Tag: neonates

Categories : HIV PaediatricsTags :

Cape Town Study Brings Hope to Newborns Left Behind in HIV Treatment Advances

On By ModernMedia
Professor Adrie Bekker explains the findings of a study on two novel formulations for the administration of dolutegravir in babies born to mothers living with HIV. (Photo: Biénne Huisman/Spotlight)

By Biénne Huisman

Research led by Professor Adrie Bekker is paving the way for an important HIV medicine to be made available to neonates in a way that is both safe and much more convenient than previous options. Spotlight met with the passionate clinician-scientist at her office in Cape Town.

Two new ways of giving the important HIV medicine dolutegravir to newborn babies have been found to be safe and effective, according to new research done in Cape Town. The new findings support for the first time the broader use of dolutegravir in infants who are less than 28 days old.

Dolutegravir is recommended by the World Health Organization (WHO) for infants, children and adults and is the preferred HIV medicine in South Africa. It exists in a scored 10 milligram child-friendly dispersible tablet. But until now, there hasn’t been any guidance on how to safely use it for newborns in their first four weeks of life. A study called PETITE-DTG aimed to bridge this critical gap in neonatal HIV care.

Forty-one full-term babies, each weighing at least 2 kilograms and born to mothers receiving dolutegravir-based HIV treatment, were enrolled in the study at Tygerberg Hospital to test two paediatric formulations of dolutegravir.

The first method involved using a 5 milligram dispersible tablet dissolved in 5 millilitres of water and given every second day for the first 14 days of life, then once daily until the baby was four weeks old. This was administered with a syringe.

The second method involved using a novel 5 milligram mint-flavoured film the size of a fingernail that dissolves on the tongue in seconds. It followed the same dosing schedule as the first method.

Findings showed that both formulations were safe and effective, achieving drug concentrations comparable to adults receiving 50 milligram of dolutegravir twice daily.

The study’s findings were presented at the Conference on Retroviruses and Opportunistic Infections in March. Researchers are currently writing up the final results of the study for publication in a peer-reviewed medical journal.

Professor Adrie Bekker, a neonatologist from the University of Stellenbosch is co-principal investigator of the PETITE-DTG study alongside Dr Tim Cressey, a clinical pharmacologist from the University of Chiang Mai in Thailand.

“The study results confirmed that the regimen [both 5 milligram dolutegravir formulations] was safe, effective, and highly acceptable to mothers, with the dolutegravir film being particularly easy to administer,”

says Bekker, speaking to Spotlight in her office at Stellenbosch University’s medical campus next to Tygerberg Hospital.

In examining dosing safety and efficacy, she says that the study found that both formulations “achieved target concentrations” in the neonates, without the newborn babies experiencing any adverse effects related to the medicine. All neonates were HIV negative at the end of the study.

Babies born to a mother living with HIV may need antiretroviral medicines for the prevention or treatment of HIV. Bekker explains that neonates are currently given an older type of liquid HIV medication that doesn’t taste good, costs more than dolutegravir, is harder to give properly, and can’t be stored for long.

The novel film method was popular with mums in the study, who cited its simplicity of administering and dose accuracy as highly advantageous, with no risk of the medicine being spit out or other spillage.“I wash and dry my hands and I cut the paper, it’s quick. As soon as I put it on his tongue, it just dissolves in a few seconds, he enjoys it,” said one mother, as quoted on a poster highlighting the results of the study.

Commenting on the film strip, Bekker notes it is one of the least disruptive ways to give medication.

“So what has been amazing to me is that the babies seem to be completely oblivious of what is happening when the mother puts the film in their mouth,” she says pointing out a video clip on her desktop of a film strip being placed in a tiny baby’s mouth.

“If they were crying, they would just keep on crying. If they were sleeping, they would just keep on sleeping. If they were happy, they would just keep on being happy. It really is the most unintrusive way of administering medication.”

Bekker says the colourless dolutegravir film is made by the Indian multinational pharmaceutical company Laurus Labs. Previously, it had only been tested in adults and is not yet commercially available. “It’s actually never even been used in children…And so our study for the first time tested the dolutegravir film in newborns to see what drug levels are found in a baby when you use it,” she says.

She says the research findings have been presented to the World Health Organization (WHO) and expects they will be included in the organisation’s upcoming updated dosing guidelines for infants and children.

Commenting on dolutegravir for neonates, Bekker says: “I think the first step is to actually get this recommendation into the WHO guidelines. As soon as the WHO releases their updated HIV guidelines, then countries can decide whether they want to adopt it or not.”

Commenting on the availability and possible roll-out of dolutegravir for neonates, she adds: “The generic 10 milligram dolutegravir scored dispersible tablet is already available and being used in children. What we’ve shown now is that 5 milligram of dolutegravir with this dosing strategy is safe for neonates…The film is a bit more complicated because it is not yet commercially available. And we don’t know the price of the drug; all of that will need to be discussed and negotiated with the company and relevant parties before it can become available.”

The PETITE-DTG research has been welcomed by fellow scientists.

“Adrie Bekker and her colleagues at Tygerberg Hospital and in Thailand have done great work and are really moving the field forward for neonatal antiretroviral treatment,” says Associate Professor James Nuttall, a paediatric infectious diseases sub-specialist at the Red Cross War Memorial Children’s Hospital and the University of Cape Town.

He says the research “provides really nice information about how we could use our existing drugs to treat neonates, potentially”.

Nuttall described the new film as extraordinary, and suggested that it might eventually replace the current drug formulations.

For Nuttall though, making provision for using a pill like the scored 10 milligram dispersible tablet that’s already available and routinely used to treat children in South African hospitals is more immediately relevant. “Using this 5 milligram dispersible tablet in neonates and working out the dosing schedule for that, that’s the real advance of this study to me, the big win.”

He anticipates these findings to be implemented in South Africa in the next few years. “From what I understand, she [Bekker] has presented this to WHO already. And once it gets accepted and included into WHO guidelines, then countries tend to really take note and follow, that’s when it makes its way into national guidelines…”

While the study focused on healthy full-term babies weighing at least two kilograms, Nuttall noted that many babies born to mothers living with HIV are either premature or have low birth weight. “So this dosing and safety information doesn’t yet apply to those children,” he said.

Bekker already has her eye set on assessing dosing safety for pre-term newborns. “So obviously our dream is to extend this to pre-term babies,” she says. “And there is a possibility that a 2.5 milligram dolutegravir film may be a good dose for pre-term neonates. Obviously, that will have to be studied very rigorously first.”

Other research goals include the hope of being involved in studies assessing long-acting antiretroviral drugs in neonates. Bekker notes that the WHO-led Paediatric Drug Optimisation group identified long-acting cabotegravir injectables as a high research priority for HIV prevention in neonates. She adds that developing patches with tiny microneedles that deliver HIV medication could hold great promise for treating newborns in the future.

Commenting on the PETITE-DTG study, Dr Moherndran Archary, who has been at the forefront of South Africa’s HIV response for children, said: “Professor Bekker’s research has directly impacted access to life-saving HIV medication for newborn infants – the most vulnerable of populations who have not traditionally benefited from the significant advances in HIV treatment.”

The PETITE-DTG study is one of many under the Unitaid-funded BENEFIT Kids project aiming to improve treatment for children with HIV or multidrug-resistant tuberculosis. UNITAID is a global health initiative that, amongst others, funds research and helps facilitate the more rapid introduction of new health technologies.

Republished from Spotlight under a Creative Commons licence.

Read the original article.

Categories : Antibiotics PaediatricsTags :

Antibiotic Resistance is Putting SA’s Newborns at Risk

On By ModernMedia
Photo by Christian Bowen on Unsplash

By Sue Segar

Experts say bacterial infections are responsible for more infant deaths than is generally recognised, and things may get worse as more of the bugs become resistant to commonly used antibiotics. We asked local experts about this growing threat to newborns.

A two-week-old baby is referred to the Red Cross War Memorial Children’s Hospital (RCWMCH) in Cape Town. The infant, who was born prematurely at six months, has come from a nearby neonatal hospital.

She’s developed complications, including a feed intolerance and constant vomiting. On investigation, she is found to have a bowel perforation and a condition called necrotising enterocolitis. Surgeons conclude she needs an operation to repair the perforation. A sample of pus from inside her abdomen is sent to a laboratory to identify any infections. While the tests are being done, the infant is started on second-line antibiotics. The doctors suspect she picked up an infection due to pathogens that may be resistant to first-line antibiotics while in the neonatal hospital.

“But 48 hours later, when the results are available, they may show that the antibiotics we’ve been treating the baby with are not treating the bacteria that have now been detected in the lab,” says Associate Professor James Nuttall, a paediatric infectious diseases sub-specialist at RCWMCH and the University of Cape Town.

“In response to those results, we’d change to a different set of antibiotics to try and target the bacteria that have been detected. In the meantime, the child has deteriorated and requires a second operation. Throughout all the subsequent treatments, we are testing samples for infections she might – and frequently will – acquire along the way.”

From then on, he says it’s a case of trying to keep up with the sequence of infections that the baby might develop. Some of these infections may have originated at the neonatal hospital, while others could have been acquired during her treatment in the Intensive Care Unit (ICU) at RCWMCH, possibly from the operating theatre, intravenous lines, or healthcare workers’ hands.

“This is the kind of scenario we are faced with all the time,” says Nuttall. “The fact is, an infant might come into hospital with one infection and, unfortunately, pick up a bunch of other infections while in the hospital from transmission of pathogens that may be resistant to one or more of the commonly used first- or second-line antibiotics.”

Sitting in a boardroom at the Red Cross Hospital, close to the paediatric wards and clinics in which he treats sick children referred from other hospitals in Cape Town and beyond, Nuttall says there are two possible outcomes for this baby.

“She might turn the corner and respond to the new antibiotics, together with interventions from the surgical doctors and expert management in an ICU. Or she might not respond to the treatment, and die two days later, because of ongoing infection that doesn’t respond to treatment.”

Nuttall is discussing the ongoing issue of rising antibiotic resistance, particularly among neonates, the group most vulnerable to this. He’s responding to Spotlight’s main question: Will the antibiotics used to treat bacterial infections, such as Klebsiella pneumoniae – which have seen hundreds of babies die in hospitals in recent years – keep working? And, how big is the risk of antibiotic resistance to infants?

“The short answer to whether the antibiotics we currently use to treat bacterial infections will keep working is no,” he says.

‘Almost endemic’

In some South African healthcare facilities, especially in the public sector, antibiotic-resistant bacteria have become “almost endemic”, says Professor Shabir Madhi, director of the Wits Vaccines and Infectious Diseases Analytics Unit at University of Witwatersrand (WITS VIDA).

“There are a large number of deaths occurring on an ongoing basis. We still have clusters of outbreaks, but those are underpinned by a really widespread dissemination of these antibiotic-resistant bacteria, and persistently high rates of hospital-acquired infections, especially in the first month of life,” he says. “Despite the best of efforts, we haven’t been able to get on top of this.”

Madhi headed up a study at the Chris Hani Baragwanath Academic Hospital in Soweto in which they used molecular testing to look at evidence of infections in 153 babies who had passed away. The researchers found that infections were the immediate or underlying cause of death in 58% of all the neonatal deaths, including the immediate cause in 70% of neonates with complications of prematurity as the underlying cause.

Overall, 74.4% of 90 infection-related deaths were hospital-acquired, mainly due to multidrug-resistant Acinetobacter baumannii (52.2%), Klebsiella pneumoniae (22.4%), and Staphylococcus aureus (20.9%).

Also asked whether the antibiotics used to treat Klebsiella and other bacterial infections will keep working, Madhi says: “The short answer is that we’ve already run out of antibiotics in the public sector that can treat all of these different bacteria.”

He says that there are two bacteria that are of particular concern in South Africa.

“The one is Klebsiella pneumoniae, which that has become resistant to almost all of the antibiotic classes that are available for use, except perhaps for colistin, (a reserve antibiotic which is seen as a last-resort treatment for multidrug-resistant Gram-negative infections), but even antibiotic resistance to colistin in bacteria is emerging.

“The other big one is Acinetobacter baumannii, which is also a common cause of hospital-acquired infections. Here the bacteria have become resistant to all classes of antibiotics including colistin.”

Madhi says compared to other African countries, South Africa is better equipped to provide high-level care, including intensive care, to prematurely-born babies.

“Consequently, we end up spending a mini fortune to get these very premature children to survive the first few days of life, only for them then to succumb to hospital-acquired infections. Whereas in other settings many of these babies will die in the first few hours of life.”

He adds: “The single leading cause of neonatal mortality in South Africa is antibiotic resistant bacterial infections, but that is underpinned by other conditions which increases the susceptibility of babies to eventually succumb to these hospital-acquired infections.”

In the public sector, Madhi says hospital-acquired infections are a major reason why children are dying. In the private sector, there is more attention on identifying these infections, along with better resources, which helps reduce the problem.

Meanwhile, physicians like Nuttall are put in impossible situations at Red Cross.

“When doing blood tests on an infant to check for infection, you can’t wait for those results. You have to start treatment with what you think is the appropriate treatment. That’s the empirical treatment,” explains Nuttall.

“Then, when you isolate a bacterium and know its resistance profile (or antibiotic susceptibility profile), you must redirect your treatment to what’s known as ‘directed’ or definitive treatment. But there’s now been a time gap of 24 to 72 hours where the infant is on treatment, and you don’t know if it’s the right treatment. That’s a critical issue, because the baby might deteriorate in that time because they’re not on the right treatment,” he says.

He says the choice of empiric antibiotics is becoming more difficult, “as what we previously used as empiric antibiotic treatment is less and less reliable to treat serious infections, particularly in patients who acquire resistant infections in hospital”.

In a position paper, Nuttall and his colleagues write that growing antibiotic resistance is linked to the increased use of “reserve” and “watch” antibiotics. The WHO classifies antibiotics into three groups. Access antibiotics are the common ones used to treat everyday infections in the community. Watch antibiotics are broad-spectrum antibiotics that carry a higher risk of causing resistance, so their use must be carefully monitored and limited. Reserve antibiotics are last-resort treatments for infections caused by multi-drug-resistant bacteria and should only be used when all other options have failed.

‘Totally underestimated’

Following the research described earlier, Madhi says they convened an expert panel, to deliberate on what the causes of death was in children.

Unfortunately, he says, it’s become completely monotonous in that there’s a clear series of events for children born prematurely, who die: They’re admitted to hospital, they usually require ICU, they improve in ICU, and two to three days later, they appear very sick again. “Often you don’t actually identify the bacteria causing the clinical deterioration when you investigate ante-mortem, and you only realise the child actually succumbed to antimicrobial resistant bacterial infections after you’ve done the postmortem sampling”. Postmortem sampling is not done systematically across the country.

“What the post-mortem sampling has unmasked, is that we’ve totally underestimated the contribution of antibiotic-resistant bacteria in relation to causes of neonatal death. If we were to do the same investigations in other facilities, there would be much greater heightened awareness of what is really an unrecognised endemic public health crisis across our healthcare facilities,” says Madhi.

Professor Angela Dramowski, Head of the Clinical Unit: General Paediatrics at Tygerberg Hospital, agrees that outbreaks in low- and middle-income country hospitals, including South Africa are under-reported.

“What we see in the literature and in the headlines of newspapers is the tip of the iceberg. The vast majority of outbreaks in fact are either undetected or unreported. This is almost an invisible problem because a lot of the deaths are currently labelled due to another cause, for example, prematurity.

“This is a crucial public health crisis. We cannot practice modern medicine without effective antibiotics, and, especially for newborns the situation is perilous as we have very few effective treatment options left.”

‘Existential threat’

Though more acute in some areas, the problem is a global one. Marc Mendelson, Professor of Infectious Diseases at the University of Cape Town, describes antibiotic resistance as an existential global health threat.

“If antibiotic resistance is not mitigated, in the next 25 years, 39 million people globally will die of an antibiotic-resistant bacterial infection. That will dwarf HIV, tuberculosis, and malaria,” he says.

“There are bacteria currently causing infections in our hospitals in South Africa that are totally resistant to antibiotics. Those patients would usually die or need extraordinary measures to keep them alive such as amputating a limb to remove the infection in a bone or joint,” Mendelson says.

“People have always assumed if you get sick with a bacterial infection, there will be an antibiotic to treat it. Doctors in and out of hospitals have been too lax in how they prescribe antibiotics. Now we’re paying the price as some bacterial infections are not easily treatable,” he says.

As Dramowski points out, there is a lot of good science confirming the extent of the problem. A systematic review published in The Lancet found that almost 5 million deaths in 2019 were associated with bacterial infections resistant to antibiotics.

“That huge number is more than deaths from HIV and malaria combined,” she says.

Dramowski also points to another review study that found 3 million cases of neonatal sepsis globally each year, with at least 570 000 deaths (likely an underestimate). Over 95% of deaths from neonatal antibiotic resistance occur in low- and middle-income countries (LMICs).

“In a nutshell, in five big studies … they showed that antibiotic resistance to the World Health Organization-recommended antibiotic treatments ranges anywhere between 40 to 70%, so almost half of all babies with severe bacterial infection have resistance to the recommended antibiotic treatment,” she says.

What to do?

To address the major issue of antibiotic resistance in infants, Dramowski stresses the importance of prevention. This includes improving Water, Sanitation, and Hygiene (WASH) as well as Infection Prevention and Control programmes to reduce the spread of antibiotic-resistant bacteria in communities and healthcare facilities. She also stresses the need to prevent pre-term births as much as possible, as hospital admissions carry a high risk of acquiring antibiotic-resistant bacteria and developing infections.

She says increased surveillance of infections in LMICs is also crucial, along with more antibiotic trials to provide better alternatives. Additionally, there is a strong need for responsible antibiotic use (stewardship) to ensure they are only used when necessary, helping to prevent the development of antibiotic resistance.

A challenge in practicing stewardship is the difference in resources between the public and private sectors, says Professor Vindana Chibabhai, Head of the Centre for Healthcare-associated Infections, Antimicrobial Resistance, and Mycology (CHARM) at the National Institute for Communicable Diseases. Expensive antibiotics are more easily accessible in the private sector, while they are often not available in the public sector.

“Antibiotic stewardship is happening all over the country but we need to have a national monitoring system,” she says.

Chibabhai says that private sector clinicians often work independently and are not required to follow stewardship programmes as strictly as those in public sector hospitals. To address antibiotic resistance, she says we need monitoring systems to track the effectiveness of these programmes and provide support to hospitals struggling with them. Even though some hospitals have dedicated pharmacists, microbiologists, and clinicians, Chibabhai says they may need additional help to strengthen their antibiotic stewardship efforts.

‘Lots of lovely paper’

A major issue highlighted by experts is the lack of a clear AMR strategy in South Africa. The last strategy, which covered 2019 to 2024, was not funded, and its impact has not been evaluated.

“We have lots of lovely paper and lots of committed people doing great work but in terms of interventions, none of it is funded,” says Mendelson, who chaired the Ministerial Advisory Committee on Antimicrobial Resistance for the eight years until 2022. “If these interventions were funded, we could save lives.”

Madhi says the consequences of not implementing South Africa’s AMR plan are exactly what we are seeing now. “The problems have become endemic and entrenched in public healthcare facilities and lead to large numbers of unnecessary deaths which could have been prevented if we implemented a proper strategy in place.”

He says the situation now calls for a multi-faceted approach. “It’s not just about the type of antibiotics that should be available but about mitigating the many contributing factors that resulted in these outbreaks. That requires immense investment in terms of resources and expertise.”

Republished from Spotlight under a Creative Commons licence.

Read the original article.

Categories : Cardiovascular Disease Regenerative MedicineTags :

Born to Heal: Why Babies Recover, but Adults scar, After Heart Damage

On By ModernMedia
Photo by William Fortunato on Pexels

Newborns with heart complications can rely on their newly developed immune systems to regenerate cardiac tissues, but adults aren’t so lucky. After a heart attack, most adults struggle to regenerate healthy heart tissue, leading to scar-tissue buildup and, often, heart failure.

A new Northwestern Medicine study in experimental animals reveals a critical difference in how macrophages help repair the heart in newborns versus adults after a heart attack. The study highlights a fundamental difference in how the immune system drives healing based on age.

The study appears in the journal Immunity.

“Understanding why newborns can regenerate their hearts while adults cannot will open the door to developing treatments that could ‘reprogram’ adult macrophages,” said first and co-corresponding author Connor Lantz, lead scientist of the bioinformatics core at the Comprehensive Transplant Center at Northwestern University Feinberg School of Medicine.

In newborns, macrophages perform a process called efferocytosis, which recognizes and eats dying cells. This process triggers the production of a bioactive lipid called thromboxane, signaling nearby heart muscle cells to divide, and allowing the heart to regenerate damaged heart muscle, the study found. In adults, macrophages produce much less thromboxane, leading to a weaker repair signal.

“By mimicking the effects of thromboxane, we might one day improve tissue repair after a heart attack in adults,” Lantz said.

How the study worked

The study examined how the immune system responds to heart injury in mice of different ages, including newborn mice (one day old) and adult mice (eight weeks old). The researchers found the ability of macrophages to engulf dying cells was enhanced in newborn mice due to increased expression of MerTK, a receptor that recognizes dying cells. Therefore, when the scientists blocked this key receptor, newborn mice lost their ability to regenerate their hearts, resembling adult hearts after a heart attack.

Engulfment of dying cells by newborn macrophages triggered a chemical chain reaction that produced a molecule called thromboxane A2, which unexpectedly stimulated heart muscle cells to multiply and repair the damage, the study found. Additionally, nearby muscle heart cells in newborns are primed to respond to thromboxane A2, leading them to change their metabolism to support their growth and healing. But in adults, this process did not work the same way – after an injury, their macrophages did not produce enough thromboxane A2, limiting their ability to regenerate heart tissue.

Source: Northwestern University

Categories : Mental Health Obstetrics & GynaecologyTags :

Antidepressants Impact Prefrontal Cortex Development

On By ModernMedia
Photo by William Fortunato on Pexels

A new study published in Nature Communications suggests that use of antidepressants can impact early post-natal brain development, potentially contributing to the development of mental health disorders. The study, led by researchers at the University of Colorado Anschutz Medical Campus, focused on the effect of fluoxetine, commonly used in medications such as Prozac and Sarafem for treating depression and perinatal depression, on the developing prefrontal cortex of mice.

Since fluoxetine works by increasing the levels of serotonin in the brain, the researchers looked at the impact serotonin has on prefrontal cortex development.

“While it is known that serotonin plays a role in the brain development, the mechanisms responsible for this influence, specifically in the prefrontal cortex, have been unclear, ” said lead author Won Chan Oh, PhD, assistant professor in the Department of Pharmacology at CU Anschutz.

Changes in gestational and early postnatal serotonin levels can arise from many causes including maternal deprivation or abuse, diets high or low in tryptophan, or the use of medications such as selective serotonin reuptake inhibitors (SSRIs) that can readily cross the placenta or be passed to offspring through breast feeding. Disbalances of 5-HT during brain development are associated with increased risk of neurodevelopmental disorders such as autism spectrum disorder and long-lasting behavioural deficits, but the underlying mechanisms remain elusive.

Oh and his student, Roberto Ogelman, a neuroscience PhD candidate, found serotonin directly influences nascent and immature excitatory synaptic connections in the prefrontal cortex, which if disrupted or dysregulated during early development can contribute to various mental health disorders.

“Our research uncovers the specific processes at the synaptic level that explain how serotonin contributes to the development of this important brain region during early-life fluoxetine exposure,” adds Oh. “We are the first to provide experimental evidence of the direct impact of serotonin on the developing prefrontal cortex in mice.”

To study the effect, the researchers looked at the impact of deficiency and surplus of serotonin on brain development in mice. They discovered that serotonin is not just involved in overall brain function but also has a specific role in influencing how individual connections between neurons change and adapt, contributing to the brain’s ability to learn and adjust.

“Understanding this correlation has the potential to help with early intervention and the development of new therapeutics for neurodevelopmental disorders involving serotonin dysregulation,” said Oh.

The researchers plan to continue studying the impact of fluoxetine, next examining its impact on a developing brain later in life.

Source: Colorado University Anschutz Medical Campus

Categories : HIV PaediatricsTags :

Treating Newborns with HIV in 1st 48 Hours may Result in Medication-free Remission

On By ModernMedia
Photo by Christian Bowen on Unsplash

An unexpectedly high percentage of children, who were born with HIV and started treatment within 48 hours of life, exhibit biomarkers by two years of age that may make them eligible to test for medication-free remission, according to a multinational study published in The Lancet HIV.

“Moving away from reliance on daily antiretroviral therapy (ART) to control HIV would be a huge improvement to the quality of life of these children,” said Protocol Co-Chair and senior author Ellen Chadwick, MD, at Ann & Robert H. Lurie Children’s Hospital.

Conducted in 11 countries including South Africa, the proof-of-concept study was charged with replicating the case of HIV remission as seen in the “Mississippi baby” that was reported in 2013. In that case, the infant started ART at 30 hours of life, was treated for 18 months, and achieved 27 months of ART-free remission before the virus rebounded. Typically, if ART is stopped, the virus rebounds within a month.

The study included a three-drug ART regimen initiated within 48 hours of life, with the fourth drug added within 2-4 weeks. This is very early treatment compared to the standard of care where three-drug ART may not begin until 2-3 months of age.

In the US, however, based on earlier findings from this study, very early treatment is now the norm for infants at high risk of acquiring HIV infection from their mother.

“With earlier treatment, we hope to limit or prevent the establishment of viral reservoirs in the body. These viral reservoirs hold small amounts of hidden virus which are hard to reach with ART. By shrinking these reservoirs, we expect to increase the amount of time that patients can be in remission, without needing daily ART,” said co-author and Protocol Co-Chair Jennifer Jao, MD, MPH, from Lurie Children’s.

Dr Chadwick adds: “Another benefit of smaller viral reservoirs might be that newer treatments such as long-acting antibody therapies or therapeutic vaccines could potentially be used instead of daily ART.”

“Our results show a higher percentage of children might be eligible to interrupt therapy than we expected, and the next step is to stop ART and see how many children actually achieve remission,” said Dr Chadwick.

“If even one child achieves remission, that would be considered a success. Today, newer more effective and better tolerated HIV medications are available for infants than when the study began, strengthening the prospect of limiting viral reservoirs and testing for possible remission in infants and children with HIV. Overall, this is an exciting advancement and an opportunity to change the course of pediatric HIV infection.”

The study was conducted in 11 countries – Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, USA, Zambia and Zimbabwe.

Source: Ann & Robert H. Lurie Children’s Hospital of Chicago

Categories : Ethics and Law PaediatricsTags :

UK Nurse Sentenced to Life for Murders of 7 Babies

On By ModernMedia
Photo by Tingey Injury Law Firm on Unsplash

A UK nurse has been sentenced to life in prison for murdering seven babies in a neonatal unit. In what is the longest murder trial in recent UK history, 33-year old Lucy Letby was also convicted of attempting to kill six other babies, and further investigation by the BBC has also revealed how hospital management at the time deflected concerns by doctors and actively silenced them.

Between June 2015 and June 2016, Letby deliberately injected air into babies’ parenteral nutrition lines, force-fed milk to others and administered huge doses of insulin to two others. In the years before, less than three death per year had been recorded at Countess of Chester Hospital at the neonatal unit where she worked.

According to The Guardian, Mr Justice Goss said during her sentencing: “This was a cruel, calculated, and cynical campaign of child murder involving the smallest and most vulnerable of children, knowing that your actions were causing significant physical suffering and would cause untold mental suffering.”

She was found not guilty of two other counts of attempted murder, but the jury consisting of four men and seven women were unable to reach a verdict on six additional attempted murder charges. The court will consider whether to attempt to retry these six charges.

Dr Stephen Brearey, lead consultant at the neonatal unit where Letby worked told the BBC he first raised concerns about the nurse in October 2015, but not no action was taken and she went on to attack five more babies.

He that hospital management failed to investigate allegations against her and also tried to silence doctors. An investigation by BBC Panorama BBC News revealed just how Letby was able to get away with murdering and harming the babies for so long.

The hospital’s top manager ordered doctors to make written apologies to to Letby, and two consultants had to undertake mediation with the nurse, despite their suspecting she had killed babies. Efforts to bring in the police were also quashed by senior management, who said in an email “This is absolutely being treated with the same degree of urgency … All emails cease forthwith”.

Dr Ravi Jayaram, a consultant paediatrician at the hospital, wrote on social media that he felt relief at the oft-maligned justice system working “this time”.

But he continued there were “things that need to come out about why it took several months from concerns being raised to the top brass before any action was taken to protect babies”.

He also added: “And why from that time it then took almost a year for those highly-paid senior managers to allow the police to be involved.”

Categories : Neurology PaediatricsTags :

Newly Identified Lipid in Breast Milk Might Reduce Cerebral Palsy in Infants

On By ModernMedia

Ten percent of babies born before 32 weeks will develop cerebral palsy resulting from infections that damage white matter, nerve fibres deep in the brain. While it’s known that the white matter loss will lead to neurological deficits, there is currently no treatment to avoid this.

Now, researchers at Duke Health have conducted experiments using neonatal mice and identified a fatty molecule in breast milk that triggers a process in which stem cells in the brain produce cells that create new white matter, reversing the injury.

The study appears in the journal Cell Stem Cell. Corresponding author Eric Benner, MD, PhD, said that further study in a clinical trial is needed, but the finding is promising.

“Developing therapies for children – especially such medically fragile children – is very difficult to do because there are justifiably strict safety concerns,” Benner said. “The fact that this molecule is already found in something that is safe for premature babies – breast milk – is extremely encouraging.

“It’s been known that fats in breast milk benefit a child’s brain development, but there are many types of fats in breast milk,” Benner said. “This work has identified a lipid molecule in breast milk that promotes white matter development. Now, we can begin to develop a therapy that isolates and delivers this lipid in a way that is safe for the unique challenges of these infants.”

Benner is a neonatologist at Duke University and one of the co-founders of Tellus Therapeutics, a Duke spinout company developed with the help of the Duke University Office for Translation & Commercialization to bring this therapy from the bench into the neonatal intensive care unit.

The fatty molecule identified in the study will be administered intravenously to patients in an upcoming clinical trial. This is significant because many of the infants who are part of this vulnerable population also have gastrointestinal issues and cannot safely be given milk or medication by mouth.

The lipid molecule enters the brain and binds with stem cells there, encouraging the stem cells to become or produce a type of cell called oligodendrocytes.

The oligodendrocytes are like a hub that allow for the production of white matter in the central nervous system. This newly produced white matter in pre-term infants prevents the neurological damage that would otherwise impact the child’s ability to move – the hallmarks of cerebral palsy.

“The timing of brain injury is extremely difficult to predict, thus a treatment that could be safely given to all preterm babies at risk would be revolutionary,” said Agnes Chao, MD, a former fellow in the Division of Neonatology and first author of the paper.

“As a neonatologist, I’m so excited that I may be able to offer a treatment to families with babies that are affected by preterm brain injury who would otherwise have no other options,” Chao said.

Source: Duke University Medical Center

Categories : Antibiotics PaediatricsTags :

Antibiotic-resistant Bugs Claim Over 200 000 Infants Globally per Year, Finds Major Study

On By ModernMedia
Photo by Christian Bowen on Unsplash

By Adele Baleta for Spotlight

“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.

Republished from Spotlight under a Creative Commons NoDerivatives 4.0 Licence.

Source: Spotlight

Categories : Paediatrics Pain ManagementTags :

E-learning Helps Nurses Gauge Newborns’ Pain

On By ModernMedia
Photo by Christian Bowen on Unsplash

For newborns, caregivers have to identify and evaluate any pain they may be in. Until the turn of this century, many clinicians did not even recognise that neonates could even experience pain, resulting in infrequent, nonstandard training for medical workers. The COVID pandemic also disrupted opportunities for training. Now, researchers are reporting that a flexible e-learning program improves neonate pain management knowledge and skills for nurses.

They published the results of their randomised, controlled study in Pain Management Nursing.

“Continuing education is essential to maintain and increase nurses’ proficiency in neonatal pain assessment and treatment,” said corresponding author Mio Ozawa, associate professor in the Graduate School of Biomedical and Health Science at Hiroshima University. “Our results showed that e-learning programs were more effective as compared to no training.”

The researchers randomly divided recruited certified neonatal intensive care nurses from across Japan into two groups. One group received four weeks of online training in pain measurement, using structured scales designed for pre-term newborns, called the e-Pain Management of Neonates program. The other group did not receive training. Both groups took pre- and post-tests. While the pre-test results were the same across both groups, the e-learning group scored higher for both knowledge and skill.

The research builds on a prior pilot study, in which 52 nurses completed the e-learning program and improved their test scores. However, without a control group for comparison, the evidence was not sufficient to illustrate the intervention’s effectiveness, according to Prof Ozawa.

“In the current study, we tested the e-learning program with a randomised control trial, a more powerful research design than used with the pilot study,” Prof Ozawa said. “To the best of our knowledge, this is the first such trial that investigates the effects of e-learning on the knowledge and skill in neonatal pain measurement for certified nurses across NICUs across multiple hospitals.”

The e-learning program consists of four modules, each of which takes about 15 minutes to complete. Participants could save their progress and return at any point, as well as review as many times as they wanted. While more nurses were more likely to access the program in the middle of the day or late at night on a weekday, participants still accessed the program at odd hours and over the weekend.

“An e-learning program may be a more efficient method as nurses can participate in the program at their own convenience,” Prof Ozawa said. “In comparison with other health care professionals, NICU nurses stay at the bedside of newborns for the longest time to provide care, including invasive procedures. It is vital for nurses to be educated and train in using the neonatal pain management scale.”

Prof Ozawa stressed that while this study did not demonstrate e-learning’s superiority as a learning method compared to traditional approaches, such as in-person training, it does indicate that e-learning can improve skills and knowledge.

“Learning in this program would allow nurses to acquire knowledge and skills concerning newborn pain, which is preferred over no education,” Prof Ozawa said. “Further research is needed to determine how nurses’ training through e-learning programs is related to patient outcomes, such as more frequent pain assessment of infants by nurses and improved pain management.”

Source: Hiroshima University

Categories : VaccinesTags :

BCG Vaccine Activates Immune System in Newborns

On By ModernMedia
Syringe
Source: Raghavendra V Konkathi on Unsplash

In the century since it was first used in humans, the Bacille Calmette-Guérin (BCG) vaccine against tuberculosis has become one of the world’s most widely used vaccines. Administered in countries with endemic TB, it has surprisingly been found to protect newborns and young infants against multiple bacterial and viral infections unrelated to TB. Some evidence even suggests that it can reduce severity of COVID. Now, a new study in Cell Reports sheds light on the mechanisms behind its extra protective effects.

Surprisingly little is known about how BCG exerts its many side benefits. To better understand its mechanism of action, researchers collected and comprehensively profile blood samples from newborns vaccinated with BCG, using a powerful ‘big data’ approach analysing lipid and metabolite biomarkers.

Their study found that the BCG vaccine induces specific changes in metabolites and lipids that correlate with innate immune system responses. The findings provide clues toward making other vaccines more effective in vulnerable populations with distinct immune systems, such as newborns.

First author Dr Joann Diray Arce and her colleagues started off with blood samples from low-birthweight newborns in Guinea Bissau who were enrolled in a randomised clinical trial to receive BCG either at birth or after a delay of six weeks. Blood samples were taken at four weeks for both groups (after BCG was given to the first group, and before it was given to the second group).

The researchers comprehensively profiled the impact of BCG immunisation on the newborns’ blood plasma. They found that BCG vaccines given at birth changed metabolite and lipid profiles in newborns’ blood plasma in a pattern distinct from those in the delayed-vaccine group. The changes were associated with changes in cytokine production, a key feature of innate immunity.

The researchers had parallel findings when they tested BCG in cord blood samples from a cohort of Boston newborns and samples from a separate study of newborns in The Gambia and Papua New Guinea.

“We now have some lipid and metabolic biomarkers of vaccine protection that we can test and manipulate in mouse models,” said Dr Arce. “We studied three different BCG formulations and showed that they converge on similar pathways of interest. Reshaping of the metabolome by BCG may contribute to the molecular mechanisms of a newborn’s immune response.”

“A growing number of studies show that BCG vaccine protects against unrelated infections,” said Ofer Levy, MD, PhD, the study’s senior investigator. “It’s critical that we learn from BCG to better understand how to protect newborns. BCG is an ‘old school’ vaccine – it’s made from a live, weakened germ – but live vaccines like BCG seem to activate the immune system in a very different way in early life, providing broad protection against a range of bacterial and viral infections. There’s much work ahead to better understand that and use that information to build better vaccines for infants.”

Source: Boston Children’s Hospital via News-Medical.Net