumours are, when did they first appear, and whether they will resolve over time? We don’t have much evidence to date to address these questions.”

To address these questions, the researchers analysed annual x-rays taken of children’s bones as they grew, however such studies today are not feasible today due to ethical concerns over sensitivity of children to ionising radiation. Therefore, they drew on a unique collection of radiographs from the Brush Inquiry, a study in which a series of healthy, ‘normal’ children in Ohio, underwent annual radiographs from 1926 to 1942.

Dr Collier’s team analysed a total of 25 555 digitised radiographs of 262 children, followed from infancy to adolescence, finding a high prevalence of bone tumours. A total of 35 benign bone tumors were found in 33 children – an overall rate of 18.9 percent when considering that only the left side of the children was radiographed.

Over half of the tumours were non-ossifying fibromas, which are connective tissue masses that have not hardened into bone. Generally, these fibromas appeared around age five, and again around the time of skeletal maturation, possibly linked to growth spurts. Of 19 non-ossifying fibromas detected, seven disappeared over time. Others may have resolved some time after the annual radiographs stopped.

Rarer benign bone tumoors included enostoses, sometimes called ‘bone islands’; and osteochondromas or enchondromas (tumours in cartilage). In patients with these tumours, they persisted to the last available radiograph.

The findings are similar to the rates of benign bone tumours in healthy adults. Dr Collier noted: “Despite the inherent limitations of our historical study, it may provide the best available evidence regarding the natural history of asymptomatic benign childhood bone tumors.”

Source: News-Medical.Net

Researchers Say New Vaccines Needed for Childhood Pneumonia


Research in Australia on new pneumonia vaccines show that while pneumonia in children is being suppressed,  empyaema is increased.

The research, which was led by the University of New South Wales (UNSW), examined the impact of the new 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyaema.
Empyaema, which is the collection of pus in the lungs, occurs in about 1% of children with pneumonia. In children, empyaema is far less fatal than it is in adults, but it does extend hospitalisation, requiring antibiotics and surgery or installation of a drain.
The findings of the study showed that while 13vPCV resulted in a 21% drop in childhood pneumonia hospitalisations, there was a contemporaneous 25% rise in empyaema hospitalisations.

According to senior author Professor Adam Jaffe, Head of the School of Women’s and Children’s Health at UNSW Medicine & Health, said the findings suggested an emergence of non-vaccine serotypes—those which 13vPCV does not cover.

13vPCV was introduced to cover the 13 most common serotypes that cause invasive pneumococcal infection, adding six more serotypes over the seven serotypes covered by its predecessor, 7cPCV.

Prof Jaffe said: “Although we found a substantial reduction in serotype 1, serotype 3 is now the predominant organism which causes childhood empyema—in 76% of cases—so, efforts must be made to create a vaccine which is more effective against serotype 3.

“In fact, Australia recently changed the vaccination dosage schedule to try and improve the effectiveness of 13vPCV against serotype 3, but we need to continue monitoring patients using molecular techniques to see if this change has had an impact.

“Childhood bacterial pneumonia and empyema are potentially preventable diseases through vaccination. So, if Australia can develop an effective vaccine, we could prevent children from being hospitalized with pneumonia and empyema.”

The researchers conducted a similar study over four years during the 7vPCV era.   

“Our new study had two parts,” Prof Jaffe said. “We analysed national hospitalisations for childhood empyaema and childhood pneumonia, then we conducted an enhanced surveillance study on children with empyaema.”

The first part of the research used publicly available hospitalisations data to find out if the introduction of 13vPCV changed how many children were admitted to hospital with pneumonia and empyaema.

The enhanced surveillance study involved the collection of blood and lung fluid samples from 401 children  with empyaema, followed by molecular testing on these samples and comparing the results to their previous study undertaken during the period of 7vPCV.

Prof Jaffe said research with a larger sample was ongoing, and 13vPCV monitoring was needed.

Source: Medical Xpress

Journal information: Roxanne Strachan et al. Assessing the impact of the 13 valent pneumococcal vaccine on childhood empyema in Australia, Thorax (2021). DOI: 10.1136/thoraxjnl-2020-216032

Regular Sleep Patterns in Toddlers Important for BMI

Although getting regular sleep patterns in toddlers has long been a priority for parents, researchers have shown it is important for toddlers’ BMI.

The researchers, led by Lauren Covington, an assistant professor in the University of Delaware School of Nursing, investigated the link between poverty, regular sleep patterns and BMI in toddlers. According to The National Sleep Foundation, toddlers 1- to 3-years-old should have 12 to 14 hours of sleep in a 24-hour period.

“We’ve known for a while that physical activity and diet quality are very strong predictors of weight and BMI,” said Prof Covington, the lead author of the article. “I think it’s really highlighting that sleep may be playing a bigger role here than it’s been given credit for.”

The researchers aimed to investigate the relationship between poverty and BMI in toddlers, and wanted to see whether sleep behaviour, activity or food intake could provide the explanation.

Using data from families in an obesity prevention trial, 70% of whom were below the poverty line, and all eligible for nutritional supplementation grants, Toddlers were given accelerometers to wear to measure physical activity and parents filled out food diaries.

The researchers found that children from households with greater poverty were more likely to have greater inconsistent bedtimes, and those with more inconsistent bedtimes had higher BMI percentages.

Prof Covington said this is likely to be a bidirectional relationship. “There’s a lot of teasing out the relationships of the mechanisms that are at play here, which is really difficult to do because I think they’re all influencing each other,” she said.

Having consistent bedtimes where children go to bed within one hour of the normal time is a recommended guideline, but for families in poverty this may be impossible for a variety of reasons. Single parent households and juggling multiple jobs are part of the challenges they face.

“Implementing a consistent bedtime could be one behavioural change that a family could potentially do,” said Prof Covington. “It’s more attainable than maybe getting healthy food at the grocery store or playing outside on the playground, especially now with the cold weather. Just having a consistent bedtime can help provide some sense of structure, but then maybe have better implications for health and BMI as well.”

Source: Medical Xpress

Journal information: Lauren Covington et al. Longitudinal Associations Among Diet Quality, Physical Activity and Sleep Onset Consistency With Body Mass Index z-Score Among Toddlers in Low-income Families, Annals of Behavioral Medicine (2020). DOI: 10.1093/abm/kaaa100

Novel Transplant Technique Yields More Donor Hearts for Children

Two hospitals in the UK have reported great success in a new heart transplant technique, resulting in a record number of children receiving heart transplants in 2020.

Royal Papworth Hospital in Cambridge and Great Ormond Street Hospital (GOSH) have collaborated on a new procedure which has enabled a much larger supply of donor hearts for children, who have had to wait two and a half times as long as adults for a donation.

Royal Papworth Hospital was the first in Europe to harvest non-beating hearts from adult patients whose life support had been withdrawn, and then been restarted for transplantation, instead of waiting for brain death with a still-beating heart.

By using a special device called the organ care system, surgeons can effectively restart the heart and keep it healthy until transplantation. The first non-beating heart transplant was performed in Australia in 2014. Since February last year, the two hospitals have been offering the service to children.

The use of non-beating hearts had previously been ruled out for transplantation until recently, due to tissue damage from lack of oxygen. The new organ care system, which supplies the heart with oxygenated blood and nutrients, can be used to keep the heart alive and pumping outside the body for up to 12 hours. This is long enough for checks to be performed prior to the transplant procedure, or even transferred to another hospital.

GOSH and Freeman Hospital are the only two centres in the UK with paediatric heart transplant units. In the past five years, 39 children died while waiting for donors.

“Some patients will just not survive the wait,” said Jacob Simmonds, a transplant surgeon at GOSH. “There is also a risk that while waiting they could damage other organs, particularly the lungs.” 

Last year, six paediatric heart transplants were carried out in the UK using the new procedure, and only four elsewhere in the world. The organs came from adult donors, as the organ care system is designed to accommodate hearts from people weighing over 50kg. Development is being carried out on a system which could allow harvesting organs from children. This would increase the available transplants for infants and babies, who have a critical lack of donors.

Source: BBC News

TB Vaccine Shown to Protect Against Common Infections

The tuberculosis (TB) vaccine Bacillus Calmette-Guerin (BCG) could protect newborns against a variety of common infections, such as upper respiratory tract infections, chest infections, and diarrhoea, according to a new study from the London School of Hygiene and Tropical Medicine (LSHTM).

It has been known that BCG protects against diseases other than TB, offering protection against non-tuberculous mycobacteria infection like leprosy and Buruli ulcer. It is also used in the treatment of superficial carcinoma of the bladder.

However, this is the first research to rigorously investigate the full range. The results suggest that vaccinating all babies with BCG on their day of birth could save lives by reducing neonatal infections in areas with high rates of infectious disease.

The study involved a randomised control trial of 560 newborns in Uganda, who were monitored for a range of illnesses. After six weeks, infection rates from any disease were 25% lower in the group that received the vaccine at birth, compared to the group that had not yet received the vaccination. The most protected appeared to be vulnerable groups such as low birth weight babies, and boys. Importantly, BCG appeared to protect against even severe infections.

Sarah Prentice, the lead author from LSHTM, said: “Nearly a million babies die every year of common infections so we urgently need better ways to protect them. Our research suggests that ensuring that BCG is given at birth could make a big difference in low-income countries, potentially saving many lives.”

The newborns were randomly assigned to receive BCG either at birth or at six weeks of age. They were followed-up by doctors, blinded to the intervention, for 10 weeks, who looked for any type of illness or infection.

The research team then compared how often infants in the two groups presented to doctors with infections of any kind, except TB, to see whether having BCG made a difference. They also took blood samples from both groups, to look at differences in their innate immune system, the body’s first line of defense against infections.

Infants vaccinated with BCG at birth presented to doctors with any kind of infection 25% less often than infants who had not. BCG seemed to protect against all kinds of infections, such as common colds, chest infections, and skin infections.

After the delayed group had been vaccinated, the rates of infection were identical between the two groups: the delayed group’s immunity ‘brought up to speed’ when they received BCG.

Study co-author Prof Hazel Dockrell, LSHTM, said: “It’s very exciting to think that BCG vaccination might help keep newborns safe against other dangerous infections, in addition to providing protection against TB. Although BCG is recommended at birth in many countries, it is often delayed due to logistical difficulties. Ensuring that the vaccine is given on day one, in areas with high rates of infectious disease, could have a major impact on infections and deaths in the newborn period.”

Though the study could not definitely determine whether the BCG vaccine was responsible for the lowered rate of infections, there is nonetheless great interest in applying the vaccine as a protection for novel disease outbreaks, such as COVID or Ebola, before a specific vaccine can be developed.

Dr Prentice said, “Since the findings show that BCG seems to offer wider protection against a range of infections, our study also raises hopes it might be useful in protecting the general population against COVID-19 and future pandemics – though we will need to see the results of other, more specific studies to know for sure.”

Source: News-Medical.Net

Journal information: Prentice, S., et al. (2021) BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial. The Lancet Infectious Diseases. doi.org/10.1016/S1473-3099(20)30653-8.

Study Reveals More Sugar in Breakfast Products Aimed at Children

Breakfast products that are aimed at children contain significantly more sugar than those aimed at adults, a Spanish study has revealed.

The researchers analysed a 355 advertisements from 117 different products from 2015 to 2019, and found that the average amount of sugar in the breakfast products analysed and advertised for adults was 10.25%, while for children it was 36.20%.

“Although much of the adult population still adhere to the Mediterranean diet, it is a practice that is waning among children and young people, who are increasingly opting to eat processed industrial products with a high sugar content for breakfast,” explained Mireia Montaña, UOC Faculty of Information and Communication Sciences professor and researcher.

Mònika Jiménez, professor of Advertising and Public Relations at Pompeu Fabra University (UPF) and co-author of another study on breakfast food advertising involving Prof Montaña, warned of persuasive advertising for foods with little nutritional value.

She said, “The less closely a product correlates to that which would be deemed healthy nutritional parameters, the greater the tendency for the advertising discourse to focus on hedonism or happiness and tend towards persuasion.” As Jiménez explained, when such discourse alludes to positive feelings, it stimulates certain areas of the brain that lead us to consume, a strategy which “is especially harmful in relation to certain audiences, such as minors, because they are very susceptible to these kinds of stimuli.”

Profs Montaña and Jiménez found that low nutritional quality breakfast foods were advertised mostly through television (39%), followed by radio (28%), the internet (18%), newspapers (6%), magazines (5%), outdoor advertising (2%) and cinema (0.56%). “TV is the most effective medium when it comes to persuading children. And when is it that children are going to the supermarket with their parents and end up imposing their preferences with regard to what goes into the shopping trolley? Precisely when they are younger, up until preadolescence,” Prof Jiménez pointed out.

Though there are regulations in Spain preventing advertisers from targeting children directly, there are no such restrictions for products which can be aimed at any age group, such as hot chocolate. Advertising aimed at children to use ‘pester power’ on their parents results in food being bought which is then consumed by the entire family. 

Their recommendations included more stringent regulatory frameworks, better nutritional education aimed at parents and children, and added taxes on certain products such as soft drinks.

Source: News-Medical.Net

Journal information: Blasco, M.M., et al. (2021) Breakfast Food Advertisements in Mediterranean Countries: Products’ Sugar Content in the Adverts from 2015 to 2019. Children. doi.org/10.3390/children8010014.

No Evidence for Strep Exacerbating Chronic Tics in Kids

A new study has found that children with chronic tic disorders, mainly Tourette syndrome, do not have tic exacerbations when exposed to group A Streptococcus.

No significant association with tic exacerbations emerged across four definitions of pharyngeal strep exposure with a mean follow-up of 16 months, though a weak link was observed in trend, reported Davide Martino, MD, PhD, of the University of Calgary, and co-authors.

Strep was however significantly associated with longitudinal changes in hyperactivity-impulsivity symptom severity of 17% to 21%.
“The link between Streptococcus and tics in children is still a matter of intense debate,” Martino stated. “We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder.

“While our findings suggest that strep is not likely to be one of the main triggers for making tics worse, more research is needed into other possible explanations. For example, the social stress of having this disorder could be implicated in making tics worse more than infections. It’s also possible another pathogen might be triggering an immune response associated with tic worsening.”

In an invited editorial, Andrea Cavanna, MD, PhD, of the University of Birmingham, and Keith Coffman, MD, of Children’s Mercy Hospital in Kansas City, observed that group A Streptococcus had been posited as a potential environmental factor in tic disorders for the past two decades.

The editorialists noted that, on the basis of isolated clinical observations, tic disorders should be included as a collateral feature in conditions which are known as pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS) infections. However, the results of longitudinal clinical studies were inconclusive, with a case control study even arguing against the association.

Drawing data from the EMTICS study, recruiting children with chronic tic disorders from 2013 to 2016, one arm of the study prospectively examined associations between new group A Streptococcus throat exposures and tic exacerbations, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD) symptoms.

Four definitions of strep exposure were used: new definite (newly positive throat swab regardless of serological results), new possible (elevated anti-streptolysin O [ASOT] or anti-DNAseB [ADB] titers with negative or no throat swab), ongoing definite, and ongoing possible.

Initially, 59 children had a positive throat swab; as the study progressed, 103 children had new definite strep exposure. During follow-up, 308 children (43%) had tic exacerbations. The proportion of exacerbations temporally associated with strep exposure ranged from 5.5% to 12.9%, depending on exposure definition. No association between OCD symptoms and strep exposure was seen.

“Our study of the largest prospective cohort of youth with chronic tic disorders ever documented to date provides evidence against a temporal association between group A Streptococcus exposure and clinically relevant tic exacerbations,” the researchers wrote.

“This result indicates that specific diagnostic work-up or active management of group A Streptococcus infections in the context of worsening of tic severity in patients with chronic tic disorders is not warranted,” the researchers added.

The researchers noted that limitations included the data being collected from specialist centres in different countries, and that some cases of strep may have been missed.

Source: MedPage Today

Journal information (article): Martino D, et al “Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders: A Multinational Prospective Cohort Study” Neurology 2021; DOI: 10.1212/WNL.0000000000011610.

Journal information (editorial): Cavanna A, Coffman K “Streptococcus and Tics: Another Brick in the Wall?” Neurology 2021. DOI: 10.1212/WNL.0000000000011608.

Foetal Repair of Spina Bifida Improves Outcomes in Children

A follow-up study found further evidence that foetal surgery for spina bifida extends benefits even further into childhood.

Adding to a growing body of research affirming the benefits of fetal surgery for spina bifida, new findings show prenatal repair of the spinal column confers physical gains that extend into childhood.

Spina bifida is a birth defect where the vertebral column is open (bifid), often involving the spinal cord. Myelomeningocele (MMC; open spina bifida) is the clinically most significant, where the spinal neural tube fails to close during development of the embryo. The exposed neural tissue degenerates in utero, causing a neurological deficit that varies with the amount of lesion. This occurs in 1 in 1000 births worldwide.

“This study shows that the benefits of fetal surgery for spina bifida extend beyond early childhood and well into a child’s first decade of life,” said co-author of the study N Scott Adzick, MD, Surgeon-in-Chief at Children’s Hospital of Philadelphia (CHOP), Director of CHOP’s Center for Fetal Diagnosis and Treatment. “This is especially important because of previously raised concerns that the advantages from fetal surgery may decrease over time. Contrary to those concerns, there appears to be a long-term benefit from neural protection in utero.”

The present study is a follow-on of the Management of Myelomeningocele Study (MOMS), which was co-led by investigators at CHOP, Vanderbilt University Medical Center, and the University of California, San Francisco, along with the data coordinating centre at the George Washington University Biostatistics Center. MOMS compared the outcomes of prenatal and traditional postnatal repair of myelomeningocele at 12 and 30 months, showing that there are considerable benefits from prenatal repair. Babies with spina bifida who received foetal surgery were less likely to need a shunt for the buildup of spinal fluid in the brain. Two and a half years after surgery, they walked better and had better overall motor function.

In MOMS2, the children from MOMS were comprehensively examined at ages from five to ten. They were assessed on a range of indicators, including fine motor skills and ability to do tasks unaided. The researchers found continuing benefits, including the foetal repair group being six times more likely to go to the toilet unaided than the postnatal repair group, and were 70% more likely to walk unaided, and twice as likely to walk without braces. They also had greater likelihood of engaging in self-care skills such as brushing teeth and using a fork.

“These data are important for demonstrating that fetal surgery for spina bifida improves mobility well into school age, but the implications of these results are even more profound,” said first author Amy J Houtrow, MD, PhD, MPH, Pediatric Rehabilitation Medicine Division Chief at UPMC Children’s Hospital of Pittsburgh. She said that when children are able to move around by themselves, it has significant positive impacts on their quality of life.

“When we began performing fetal surgery more than two decades ago, we did so with the hope that the procedure would improve lives for children and their families,” explained Dr Adzick. “As we continue to improve the technique, shortening surgery times and increasing the gestational age at birth, we are heartened by these results, which show the lasting benefits of fetal surgery.”

Source: Medical Xpress

Children with Sepsis Respond Better to ‘Relaxed’ Care Bundle

Following a ‘relaxed care bundle’ was linked to lower 30-day mortality and shorter hospital stays among children with sepsis, according to preliminary data from the Improving Pediatric Sepsis Outcomes (IPSO) FACTO trial.

The study findings were presented virtually at the Society of Critical Care Medicine’s Critical Care Congress.

Sepsis is the leading cause of death in children, with an estimated 7.5 million deaths a year. Childhood sepsis includes severe pneumonia, severe diarrhoea, severe malaria, and severe measles. Some 25-40% of children who recover from sepsis still have long-term consequences.

The ‘relaxed’ sepsis bundle is based on a group of best evidence-based interventions. It involves an initial fluid bolus delivery within 60 minutes, as opposed to 20 minutes; and antibiotic delivery within 180 instead of 60 minutes. Accepted sepsis recognition protocols (screen, huddle, or care order) were also involved with the bundle.

This trial data came from about 40 000 patients with sepsis or suspected sepsis at a range of children’s hospitals across the US, from 2017 to 2019. Raina M Paul, MD, of Advocate Children’s Hospital, Illinois, USA reported the data, saying that the relaxed bundle saw better outcomes than the more original bundle which was more time-restrictive. 
Sepsis-attributable mortality fell by 48.9% among the relaxed bolus-compliant versus non-compliant group (3.1% vs 3.5%), and by 13.7% in original bundle-compliant vs non-compliant cases. Following all aspects of the relaxed bundle was associated with a reduction in median days in hospital from 9 to 6 days.

In a separate presentation, Kayla Bronder Phelps, MD, of CS Mott Children’s Hospital in Michigan, USA, reported the results of a study that showed children hospitalised for severe sepsis were likely to have longer hospital stays if they were from lower-income neighbourhoods. Using a national database, she identified 10 130 cases of children with severe sepsis. Severe sepsis hospitalisations were also highest among the lowest-income quartile, reflecting the fact that there were more children living in low-income neighbourhoods.

Overall, 8.4% of children in the cohort died of sepsis during hospitalisation, with no association between mortality rates and income level. However, children in the lowest-income areas spent a median 9 days in the hospital, while children from the highest-income areas spent 8 days.

Bronder Phelps noted that the study is among the first to examine the impact of poverty on paediatric sepsis outcomes. Poverty is a known risk factor for a wide range of paediatric diseases, such as neonatal bacterial infection, asthma, and migraine, and in adults, poverty is associated with poorer outcomes including higher mortality rates.

Source: MedPage Today

Presentation information 1: Paul R, et al “Improving pediatric sepsis outcomes for all children together (IPSO FACTO): Interim results” SCCM 2021; Abstract 32.

Presentation information 2: Phelps K, et al “The association of socioeconomic status and pediatric sepsis outcomes” SCCM 2021; Abstract 37.

Misuse of Psychiatric Meds Common in Teens

A study into the use and misuse of psychoacttive drugs by US teens has found that about a fifth report misusing their prescribed medications.

Israel Agaku, PhD, of Harvard School of Dental Medicine in Boston, and colleagues used data from a survey of adolescents aged 12-17 prescribed opioids, stimulants, tranquilizers, or sedatives, and found that 20.9% reported using them not as prescribed or directed. There has been considerable concern in recent years over whether adolescents in the United States were being overprescribed psychiatric medication, although a 2018 study concluded that they are not. However, as with adults, the prospect of misuse, possibly leading to substance use disorders is a concern.
Of these youths, 3.4% reported having substance misuse disorders, and this proportion increased to nearly half when youths were taking two or more prescribed medications.

Some 25% of 12-17 year olds reported receiving a psychiatric prescription in the past year. The most common psychoactive prescription in the past year was opioids in 19% of all youth, followed by stimulants (7.2%), tranquilisers (4.3%), and sedatives (2.2%). Tranquilisers were the most commonly misused (40.1%), with substance use disorder in 7%. Stimulants were misused by 24.2%, 3% having a substance use disorder.
Among adults aged 18-25, 41% had been prescribed and had used psychoactive medication, with a third saying they had used opioids in the past year, Similarly to the 12-17 age group, stimulants and tranquilisers were most likely to be misused. 

“The largely overlapping population profiles for medical use versus misuse indicates the high abuse liability of these prescription substances,” the researchers noted. “Having serious psychological distress was consistently associated with misuse of every assessed psychoactive prescription medication.”

The researchers suggested that an open-minded, collaborative approach by healthcare providers was the best approach to dealing with the situation.

“Rather than asking only about cigarette smoking, pediatric practitioners should screen for different commonly used substances, including ‘social use.’ Specifically asking youth and young adults if they have used certain substances, including occasional use, is important as those who use such substances infrequently or only occasionally may not self-identify as users if asked in generic terms,” the researchers explained.

Source: MedPage Today

Journal information: Agaku I, et al “Medical use and misuse of psychoactive prescription medications among US youth and young adults” Fam Med Com Health 2021; DOI: 10.1136/ fmch-2020-000374.