After implementation of a multidisciplinary quality improvement project, the percentage of infants from the neonatal intensive care unit (NICU) experiencing hypothermia upon operating room (OR) arrival and at any point during the operation decreased from 48.7% to 6.4% and 67.5% to 37.4%, respectively. Conducted at Ann & Robert H. Lurie Children’s Hospital of Chicago, the successful project and was featured in the journal Pediatric Quality and Safety.
About one-third of infants admitted to children’s hospitals’ NICUs require surgery and are at increased risk for intraoperative hypothermia due to environmental heat loss, anaesthesia, and inconsistent temperature monitoring. Hypothermic infants are at risk for infection, excessive bleeding, increased oxygen consumption, the need for cardiorespiratory support, and mortality.
Upon return to the NICU, the percentage of infants experiencing postoperative hypothermia decreased from 5.8% to 2.1% while postoperative hyperthermia increased from 0.8% to 2.6%.
“Intraoperative hypothermia is more prevalent than postoperative hypothermia, yet the problem appears to be recognized less. Several improvement projects have addressed postoperative hypothermia, however, few have focused on reducing intraoperative hypothermia,” said senior author Gustave Falciglia, MD, MSCI, MSHQPS, neonatologist at Lurie Children’s. “The strengths of our project were the large cohort of infants and the use of continuous, secure and automated data to ensure normal temperature for infants before, during and after an operation. Using our current approach, however, further decreasing intraoperative and postoperative hypothermia may not be possible without further increasing postoperative hyperthermia.”
Dr Falciglia and colleagues from Lurie Children’s Center for Quality and Safety, anaesthesiology, NICU and OR nursing, surgery, neonatology and Data Analytics and Reporting succeeded in reducing rates of intraoperative hypothermia by standardising temperature monitoring, the transport process to the OR and intraoperative warming.
“In this project, we used improvement science methodology to understand the barriers to maintaining normal temperature in NICU infants before, during and after surgery, and then to design and implement solutions,” said lead author Abbey Studer from the Center for Quality and Safety at Lurie Children’s. “We found variation in processes that contributed to intraoperative hypothermia, so we focused on standardizing temperature monitoring and thermal support during the infant’s transport and operation. Automated monitoring using a preoperatively placed continuous temperature probe enhanced providers’ situational awareness of infant temperature and guided clinical adjustments.”
For this improvement project, the hospital’s Center for Quality and Safety coordinated care and resources between multiple departments. It achieved consensus and buy-in from providers despite competing factors such as perspiring surgeons and busy anaesthesia providers transporting all infants to the OR. It identified key participants who were vested in revising processes and facilitated adoption with their colleagues, following up on missed opportunities and gaps in the processes identified through observation and surveys. The centre provided data analysts who worked iteratively with providers to generate valid, actionable, and real-time data.
“Although medicine prizes specialisation, our success relied upon individuals with various talents sharing their skills and knowledge,” said Dr Falciglia. “Working together we can continue to improve the care of infants in the NICU who need surgery.”
Use of low-dose atropine eyedrops (concentration 0.01%) was no better than placebo at slowing myopia progression and elongation of the eye among children treated for two years, according to a randomised controlled trial conducted in the US. The trial aimed to identify an effective way to manage this leading and increasingly common cause of refractive error, which can cause serious uncorrectable vision loss later in life. Results from the trial, published in JAMA Ophthalmology, contradict those from recent trials in East Asia.
The study was conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and funded by the National Eye Institute (NEI).
“The overall mixed results on low-dose atropine show us we need more research. Would a different dose be more effective in a US population? Would combining atropine with other strategies have a synergistic effect? Could we develop other approaches to treatment or prevention based on a better understanding of what causes myopia progression?” said Michael F. Chiang, MD, director of the NEI, which is part of the National Institutes of Health.
Identifying an optimal approach for preventing high (advanced) myopia is urgently needed given the escalating prevalence of myopia overall and the risk of it progressing to high myopia. By 2030, it’s predicted that 39 million people in the U.S. will have myopia. By 2050, that number is expected to grow to 44 million in the U.S. and to 50% of the global population.
Much stronger concentrations of atropine eyedrops (0.5-1.0%) have long been used by pediatric eye doctors to slow myopia progression. While effective, such doses cause light sensitivity and blurry near vision while on the nightly eyedrops. Thus, there is interest in clinical studies assessing lower concentrations that have been shown to have fewer side effects.
“The absence of a treatment benefit in our US-based study, compared with East Asian studies, may reflect racial differences in atropine response. The study enrolled fewer Asian children, whose myopia progresses more quickly, and included Black children, whose myopia progresses less quickly compared with other races,” noted the study’s lead co-author, Michael X. Repka, M.D., professor of ophthalmology, Johns Hopkins University.
For the study, 187 children ages 5 to 12 years with low-to-moderate bilateral myopia were randomly assigned to use nightly atropine (0.01%) (125 children) or placebo (62 children) eyedrops for two years. Study participants, their parents, and the eye care providers were masked to the group assignments.
After the treatment period, and 6 months after treatment stopped, there were no significant differences between the groups in terms of changes in degree of myopia compared with baseline. Nor were there significant differences in axial length within the two groups when compared with baseline measurements.
“It’s possible that a different concentration of atropine is needed for US children to experience a benefit,” noted the study’s other lead co-author, Katherine K. Weise, OD, professor, University of Alabama at Birmingham. “Clinical researchers could evaluate new pharmaceuticals and special wavelengths of light in combination with optical strategies, like special glasses or contact lenses, to see what works in reducing the progression of myopia.”
Among children, myopia will stabilise in about half of children around age 16 years, and among an increasingly larger percentage as they get older. By their early twenties, about 10% of individuals with myopia will continue to grow more nearsighted, and by age 24 years that percentage is 4%.
“Vision scientists may help us figure out what’s different about the myopic eye, even among different races and ethnicities, to help create new treatment strategies,” she said. It will take a real convergence of eye research to solve the environmental, genetic, and structural mystery of myopia.”
Children with autism have memory challenges that hinder not only their memory for faces but also their ability to remember other kinds of information, according to new research. These impairments are reflected in distinct connection patterns children’s brains, the study found.
Published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, the study findings clarify a debate about memory function in children with autism, showing that their memory struggles surpass their ability to form social memories. The finding should prompt broader thinking about autism in children and about treatment of the developmental disorder, according to the scientists who conducted the study.
“Many high-functioning kids with autism go to mainstream schools and receive the same instruction as other kids,” said lead author Jin Liu, PhD at Stanford University. Memory is a key predictor of academic success, said Liu, adding that memory challenges may academically disadvantage children with autism.
The study’s findings also raise a philosophical debate about the neural origins of autism, the researchers said. Social challenges are recognised as a core feature of autism, but it’s possible that memory impairments might significantly contribute to the ability to engage socially.
“Social cognition can not occur without reliable memory,” said senior author Vinod Menon, PhD.
“Social behaviours are complex, and they involve multiple brain processes, including associating faces and voices to particular contexts, which require robust episodic memory,” Menon said. “Impairments in forming these associative memory traces could form one of the foundational elements in autism.”
Comprehensive memory tests
Affecting about one in every 36 children, autism is characterised by social impairments and restricted, repetitive behaviours. The condition exists on a wide spectrum, with those on one end having severe intellectual disability and about a third of people with autism have intellectual impairments. On the other end of the spectrum, many people with high-functioning autism have normal or high IQ, complete higher education and work in a variety of fields.
Children with autism are known to have difficulty remembering faces. Some small studies have also suggested that children with autism have broader memory difficulties. They included children with wide ranges of age and IQ, both of which influence memory.
To clarify the impact of autism on memory, the new study included 25 children with high-functioning autism and normal IQ who were 8 to 12 years old, and a control group of 29 typically developing children with similar ages and IQs.
All participants completed a comprehensive evaluation of their memory skills, including their ability to remember faces; written material; and non-social photographs, or photos without any people. The scientists tested participants’ ability to accurately recognise information (identifying whether they had seen an image or heard a word before) and recall it (describing or reproducing details of information they had seen or heard before). The researchers tested participants’ memory after delays of varying lengths. All participants also received fMRI scans of their brains to evaluate how memory-associated regions are connected to each other.
Distinct brain networks drive memory challenges
In line with prior research, children with autism had more difficulty remembering faces than typically developing children, the study found.
The research showed they also struggled to recall non-social information. On tests about sentences they read and non-social photos they viewed, their scores for immediate and delayed verbal recall, immediate visual recall and delayed verbal recognition were lower.
“We thought that behavioural differences might be weak because the study participants with autism had fairly high IQ, comparable to typically developing participants, but we still observed very obvious general memory impairments in this group,” Liu said.
Among typically developing children, memory skills were consistent: If a child had good memory for faces, he or she was also good at remembering non-social information.
This wasn’t the case in autism. “Among children with autism, some kids seem to have both impairments and some have more severe impairment in one area of memory or the other,” Liu said.
“It was a surprising finding that these two dimensions of memory are both dysfunctional, in ways that seem to be unrelated – and that maps onto our analysis of the brain circuitry,” Menon said.
The brain scans showed that, among the children with autism, distinct brain networks drive different types of memory difficulty.
For children with autism, the ability to retain non-social memories was predicted by connections in a network centred on the hippocampus. But face memory was predicted by a separate set of connections centred on the posterior cingulate cortex, a key region of the brain’s default mode network, which has roles in social cognition and distinguishing oneself from other people.
“The findings suggest that general and face-memory challenges have two underlying sources in the brain which contribute to a broader profile of memory impairments in autism,” Menon said.
In both networks, the brains of children with autism showed over-connected circuits relative to typically developing children. Over-connectivity, likely from insufficient selective pruning of neural circuits, has been found in other studies of brain networks in children with autism.
New autism therapies should account for the breadth of memory difficulties the research uncovered, as well as how these challenges affect social skills, Menon said. “This is important for functioning in the real world and for academic settings.”
Children prescribed a stimulant to manage symptoms of attention deficit hyperactivity disorder (ADHD) do not have more substance use or substance use disorder (SUD) as adolescents or young adults, according to a new study appearing in JAMA Psychiatry.
The study’s findings may provide some reassurance to parents and clinicians who may be hesitant to prescribe ADHD stimulant medications out of fear that this may result in future substance abuse.
“Stimulants are the first-line treatment recommended for most individuals with ADHD – the drug class is an evidence-based treatment with few side effects,” said Brooke Molina, PhD, professor of psychiatry, psychology and paediatrics at University of Pittsburgh. “Because stimulant medications are classified by the Drug Enforcement Administration as schedule two substances with the potential for misuse, many people fear that harmful substance use could result.”
Marked by chronic patterns of inattention, hyperactivity or impulsivity, ADHD is a chronic condition that must be monitored throughout an individual’s life.
Molina and her colleagues assessed patients with ADHD over a 16-year period from childhood through adolescence to early adulthood to see if there was any association between stimulant treatment and subsequent substance use. The study accounting for dozens of demographic, clinical and psychosocial factors that may predispose an individual to treatment and substance use to address the relationship between childhood use of prescription stimulants and later SUD.
“Our study not only accounted for age, but also used a statistical method that adjusted over time for the many characteristics that may distinguish treated from non-treated individuals,” said study co-author Traci Kennedy, PhD, assistant professor of psychiatry at Pitt. “Considering these factors allowed us to more accurately test the relationship between stimulants and substance use.”
While other studies have sought to uncover and define a possible connection between prescription stimulant use for ADHD and SUD, the association between the two has remained controversial. Some studies suggested a protective effect of prescription stimulant use on the risk of having SUD later in life, while others failed to find an association.
After accounting for a number of factors, the researchers found no evidence that prescription stimulant treatment in childhood provided protection against developing a SUD for adolescents or young adults with ADHD. Nor did they find an association between stimulant use during childhood and increased substance misuse in the future
While some study participants self-reported an increase over time in heavy drinking, marijuana use, daily cigarette smoking and using other substances, an association with age was also found for stimulant treatment, with older participants being less likely to continue taking medication. When these trends were paired with rigorous statistical analysis, results provided no evidence that prolonged stimulant use is associated with reduced or increased risk for SUD.
“We hope the results of this study will help educate providers and patients,” Molina said. “By understanding that stimulant medication initially prescribed in childhood is not linked to harmful levels of substance use, I anticipate that parents’ and patients’ fears will be alleviated.”
Pitt researchers plan to study individuals who were first diagnosed with ADHD and treated with stimulants in adulthood. The study aims to learn if there are differences in the characteristics and outcomes of these adults compared to people who were diagnosed and first treated with stimulants in childhood.
Several sessions at the 11th SA AIDS conference, recently held in Durban, highlighted the worrying fact that key HIV numbers such as treatment coverage are much lower in children than in adults. There is hope, however, that new treatments and new treatment guidelines might help close the gap.
In a plenary session, Dr Sandile Buthelezi, Director General of the National Department of Health, told delegates that on UNAIDS’ 95-95-95 targets, children in South Africa are at 81-65-68. This means that 81% of children living with HIV have been diagnosed, 65% of those diagnosed are on antiretroviral treatment, and 68% of those on treatment are virally suppressed. For the South African population as a whole, the numbers are at 94-76-92.
Throughout the conference, various speakers highlighted the fact that only 65% of children who have been diagnosed are on treatment as a particular concern. To close the gap and reach UNAIDS’ target of 95%, just over an additional 88 000 children would need to be initiated on treatment.
Professor Lee Fairlie, Director of Maternal and Child Health at Wits RHI, said in a presentation that only 52% of children younger than 14 living with HIV are on treatment. Fairlie also pointed out that children lagged behind substantially when it comes to viral suppression, and this is particularly challenging in the youngest age groups.
Not all bad news
But it was not all bad news at this year’s conference. One piece of good news is that new and better child-friendly antiretroviral formulations are being rolled out in South Africa. These new treatments should make it easier for children to start and stay on treatment – children often find it difficult to take medicines formulated for adults, due to factors like incorrect dosing, large pills, and bad taste.
The National Department of Health recently updated the country’s antiretroviral treatment guidelines to allow for the use of several of these new formulations and better HIV treatment regimens for children. Most notable is the introduction of a new regimen consisting of the medicines abacavir, lamivudine and dolutegravir (ALD for short).
Speaking at the conference, Dr Leon Levin, a paediatrician who has been treating infants, children, and adolescents living with HIV for almost three decades, pointed out that the availability of new paediatric formulations had a major impact on the new treatment guidelines. (Spotlight previously reported on the registration of some of these new formulations here.) Levin is also the Senior Technical Advisor in Paediatrics at the NGO Right to Care.
One such child-friendly formulation is a 120/60mg scored, dispersible tablet of abacavir and lamivudine that can be taken in patients who weigh between 3 and 25kg. It is given once daily and two generics are registered with the South African Regulatory Authority (SAHPRA). “It’s going to literally replace all the other paediatric Abacavir+3TC formulations. You can swallow it, chew it, crush it, or dissolve it in water. So [it’s] very versatile,” he said.
Also important is a paediatric formulation of the antiretroviral dolutegravir – a medicine that forms the backbone of HIV treatment in adults. According to Levin, the child-friendly version of dolutegravir is not available to everyone yet, and many clinicians still need to undergo training on how to use it. It is a 10mg dispersible, scored tablet given once daily that can be used at 3kg and higher and from four weeks of age onward. There are two generic versions of this product registered with SAHPRA.
The introduction of paediatric dolutegravir is likely to overshadow the introduction of a four-in-one formulation of abacavir, lamivudine, lopinavir/ritonavir. The four-in-one combination has to be taken twice daily, is strawberry flavoured and comes in a powder form. “Unfortunately, this product to nobody’s fault was launched at the same time as paediatric dolutegravir. Which means paediatric dolutegravir is going to take centre stage and this product unfortunately is not going to be used much,” Levin said.
Updated guidelines
Levin explained that the changes to South Africa’s treatment guidelines focused on doing two main things when it comes to children living with HIV, the first is to implement an optimised regimen – the ALD regimen and the second is to create an “enabling environment to support engagement in care and adherence”. He said that with the new guidelines, we can expect “much improved [viral] suppression, optimised regimens, improved synchronisation of clinic visits, happier patients and their families and clinicians as well”.
A big change to the guidelines is that now children who weigh 3kg and are four weeks of age should be started on the ALD regimen, instead of the abacavir, lamivudine, and lopinavir/ritonavir regimen that was previously recommended. “This is a major change. It’s a fantastic, well-tolerated regimen. It’s potent and you’re going to get around a lot of the issues you had with these younger children,” Levin said.
Once the children on this regimen get to 30kg, they will be switched to a regimen containing tenofovir, dolutegravir, and lamivudine (TLD for short). TLD is also the regimen adults living with HIV in South Africa are offered when starting treatment for the first time.
For children who are already on treatment, the new guidelines recommend that all children who are four weeks of age and older and weigh 3kg or more should be transitioned to a dolutegravir-containing regimen. For children with suppressed viral loads, the switch to ALD or TLD is straightforward, while for children without viral suppression, it can get more complicated.
Another important change is that children over five years of age are now eligible for Repeat Prescription Collection Strategies (RPCs) if they are virally suppressed and had an age-appropriate disclosure, which means that their HIV status has been explained to them in a way that is appropriate for their age, as outlined in the guidelines. For children under five, they can be given a three months supply at a time, providing they are at least six months old. Levin pointed out that whenever RCPs or a three months supply is considered for children, it is essential to look at where and how the parents may be receiving their own antiretroviral treatment so that it can be co-ordinated, and parents don’t have to go to two different places to collect the medications.
New options in the pipeline
While the paediatric formulations included in the new guidelines are a step forward, there are experimental treatments in the pipeline that may make treatment yet more convenient for children.
“There’s a rich pipeline of new combinations and drug delivery developments. Hopefully, this will further improve access, clinical and virological outcomes,” Fairlie said in a conference presentation. “Obviously, the paediatric market is extremely small and then one has to maintain enthusiasm for manufacturers to actually continue to look at the paediatric population. And so, merging of treatments and prophylaxis regimens is really what would work going forwards.”
In her presentation, she specifically referred to long-acting formulations of cabotegravir (CAB-LA) and rilpivirine (RPV). CAB-LA has already been approved by SAHPRA for HIV prevention in adults and, as Spotlight reported last week, pilot projects evaluating how to best provide the CAB-LA injection in South Africa are set to start soon. The combination of CAB-LA and rilpivirine injections has been approved for the treatment of HIV in adults by the United States Food and Drug Administration, but not yet by SAHPRA. The injections are administered every two months.
Fairlie says that currently there are several studies either ongoing or set to start soon for the use of these agents in the paediatric and adolescent age groups. In addition, there are also trials planned to test another long-acting medication called lenacapavir in adolescents and broadly neutralising antibodies (bNAbs) in children.
She also highlighted several improved delivery methods that are in the pipeline for paediatrics. These include a mechanism that doesn’t require water, like oro-dispersible tablets, also known as fast melts, which disintegrate in the mouth as well as oral films that stick to the mouth, disintegrate there, and dissolve. There are also various tablet options that are small enough for children to swallow easily. Like multi-particulates, which are small and solid, multiple-unit dosages that can take the form of granules, pellets, or beads. Mini-tablets are also a prospect – these are compressed tablets no larger than 4ml. Finally, there are novel mechanisms like long-acting oral drug delivery systems and micro-array patches. Fairlie explained that long-acting oral drugs are where a drug is stored in the centre of a capsule that has a number of “arms”, which are able to keep the capsule in the stomach and slowly dissolve and release the drug into the stomach. This allows for slow-release dosing. The “arms” tend to break down after about seven days.
While grandmothers today have a popular image of spoiling their grandchildren with treats, in premodern times they also acted as healthcare providers. To find out more, University of Turku researchers looked at historical data on childhood mortality from infectious diseases in the 18th and 19th century in Finland. The study, which is published in the journal Proceedings of the Royal Society B, found that grandmothers decreased all-cause and cause-specific mortality of children.
In historical and in several contemporary societies, children with living grandmothers are more likely to survive into adulthood, but the mechanism behind this effect remains poorly known.
As childhood infections have been a leading cause of death in children under the age of 5 years, the researchers aimed to investigate whether the effect of grandmothers on childhood survival was related to providing knowledge in childcare, particularly during critical times such as epidemics. One way for grandmothers to do so could be by encouraging vaccine uptake or earlier vaccination against childhood infections, as has been observed in some contemporary populations.
Researchers first studied the effects of grandmothers on children’s cause-specific mortality, using historical records of five causes of death: smallpox, measles, pulmonary infections, diarrhoeal deaths, and accidents. The large multigenerational dataset of pre-industrial Finnish families included 9705 individuals from 12 parishes across Finland, where the survival of individuals until the of age 15 years was monitored from 1761 to 1900. In the second part of the study, the researchers determined whether increased survival against the childhood infection smallpox was mediated by vaccination. To this end, they used 1594 vaccination records from two rural parishes and matched them to their individual family histories.
The results show that grandmothers decreased all-cause mortality, an effect which was mediated through improved survival from smallpox, pulmonary and diarrhoeal infections, but not from measles or accidents. However, the researchers found no evidence of increased or earlier vaccination between children with or without grandmothers.
“Our results show that the grandmother’s presence protected against some childhood infections, which could indicate that in historical Finnish society, the assistance provided by grandmothers in childcare was likely an important factor in ensuring the survival of children,” says study lead author, Doctoral Researcher Susanna Ukonaho.
Grandmothers in contemporary societies
Although grandmother care provided health benefits in many historical societies, these benefits may no longer be relevant in contemporary societies. The progress in healthcare during the 20th century especially in high-income countries likely decreased the role of grandmothers. However, some studies indicate that grandmothers improve childhood survival in several contemporary middle- and low-income countries.
“The type of benefits that grandmothers provide may vary depending on cultural contexts and individual circumstances. Even though in many societies grandmothers are no longer essential for childhood survival, their efforts in childcare remain valuable for the well-being of the whole family,” says Ukonaho.
“The death of a child affects us all. Witnessing the loss of a newborn baby who has sepsis is terribly traumatic, especially so when antibiotics used to treat the child are ineffective,” says neonatologist Professor Sithembiso Velaphi.
“It’s very heavy for a mother to carry her baby, give birth, watch as her newborn gets seriously sick from infection, suffers while being pricked with drips and pumped with drugs to try and save the child – only for her to leave the hospital empty handed. It’s painful,” says Velaphi, who is the head of Paediatrics at Chris Hani Baragwanath Academic Hospital in Johannesburg.
Professor Sithembiso Velaphi, head of Paediatrics at Chris Hani Baragwanath Academic Hospital in Johannesburg. PHOTO: Kim Cloete for GARDP
Nurses and doctors feel sad and crushed too when they cannot save a newborn’s life because of antibiotic resistance to bacterial infections. “We need to prioritise the development of antibiotics to treat these babies. For us, success is seeing a baby get better and going home,” he says.
Velaphi was speaking to Spotlight about a landmark global observational study published in the journal Plos Medicine (June 8) which found that many neonates (within 60 days of birth) get life-threatening bloodstream infections, or sepsis, and are dying because the antibiotics used to treat them are not effective. This is the first global overview to assess the extent of the problem. Spotlight last year reported on interim findings from the same study.
The study, called NeoOBS, led by the Global Antibiotic Research and Development Partnership (GARDP) recruited more than 3 200 babies in 19 hospitals in 11 countries – South Africa, Kenya, Uganda, Thailand, Vietnam, India, Greece, Italy, Bangladesh, Brazil, and China.
The researchers reported great variability in mortality rates of babies with sepsis across the 19 hospitals, ranging from 1% to 27.3%.
Sepsis affects up to 3 million babies a year globally. Importantly, the study’s 80 authors estimate that 214 000 newborns die every year from sepsis that has become antibiotic resistant, and this is mostly in low- to middle-income countries (LMIC). Many survivors suffer from neurodevelopmental problems. Treatment options have become increasingly limited as about 40% of infections are reported to be resistant to standard antibiotic treatments.
Many infections acquired in hospital
Almost 60% of infection-related deaths were due to infections acquired at the 19 hospitals under review. Klebsiella pneumoniae was the most common pathogen isolated.
Of the 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared to only six trials recruiting neonates, researchers say.
New antibiotic treatments are urgently needed, especially in LMICs where almost 1 in 5 babies with sepsis died. Premature babies are particularly vulnerable to infections because of their immature immune systems.
More than 200 different antibiotic combinations were used by hospitals included in the NeoOBS study, with repeated switching of antibiotics due to high resistance to treatments. This showed a pattern of limited use of the World Health Organization’s recommended first-line treatment.
Many doctors have had to opt for last-line antibiotics such as carbapenems because of the high degree of antibiotic resistance in their units or because they were the only treatment available.
Outlining various challenges, Velaphi says the risk of infections is very high in hospital settings where there is often a shortage of nurses, beds, and space between patients making it difficult to stop the spread of infection. Chris Hani Baragwanath has an 18-bed Intensive Care Unit (ICU) that is almost always full and when the situation is desperate there is a spillover of patients into the high-care area. The pressure on the facility is huge and the influx of people from other countries has made it even more challenging, he says.
“There is a major problem of infection control, specifically related to high-risk babies – sick babies with complications who need interventions such as drips and even surgery. This increases the chances of infection. “More than 70% of all deaths ascribed to prematurity at the hospital were due to hospital-acquired multi-drug resistant infections,” he says.
The NeoSep 1 trial
The authors say the NeoOBS study has yielded “a wealth of high-quality data” needed to design trials for much-needed and appropriate treatments for sepsis in babies. Encouragingly, and building on from the observational study the first global hospital-based neonatal sepsis trial called NeoSep 1 is underway in Kenya and South Africa. Chris Hani Baragwanath is taking part in the trial together with Tygerberg Hospital in Cape Town and KEMRI, Kilifi County Hospital in Kenya. It’s planned that the trial will be expanded to other countries and regions in 2024 with the aim of recruiting 3 000 newborns.
A Personalised Randomised Controlled Trial (PRACTical) design will be used. According to GARDP and partners the design is a new way of comparing antibiotic treatments for neonatal sepsis. In addition, doctors can choose treatment regimens that are likely to work well for newborns in their specific hospital settings.
Researchers say the development pipeline for new antibiotic treatments is limited and the lack of a universal, effective standard of care creates huge challenges in conducting research to tackle neonatal sepsis. The PRACTical design has been specifically developed to address these challenges in important public health emergencies such as neonatal sepsis. (You can read more about how this type of trial works in the Lancet.)
The trial will compare the safety and efficacy of three new combinations of older antibiotics (fosfomycin-amikacin, flomoxef-amikacin, and flomoxef-fosfomycin) against the current standard of care. It will also assess and validate the doses of two antibiotics (fosfomycin and flomoxef) for use in newborns. The trial will also evaluate new combinations of generic antibiotics.
“We are hoping the trial will provide robust evidence that the antibiotic combinations are safe and effective and that this will lead to a change in both WHO and local treatment guidelines,” says Christina Obiero, Principal Investigator for the NeoSep1 trial for KEMRI at Kilifi County Hospital in a statement.
Severity and recovery scores
Principal Investigator for the NeoSep1 trial at Tygerberg Hospital, Professor Adrie Bekker tells Spotlight, “We have so few antibiotics that work effectively against these very sick babies. And even for those that we have, we are still not 100% sure how to dose these drugs to get accurate concentrations in the blood and to also make sure that the outcomes in these babies are as good as can be. This trial will help give us confidence that we are delivering more effective treatment.”
Bekker who is also Professor in the Division of Neonatology, Department of Paediatrics and Child Health at Stellenbosch University says a positive outcome of the NeoOBS study is the development of two important tools which can be used in ICUs globally.
The first is the NeoSep Severity Score which is a compilation of common symptoms and signs that can occur in a baby with clinical sepsis. The second is the NeoSep Recovery Score, which will assist clinicians in deciding if they can stop antibiotics earlier.
The tools are expected to help prevent the often excessive and inappropriate use of antibiotics for over too long a period, which compounds the problem of antibiotic resistance globally.
Diagnosis in older age groups, children, and adults, is generally easier.
“It’s sometimes difficult for a clinician to know whether a baby actually has neonatal sepsis because it can present very subtly and not always with the same symptoms,” Bekker explains.
The blood culture is the gold standard for diagnosing neonatal sepsis, but Bekker says only around 10% of blood cultures will grow an organism even if the baby has sepsis, making it very difficult to get a diagnosis. “And because it’s such an aggressive disease and a baby can die very quickly from it, clinicians tend to rather over-treat than under-treat. That is correct but, just as important as it is to start antibiotics quickly, it’s important to stop them if they are not necessary. The NeoSeps Severity score will help doctors identify babies that are at very high risk from sepsis and those that would need treatment immediately.
Velaphi says a major challenge is the time it takes for an outcome of the blood culture and the general protocol is to start antibiotics immediately. Waiting between 24 to 48 hours can be too late for a child who may have sepsis and could die. On the other hand, antibiotics may be given to children who do not have sepsis and this adds to the frequency of antibiotic resistance. “So, you are damned if you do and you are damned if you don’t.”
He says we need new diagnostic tests that are reliable and that have a high degree of sensitivity and specificity. “We need antibiotics that work to reduce mortality,” he adds.
The first drug therapy to slow the progression of nearsightedness in children is a step closer after the results of a successful clinical trial.
The results of the CHAMP (Childhood Atropine for Myopia Progression) trial were published in JAMA Ophthalmology. The three-year study found that a daily drop in each eye of a low dose of atropine, a drug used to dilate pupils, was better than a placebo at limiting eyeglass prescription changes and inhibiting elongation of the eye in nearsighted children aged six to 10.
About one in three adults worldwide is nearsighted, and the global prevalence of myopia is predicted to increase to 50% by 2050. Though one federally approved contact lens can slow progression of nearsightedness, no pharmaceutical products are approved in the US or Europe to treat myopia.
That elongation of the eyeball leads to myopia which starts in young children and progresses into the teen years before levelling off in most people. In addition to requiring life-long vision correction, nearsightedness increases the risk for retinal detachment, macular degeneration, cataracts and glaucoma later in life – and most corrective lenses don’t do anything to stop myopia progression.
“The idea of keeping eyeballs smaller isn’t just so people’s glasses are thinner – it would also be so that in their 70s they don’t suffer visual impairment,” said lead study author Karla Zadnik, professor and dean of the College of Optometry at The Ohio State University.
“This is exciting work for the myopia research community, which I’ve been part of for 35 years. We’ve talked about treatment and control for decades,” she said. “And it’s exciting to think that there could be options in the future for millions of children we know are going to be myopic.”
Animal studies years ago hinted at atropine’s ability to slow the growth of the eye, but the full-strength drug’s interference with near vision and concerns about pupil dilation hindered early considerations of its potential as a human therapy for myopia. More recent research has suggested a low dose of atropine might be the ticket.
This new double-masked, randomised phase 3 trial assessed the safety and effectiveness of two low-dose solutions, with atropine concentrations of either .01% or .02%, versus placebo. Treatment for each of the 489 children ages six to 10 assessed for the drug’s effectiveness consisted of one daily drop per eye at bedtime, which minimised the disruption of any blurring effects atropine might have on vision.
Researchers were a bit surprised to find that the most significant improvements at all time points compared to placebo resulted from the solution containing .01% of atropine. Though the .02% atropine formulation was also better at slowing progression of myopia than placebo, the results were less consistent.
“The .01% story is clearer and more obvious in terms of significantly slowing both the growth of the eye as well as then resulting in a lower glasses prescription,” Zadnik said.
Including a measure of the eye’s growth was a key component of the study because “the field is actually moving toward axial elongation being as important as, or more important than, the glasses prescription in terms of the most meaningful outcome,” she said. “If we’re trying to slow eye growth to prevent bad outcomes for people in their 80s, measuring the eye growth directly is really important.”
The drugs’ safety was assessed in a larger sample of 573 participants that also included children as young as 3 and up to age 16. Both low-dose formulations were safe and well tolerated. The most common side effects were sensitivity to light, allergic conjunctivitis, eye irritation, dilated pupils and blurred vision, although reports of these side effects were few.
The CHAMP trial was the first study of low-dose atropine to include placebo controls for three years and to involve a large, diverse population recruited from 26 clinical sites in North America and five countries in Europe. In a second section of the trial, researchers are evaluating how the eyes respond when the treatment is over.
Portable ultrasound devices could provide an alternative to x-ray machines for diagnosing forearm fractures in children, which could alleviate waiting times for families in hospital emergency departments (ED).
Griffith University researchers Professor Robert Ware and Senior Lecturer Peter Snelling compared functional outcomes in children given an ultrasound and those who received an x-ray on a suspected distal forearm fracture. Dr Snelling said the ultrasounds were performed by nurses, physiotherapists and emergency physicians at four south-east Queensland hospitals.
“They treated 270 children, aged between five and 15 years, during the randomised trial, which included a check-up 28 days later and another check-in at eight weeks,” Dr Snelling said. “The findings show the majority of children had similar recoveries and returned to full physical function.”
Less than one-third of children who were given an ultrasound needed a follow-up x-ray and care at an orthopaedic clinic. Those who didn’t have a buckle fracture or fractured arm were discharged from hospital without the need for further imaging.
Professor Ware said children who had an ultrasound initially had fewer x-rays, and shorter stays in the ED. “Families were also more satisfied with the treatment they received,” he said. “The results are promising and have wider implications beyond in hospital diagnosis and follow up care.
“By using a bedside ultrasound, this frees up the x-ray machine for patients who really need it and can potentially be a cost-cutting measure for hospitals as they reduce the number of x-rays without comprising the safety of patients.
“It also would be extremely beneficial in rural or remote areas eliminating the need for children and their families to travel to a larger hospital for an x-ray.”
As childhood obesity increases the world, children are entering puberty earlier and earlier – particularly girls. According to a survey, the onset of puberty occurs on average three months earlier for girls in every decade since 1977. Early, or precocious, puberty can leave children with psychological and social problems, as well leading to shorter adult heights. Studies also suggest that early puberty can increase the risk of developing cancer, diabetes, depression and cardiovascular disease later on in life.
While a scientific explanation has been lacking, the link between childhood obesity and early puberty has long been apparent. The more body fat a child has, the greater their likelihood of beginning puberty at an earlier age. Now, researchers have found what may be part of the answer in Drosphila fruit flies, publishing their results in Current Biology.
“Cholesterol is a fat. So, if you’re overweight, your body fat harbours more cholesterol. And it turns out that higher cholesterol is a key to earlier maturation in the fruit fly, our model organism. Our results demonstrate that the amount of cholesterol in adipose tissue and in certain support cells in the brain affects the growth of fruit flies and controls when they reach maturity,” explains Professor Kim Rewitz, a lead author of the study.
He adds, “And because the systems in fruit flies and humans are remarkably similar, we believe that the same may apply to humans – ie, that cholesterol in adipose tissue may help explain the connection between childhood obesity and early puberty.”
Puberty at ‘critical weight’
Professor Rewitz and the University of Copenhagen’s Department of Biology research team tested their hypothesis by putting fruit fly larvae on a “fatty diet” of cholesterol-packed foods. The development of these larvae was compared with larvae on a normal diet.
“We observed that larvae on the cholesterol diet consistently grew faster and entered ‘puberty’ sooner. It turned out that the increase of cholesterol stored in the fruit flies’ body fat and support cells in the brain increases the release of growth hormones that cause the animals to grow faster. Growth and size is a signal to the body for when to trigger puberty,” says Kim Rewitz.
The professor explains that in fruit flies, the signal to undergo maturation is when their weight and amount of body fat reach a certain point during development:
“In one way or another, animals need to know when they’re large enough to reach sexual maturity and be able to reproduce. Organisms have a checkpoint in their development that they must pass to enter puberty known as ‘Critical Weight’. This checkpoint is found in fruit flies and most likely in humans too. This means that both fruit fly larvae and children probably need to reach a certain body size and have a certain amount of fat stored to enter puberty. What we’ve found is that the amount of cholesterol stored in body fat plays an important role in this process.
“We see that fruit flies have a mechanism that senses how much cholesterol is stored in their body fat and support cells in the brain. At a certain point, the system then sends a signal to the brain centres that triggers maturation by producing steroid hormones. In humans, these correspond to testosterone and oestrogen.”
However, it also means that if the amount of stored cholesterol increases, the organism can actually fail to estimate its overall size accurately, so that it hits the critical weight checkpoint earlier than it normally would:
“Because overweight children have more body fat, they will probably also have stored more cholesterol at an earlier point in their development. So, if our assumption that the same mechanism exists in humans holds true, it could help to explain early puberty in obese children,” says the researcher.
Cholesterol may influence cancer as well
Professor Rewitz concludes that with part of the puzzle in hand, scientists can search for more clues and treatment. In the meantime, lifestyle changes remain the best solution for childhood obesity.
Professor Rewitz and his research colleagues have now started to look deeper into the significance of the cholesterol mechanism for cancer development. Their research also shows that, via the same mechanism, cholesterol can activate cell growth that leads to cancer.
